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block or third degree [complete] AV block) or prolonged pauses are treated with permanent pacemaker placement. (See 'Arrhythmias' above.) For patients with severe aortic stenosis in whom no other etiology of syncope is identified, and the syncope is suspected to be due to the severe aortic stenosis, aortic valve replacement is indicated. Similarly, unexplained syncope (ie, not related to neurocardiogenic/vasovagal causes) in patients with hypertrophic cardiomyopathy is considered a marker for increased risk of sudden death. (See 'Obstruction to left ventricular outflow' above and "Indications for valve replacement for high gradient aortic stenosis in adults" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".) Driving restrictions are indicated for some patients at risk for recurrent syncope for the safety of themselves and others. In general, patients with untreated syncope should not drive until appropriate preventive treatment has been instituted. Following the institution of therapy for syncope, the duration of time patients should avoid driving varies significantly depending upon the underlying condition as well as the legal restrictions of the local, state, or national government ( table 4). (See 'Driving restrictions' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Brian Olshansky, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 12/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate 1. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 2. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018; 39:1883. 3. Parry SW, Tan MP. An approach to the evaluation and management of syncope in adults. BMJ 2010; 340:c880. 4. Thijs RD, Wieling W, Kaufmann H, van Dijk G. Defining and classifying syncope. Clin Auton Res 2004; 14 Suppl 1:4. 5. Thijs RD, Benditt DG, Mathias CJ, et al. Unconscious confusion a literature search for definitions of syncope and related disorders. Clin Auton Res 2005; 15:35. 6. Kapoor WN. Evaluation and outcome of patients with syncope. Medicine (Baltimore) 1990; 69:160. 7. Blanc JJ, L'Her C, Touiza A, et al. Prospective evaluation and outcome of patients admitted for syncope over a 1 year period. Eur Heart J 2002; 23:815. 8. van Dijk JG, Ghariq M, Kerkhof FI, et al. Novel Methods for Quantification of Vasodepression and Cardioinhibition During Tilt-Induced Vasovagal Syncope. Circ Res 2020; 127:e126. 9. van Dijk N, Quartieri F, Blanc JJ, et al. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol 2006; 48:1652. 10. Krediet CT, van Dijk N, Linzer M, et al. Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation 2002; 106:1684. 11. Anand V, Benditt DG, Adkisson WO, et al. Trends of hospitalizations for syncope/collapse in the United States from 2004 to 2013-An analysis of national inpatient sample. J Cardiovasc Electrophysiol 2018; 29:916. 12. Benditt DG, Adkisson WO, Sutton R, et al. Ambulatory diagnostic ECG monitoring for syncope and collapse: An assessment of clinical practice in the United States. Pacing Clin Electrophysiol 2018; 41:203. 13. Wieling W, Dambrink JH, Borst C. Cardiovascular effects of arising suddenly. N Engl J Med 1984; 310:1189. 14. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011; 21:69. https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 13/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate 15. Sheldon R, Talajic M, Tang A, et al. Randomized Pragmatic Trial of Pacemaker Versus Implantable Cardiac Monitor in Syncope and Bifascicular Block. JACC Clin Electrophysiol 2022; 8:239. 16. Santini M, Castro A, Giada F, et al. Prevention of syncope through permanent cardiac pacing in patients with bifascicular block and syncope of unexplained origin: the PRESS study. Circ Arrhythm Electrophysiol 2013; 6:101. 17. Sakaguchi S, Adkisson WO. Driving and flying: US and European recommendations. In: Sync ope: An Evidence-Based Approach, 2nd ed, Brignole M, Benditt DG (Eds), Springer Nature 20 20. p.319. 18. Num AK, Gislason G, Christiansen CB, et al. Syncope and Motor Vehicle Crash Risk: A Danish Nationwide Study. JAMA Intern Med 2016; 176:503. 19. Dischinger PC, Ho SM, Kufera JA. Medical conditions and car crashes. Annu Proc Assoc Adv Automot Med 2000; 44:335. 20. Redelmeier DA, Yarnell CJ, Thiruchelvam D, Tibshirani RJ. Physicians' warnings for unfit drivers and the risk of trauma from road crashes. N Engl J Med 2012; 367:1228. 21. Staples JA, Erdelyi S, Merchant K, et al. Syncope and the Risk of Subsequent Motor Vehicle Crash: A Population-Based Retrospective Cohort Study. JAMA Intern Med 2022; 182:934. 22. Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med 2002; 347:878. 23. Saklani P, Krahn A, Klein G. Syncope. Circulation 2013; 127:1330. 24. Kenny RA, O'Shea D, Walker HF. Impact of a dedicated syncope and falls facility for older adults on emergency beds. Age Ageing 2002; 31:272. 25. Shenthar J, Prabhu MA, Banavalikar B, et al. Etiology and Outcomes of Syncope in Patients With Structural Heart Disease and Negative Electrophysiology Study. JACC Clin Electrophysiol 2019; 5:608. 26. Ruwald MH, Hansen ML, Lamberts M, et al. Prognosis among healthy individuals discharged with a primary diagnosis of syncope. J Am Coll Cardiol 2013; 61:325. 27. Yasa E, Ricci F, Magnusson M, et al. Cardiovascular risk after hospitalisation for unexplained syncope and orthostatic hypotension. Heart 2018; 104:487. 28. Francisco-Pascual J, Rodenas-Alesina E, Rivas-G ndara N, et al. Etiology and prognosis of patients with unexplained syncope and mid-range left ventricular dysfunction. Heart Rhythm 2021; 18:597. 29. Ricci F, Sutton R, Palermi S, et al. Prognostic significance of noncardiac syncope in the general population: A systematic review and meta-analysis. J Cardiovasc Electrophysiol https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 14/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate 2018; 29:1641. Topic 1032 Version 39.0 https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 15/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate GRAPHICS Algorithm for syncope/collapse This algorithm poses key questions about a collapse episode, including whether and when LOC occurred. However, in the absence of a credible witness, information about such episodes is often limited, as the affected individual may not have accurate recall of the event. Some causes have more than one possible type of presentation. LOC: loss of consciousness; BLS: basic life support; ACLS: advanced cardiac life support; SAH: subarachnoid hemorrhage; TIA: transient ischemic attack. This includes actual LOC as well as apparent LOC. Accidental falls without LOC often have multiple causes, including gait, posture, or balance impairment, environmental hazard, vertigo, focal seizure, TIA, stroke, and presyncope. https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 16/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate These conditions result in apparent transient LOC, although consciousness may be preserved. Other causes of collapse may cause secondary head trauma. Most TIAs and strokes are not associated with LOC. An SAH may cause transient or prolonged LOC. A rare cause of LOC is a brainstem stroke. Graphic 131146 Version 1.0 https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 17/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Conditions incorrectly diagnosed as syncope Disorders with partial or complete LOC but without global cerebral hypoperfusion Epilepsy Metabolic disorders including hypoglycaemia, hypoxia, hyperventilation with hypocapnia Intoxication Vertebrobasilar TIA Disorders without impairment of consciousness Cataplexy Drop attacks Falls Functional (psychogenic pseudosyncope) TIA or carotid origin LOC: loss of consciousness; TIA: transient ischaemic attack. Reproduced with permission from: European Heart Rhythm Association (EHRA), Heart Failure Association (HFA), Heart Rhythm Society (HRS), et al. Guidelines for the diagnosis and management of syncope (version 2009): the Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Eur Heart J 2009; 30:2631. Copyright 2009 Oxford University Press. Graphic 76023 Version 6.0 https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 18/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Major cardiovascular causes of syncope Reflex-mediated* Vasovagal Orthostatic vasovagal syncope: usually after prolonged standing, frequently in a warm environment, etc Emotional vasovagal syncope: secondary to fear, pain, medical procedure, etc Unknown trigger Situational Micturition, defecation Swallowing Coughing/sneezing Carotid sinus syndrome Orthostatic hypotension* Medication-related Diuretics (eg, thiazide or loop diuretics) Vasodilators (eg, dihydropyridine calcium channel blockers, nitrates, alpha blockers, etc) Antidepressants (eg, tricyclic drugs, SSRIs, etc) Volume depletion Hemorrhage Gastrointestinal losses (ie, vomiting or diarrhea) Diminished thirst drive (primarily in older patients) Autonomic failure Primary: pure autonomic failure, Parkinson disease, multiple system atrophy, Lewy body dementia Secondary: diabetes mellitus, amyloidosis, spinal cord injuries, autoimmune neuropathy (eg, Guillain-Barr ), paraneoplastic neuropathy Cardiac Tachyarrhythmias Ventricular tachycardia Supraventricular tachycardias Bradyarrhythmias (with inadequate ventricular response) Sinus node dysfunction Atrioventricular block Structural disease https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 19/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Severe aortic stenosis Hypertrophic cardiomyopathy Cardiac tamponade Prosthetic valve dysfunction Congenital coronary anomalies Cardiac masses and tumors (eg, atrial myxoma) Cardiopulmonary/vascular Pulmonary embolus Severe pulmonary hypertension Aortic dissection SSRI: selective serotonin reuptake inhibitor. Reflex-mediated syncope and syncope due to orthostatic hypotension are more likely to occur, or are more severe, when other factors may also be contributing, such as medication(s) causing low blood pressure, volume depletion, pulmonary diseases causing reduction in brain oxygen supply, alcohol use, and/or environmental factors (excessive heat or humidity). Adapted from: Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018; 39:1883. Graphic 118175 Version 4.0 https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 20/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Examples of medications that may cause or exacerbate orthostatic hypotension Mechanism of hypotension and Drug group comments Diuretics Extracellular fluid volume depletion. Loop diuretics (eg, furosemide, torsemide) or thiazides Adrenergic antagonists Alpha-1-adrenergic blockers produce vasodilation Alpha-1-adrenergic blockers (eg, alfuzosin, tamsulosin, terazosin) via direct effect in vascular smooth muscle. Beta-adrenergic blockers reduce cardiac output and renin release. May also reduce vascular peripheral resistance. Beta-adrenergic blockers (eg, propranolol) Alpha-2-adrenergic agonists (eg, tizanidine, clonidine) Vasodilation via central inhibition of sympathetic efferent activity. Nitric oxide-mediated vasodilators Vasodilation via direct effect in vascular smooth muscle. Nitroglycerin, hydralazine Phosphodiesterase-5-inhibitors (eg, sildenafil) Renin-angiotensin system (RAS) inhibitors (eg, lisinopril, valsartan) Vasodilation via RAS inhibition. Calcium-channel blockers (eg, verapamil, diltiazem) Reduction of cardiac output, vasodilation via direct effect in vascular smooth muscle. Dopamine antagonists Vasodilation via central inhibition of sympathetic efferent activity. Phenothiazines (eg, chlorpromazine) Atypical antipsychotics (eg, olanzapine, risperidone, quetiapine) Antidepressants (eg, trazodone, amitriptyline) Vasodilation via central and peripheral inhibition of sympathetic efferent activity through stimulation of adrenergic receptors. Selective serotonin receptor reuptake inhibitors (eg, paroxetine) Unknown mechanism, possibly via central and peripheral inhibition of sympathetic efferent activity through stimulation of alpha-2-adrenergic receptors. Sodium-glucose co-transporter 2 inhibitors (eg, Volume depletion via osmotic diuresis. empagliflozin, canagliflozin) https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 21/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Graphic 130809 Version 5.0 https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 22/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Recommendations for resuming driving after syncope Condition Symptom-free waiting time* OH 1 month [1] VVS, no syncope in prior year No restriction [2] VVS, 1 to 6 syncope per year 1 month [1,2] VVS, >6 syncope per year Not fit to drive until symptoms resolved Situational syncope other than cough syncope 1 month Cough syncope, untreated Not fit to drive Cough syncope, treated with cough suppression 1 month [1] Carotid sinus syncope, untreated Not fit to drive Carotid sinus syncope, treated with permanent pacemaker 1 week [1] [1] Syncope due to nonreflex bradycardia, untreated Not fit to drive Syncope due to nonreflex bradycardia, treated with [1,3] permanent pacemaker 1 week [1] Syncope due to SVT, untreated Not fit to drive [1] Syncope due to SVT, pharmacologically suppressed 1 month [1] Syncope due to SVT, treated with ablation 1 week Syncope with LVEF <35% and a presumed arrhythmic [4,5] etiology without an ICD Not fit to drive Syncope with LVEF <35% and presumed arrhythmic etiology with an ICD 3 months [6,7] Syncope presumed due to VT/VF, structural heart disease, and LVEF 35%, untreated Not fit to drive Syncope presumed due to VT/VF, structural heart disease, and LVEF 35%, treated with an ICD and guideline-directed drug therapy 3 months [6,7] Syncope presumed due to VT with a genetic cause, Not fit to drive untreated Syncope presumed due to VT with a genetic cause, treated 3 months with an ICD or guideline-directed drug therapy Syncope presumed due to a nonstructural heart disease VT, such as RVOT or LVOT, untreated Not fit to drive https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 23/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Syncope presumed due to a nonstructural heart disease VT, such as RVOT or LVOT, treated successfully with ablation or 3 months [1] suppressed pharmacologically Syncope of undetermined etiology 1 month OH: orthostatic hypotension; VVS: vasovagal syncope; SVT: supraventricular tachycardia; LVEF: left ventricular ejection fraction; ICD: implantable cardioverter-defibrillator; VT: ventricular tachycardia; VF: ventricular fibrillation; RVOT: right ventricular outflow tract; LVOT: left ventricular outflow tract. It may be prudent to wait and observe for this time without a syncope spell before resuming driving. References: 1. Epstein AE, Miles WM, Benditt DG, et al. Personal and public safety issues related to arrhythmias that may a ect consciousness: implications for regulation and physician recommendations. A medical/scienti c statement from the American Heart Association and the North American Society of Pacing and Electrophysiology. Circulation 1996; 94:1147-66. 2. Tan VH, Ritchie D, Maxey C, et al. Prospective assessment of the risk of vasovagal syncope during driving. JACC Clin Electrophysiol 2016; 2:203. 3. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013; 61:e6. 4. B nsch D, Brunn J, Castrucci M, et al. Syncope in patients with an implantable cardioverter-de brillator: incidence, prediction and implications for driving restrictions. J Am Coll Cardiol 1998; 31:608. 5. Antonelli D, Peres D, Freedberg NA, et al. Incidence of postdischarge symptomatic paroxysmal atrial brillation in patients who underwent coronary artery bypass graft: long-term follow-up. Pacing Clin Electrophysiol 2004; 27:365. 6. Thijssen J, Borle s CJ, van Rees JB, et al. Driving restrictions after implantable cardioverter de brillator implantation: an evidence-based approach. Eur Heart J 2011; 32:2678. 7. Vijgen J, Botto G, Camm J, et al. Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter de brillators. Europace 2009; 11:1097. Reproduced from: Shen W-K, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope. J Am Coll Cardiol 2017. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 113080 Version 2.0 https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 24/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Overall survival of patients with syncope Survival was worst for patients with a cardiovascular cause of syncope. p<0.001 for the comparison between participants with and those without syncope. The category "Vasovagal and other causes" includes vasovagal, orthostatic, medication-induced, and other, infrequent cause of syncope. Sorteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med 2002; 347:878. Graphic 53302 Version 4.0 https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 25/26 7/6/23, 2:38 PM Syncope in adults: Management and prognosis - UpToDate Contributor Disclosures David Benditt, MD Equity Ownership/Stock Options: Medtronic [Pacemakers/event recorders and defibrillators]. Grant/Research/Clinical Trial Support: Medtronic [Pacemakers/event recorders and defibrillators]; St Jude Medical [Pacemakers/event recorders and defibrillators]. Consultant/Advisory Boards: Medtronic [Pacemakers/event recorders and defibrillators]; Zoll [Pacemakers/event recorders and defibrillators]. Other Financial Interest: Advanced CPR Solutions [Outside director]. All of the relevant financial relationships listed have been mitigated. Peter Kowey, MD, FACC, FAHA, FHRS Equity Ownership/Stock Options: VuMedi [Arrhythmias]. Consultant/Advisory Boards: Abbvie [Arrhythmias]; Acesion Pharma [Arrhythmias]; Allergan [Arrhythmias, cardiac safety of non-cardiac drugs]; Anthos [Anticoagulants]; Boehringer-Ingelheim [Arrhythmias]; Bristol-Meyers-Squibb [Arrhythmias]; Daiichi Sankyo [Arrhythmias]; Gilead [Arrhythmias]; Huya [Arrhythmias]; InCarda Therapeutics [Arrhythmias]; INSTA [Arrhythmias]; Johnson & Johnson [Arrhythmias]; Medtronic [Arrhythmias]; Milestone [Arrhythmias]; Novartis [Arrhythmias, cardiac safety of non-cardiac drugs]; Pfizer [Arrhythmias]; Sanofi [Arrhythmias]; Takeda [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/syncope-in-adults-management-and-prognosis/print 26/26

7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Upright tilt table testing in the evaluation of syncope : David Benditt, MD : Peter Kowey, MD, FACC, FAHA, FHRS : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 13, 2022. INTRODUCTION The upright tilt table test is a component of the evaluation of selected patients with suspected vasovagal syncope (a type of reflex syncope) or orthostatic syncope, although the clinical utility of this test is limited. Syncope is a clinical syndrome of self-limited transient loss of consciousness (LOC) caused by a period of inadequate cerebral nutrient flow, most often the result of an abrupt drop in systemic blood pressure. In evaluating a patient with suspected syncope, other causes of LOC and collapse should be excluded ( algorithm 1). (See "Syncope in adults: Epidemiology, pathogenesis, and etiologies".) Tilt table testing, including indications, protocol, interpretation, and complications, will be reviewed here. Related issues are discussed separately: (See "Syncope in adults: Clinical manifestations and initial diagnostic evaluation" and "Syncope in adults: Risk assessment and additional diagnostic evaluation" and "Syncope in adults: Epidemiology, pathogenesis, and etiologies".) (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation".) (See "Mechanisms, causes, and evaluation of orthostatic hypotension".) https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 1/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate INDICATIONS The upright tilt table test is a component of the evaluation of selected patients with syncope. However, the role for tilt table testing is limited since the initial diagnostic evaluation (without tilt testing) by experienced clinicians is often diagnostic in patients with vasovagal syncope, and tilt table testing has limited reproducibility and diagnostic accuracy (see 'Test performance' below). Interpretation of test results requires careful evaluation of the patient s overall clinical presentation. Despite criticism of the test s utility, a strong argument can be made for retaining it in the overall diagnostic toolkit [1]. In general, our approach to tilt table testing is consistent with the published major society guidelines and expert recommendations [2-6]. With the understanding that tilt table testing is an imperfect diagnostic test requiring experienced interpretation and that clinical practice varies, tilt table testing may be included as part of a comprehensive syncope evaluation for selected patients in the following settings [2,4]: Syncope of unknown cause For patients with recurrent episodes of syncope (or a single episode of syncope with high risk for physical injury or occupational hazard should syncope recur) with unknown cause after initial evaluation, tilt table testing is recommended. If structural heart disease is present, cardiac causes of syncope (eg, arrhythmias) should be excluded before further evaluation including tilt table testing is performed. (See "Syncope in adults: Clinical manifestations and initial diagnostic evaluation" and "Syncope in adults: Risk assessment and additional diagnostic evaluation".) For older adults with syncope who may have limited recollection of events and circumstances, the tilt table test may be helpful in assessing susceptibility to orthostatic and vasovagal syncope [5]. Tilt table testing may be helpful in distinguishing the following conditions: Convulsive syncope (syncope associated with convulsion-like muscular jerking movements) from epilepsy, especially if an electroencephalogram recording is obtained during the procedure. (See "Nonepileptic paroxysmal disorders in adolescents and adults", section on 'Syncope'.) Syncope from pseudosyncope or pseudoseizures (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis".) Suspected vasovagal or orthostatic syncope https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 2/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate To confirm diagnosis For patients with suspected vasovagal or orthostatic syncope with uncertain diagnosis after the initial evaluation, tilt table testing may help confirm the diagnosis. It is particularly useful if the faint is induced by testing and when patients are able to confirm verbally that this is what they experience during spontaneous spells. The latter not only helps to confirm the diagnosis but also gives patients the confidence that the clinician has witnessed a true symptom spell and are thereby better positioned to recommend appropriate treatment. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Upright tilt table test' and "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Diagnostic evaluation'.) To identify the mechanism of syncope In patients with suspected vasovagal syncope, tilt table testing is helpful to assess whether bradycardic and/or vasodepressor responses are occurring, as this influences therapy [7]. For example, an individual with a predominantly vasodepressor response would be unlikely to respond to permanent cardiac pacing. (See "Reflex syncope in adults and adolescents: Treatment", section on 'Pacemaker therapy'.) Evaluation of autonomic system function As part of the overall evaluation of interactions between the autonomic nervous system and the cardiovascular system. The "active standing" test may also be used as part of the evaluation procedure but does not replace the head-up tilt test; these tests supplement each other, but active standing is less thoroughly studied. (See "Diabetic autonomic neuropathy" and "Hereditary sensory and autonomic neuropathies" and "Mechanisms, causes, and evaluation of orthostatic hypotension" and "Immune-mediated neuropathies".) As an example, tilt table testing is often performed in patients undergoing assessment for postural tachycardia syndrome, although the diagnostic utility of tilt testing is not well established. (See "Postural tachycardia syndrome", section on 'Diagnostic approach'.) In contrast, tilt table testing is generally not helpful to identify patients with situational vagal syncope (ie, syncope due to situations associated with enhanced vagal tone such as micturition, defecation, cough, or vomiting) [8]. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Situational syncope'.) CONTRAINDICATIONS Tilt table testing should not be performed in patients who have severe coronary or cerebrovascular disease in whom hypotension may cause myocardial or cerebral ischemia. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 3/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Similarly, tilt tests are usually avoided in pregnant patients as hypotension may potentially be harmful to the fetus. Additional concerns apply to use of drug provocation, which is used only after a baseline drug- free tilt test is nondiagnostic, as discussed below (see 'Drug provocation phase' below). Although a controlled infusion of isoproterenol is generally safe in patients without heart disease, it must be used cautiously in patients with coronary artery disease and/or known arrhythmia, since angina and serious arrhythmia can be provoked [9,10]. Other contraindications to isoproterenol use include uncontrolled hypertension, left ventricular outflow tract obstruction, and significant aortic stenosis. Contraindications for nitrates include use of sildenafil or vardenafil within 24 hours or use of tadalafil within 48 hours. (See 'Drug provocation phase' below.) TILT TABLE TESTING PROCEDURE Upright tilt table testing is typically performed in an electrophysiology laboratory or dedicated procedure room using a special motorized tilt table that raises to 70 degrees above supine. Patient preparation Patient preparation includes the following measures. The patient should fast at least three to four hours before the test. Some clinicians recommend an overnight fast (ie, at least 8 hours) prior to testing. Depending upon the clinical circumstances, patients may be asked to take their usual meds or, alternatively, hold their usual drugs. The test should be performed in a quiet room with a comfortable temperature and minimal distractions for the patient. The patient should have an intravenous catheter placed prior to the procedure, allowing for administration of fluids and/or medications (eg, isoproterenol or nitroglycerin) if needed. This is best done at least 30 minutes prior to the test. Equipment The patient is placed on a motorized tilt table with a foot board and safety restraints. The table should be capable of smoothly and rapidly moving the patient passively from a supine position to a head-up position between 60 to 70 degrees and quickly (in <10 seconds) returning the patient to a horizontal supine position to minimize the duration of any precipitated asystole and/or hypotension [11]. Monitoring Continuous electrocardiogram (ECG) and beat-to-beat blood pressure (BP) monitoring are employed throughout the test. Careful monitoring of both is required, because https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 4/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate while many patients have a pronounced cardioinhibitory response detectable by ECG, many others have vasodepressor episodes (characterized by symptomatic hypotension without marked bradycardia), and some patients exhibit simultaneous cardioinhibitory and vasodepressor responses. Most tests are performed using either three or six ECG leads, although there is no defined consensus on this. Conventional limb leads are commonly used as they are convenient and offer more than adequate monitoring to assess for changes in heart rate (HR) and rhythm. Systemic BP and HR recording should be beat-to-beat and is typically noninvasive. Invasive arterial monitoring is rarely used with tilt table tests, but it is acceptable as long as the line is placed at least an hour before the procedure to allow autonomic tone to return to baseline. Intermittent BP measurement via sphygmomanometer (such as an arm cuff) is not adequate, as the number of data points precludes identifying developing problems, and, even more importantly, the cuff disturbance may alter patient autonomics and thereby undermine the objective of the study. Electroencephalogram monitoring may be warranted in certain cases, especially if pseudosyncope/pseudoseizure or ictal asystole are suspected. In the case of suspected pseudosyncope/pseudoseizure, near-infrared spectroscopy (NIRS) may also be used to confirm that cerebral blood flow has not been diminished and that true syncope has not occurred [12]. However, NIRS is limited in terms of the depth of penetration of the cerebrum and, thus, the region in which blood flow can be monitored. Tilt protocol A variety of protocols have been described for the test that vary in the angle of tilt (60 to 70 degrees above horizontal supine), duration of tilt (generally 20 to 45 minutes), and the administration of isoproterenol or nitroglycerin. The most commonly used protocol is described here. (See 'Patient preparation' above.) Other autonomic testing may be carried out during the tilt table test procedure, but sufficient time is needed between steps to allow the patient to return to basal state. These additional tests could include "active standing," Valsalva maneuver, carotid massage, respiratory sinus arrhythmia, and sweat testing. Initial supine phase To begin the test, the patient is monitored in an initial baseline horizontal supine position for 5 to 10 minutes to obtain baseline HR and BP measurements. If venous or arterial cannulation is performed just prior to the test, a longer initial supine time period of at least 20 minutes after venous cannulation and at least 60 minutes after arterial https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 5/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate cannulation is recommended to allow any stimulated circulating catecholamines to return to baseline. The patient should be instructed to report any symptoms that may develop during the test. Passive phase The first (and sometimes only) head-up tilt (angle between 60 and 70 degrees above horizontal) phase is a passive phase (ie, no provocation with isoproterenol or nitroglycerin) of 20 minutes (maximum of 45 minutes) [11]. If the patient develops complete loss of consciousness (LOC), the patient is rapidly (in <10 s) returned to a supine position. HR and symptoms are recorded every three to five minutes, and the ECG is recorded continuously. The BP should be monitored noninvasively by beat-to-beat finger plethysmographic arterial monitoring. As noted above, an arm cuff should not be used during the test. (See 'Monitoring' above.) Possible positive responses to the passive phase include a positive response for vasovagal syncope, a positive response for orthostatic hypotension (OH), or a positive response for psychogenic pseudosyncope. In patients exhibiting marked OH, testing may be repeated after hydration with intravenous saline. If no symptoms or ECG abnormalities consistent with the patient's history have developed after a period of 20 to 45 minutes of head tilt, the patient is returned to the supine position, and the passive test is considered nondiagnostic. Test interpretation is discussed further below. (See 'Test interpretation' below.) Deciding whether to use drug provocation The decision to proceed with a drug provocation phase after a nondiagnostic passive phase in a patient with suspected vasovagal syncope is up to the discretion of the clinician and is generally determined by the perceived clinical utility of inducing a response suggestive of vasovagal syncope. (See 'Test interpretation' below.) It may be possible to reduce the time necessary for the tilt table test and avoid the need for isoproterenol infusion based upon the HR response early in the passive phase. In a study of 109 patients, an HR change 18 beats per minute during the first six minutes of the test prospectively predicted a negative tilt table test with a 96 percent specificity, 98 percent positive predictive accuracy, and 87 percent sensitivity, even with the subsequent use of isoproterenol [13]. However, this shortened procedure is not widely used and is not our recommended approach. Drug provocation phase If the patient has remained asymptomatic during the passive phase of tilt table testing, a second tilt table test is often performed with administration of a vasoactive medication (usually either isoproterenol or nitroglycerin). Either drug can be used for https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 6/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate the drug provocation phase, with the choice of isoproterenol or nitroglycerin usually directed by local practice and clinician expertise. In many locations, the cost of isoproterenol has increased, and, consequently, nitroglycerin provocation (the so-called Italian protocol) is preferred. Isoproterenol If the passive phase is negative and isoproterenol infusion is chosen, the infusion is administered with the patient in the supine position, although some advocate for the infusion to be initiated with the patient already in the 60 to 70 degree head-up tilt position [4]. Isoproterenol is usually titrated from 1 to 3 mcg/minute to increase the HR by 20 to 25 percent above baseline. Once the desired HR has been achieved, the patient is placed in the 60 to 70 degree head-up tilt position for an additional 15 to 20 minutes while the infusion is continued. The infusion and tilt position are maintained until completion of the protocol or the patient develops complete LOC, whichever is sooner. Generally, LOC during isoproterenol infusion is required to consider the test positive [4]. A modest decrease in BP with symptoms is common with isoproterenol and is nonspecific. The fact that isoproterenol may trigger vasovagal syncope may seem somewhat paradoxical. The mechanism is thought to be due to activation of central circulation mechanoreceptors, but the exact basis for the effect is not absolutely known. The potential efficacy of isoproterenol infusion was illustrated in a study in which a single-stage isoproterenol tilt table test more frequently induced syncope than a standard passive tilt table test (56 versus 32 percent) and reduced the time necessary for the procedure [14]. There was, however, a lower specificity (83 versus 91 percent for passive phase testing). (See 'Test performance' below.) Nitroglycerin If the passive phase is negative and nitroglycerin is chosen as the provocative agent, we administer a fixed dose of 300 to 400 mcg of sublingual nitroglycerin with the patient in the 60 to 70 degree upright position for 15 to 20 minutes [4]. The use of intravenously administered nitroglycerin has been described but is rarely used. Generally, LOC following nitroglycerin administration is required to consider the test positive [4]. A modest decrease in BP with symptoms is common with nitroglycerin and is nonspecific. (See 'Test interpretation' below.) Nitroglycerin likely increases susceptibility to vasovagal syncope by reducing venous return to the heart and thereby enhancing cardiac activity and activating the reflex via central cardiac mechanoreceptors [15]. Nitroglycerin causes venodilation, with consequent reduction in venous return and stroke volume, without impeding the sympathetic responses of increased HR and arterial vasoconstriction [16]. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 7/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate The addition of nitroglycerin to tilt table testing increases the frequency of hemodynamic changes and reproduction of symptoms and may shorten test duration but also increases the rate of false positive tests. In a study of 232 patients, including 149 with unexplained syncope and 83 asymptomatic controls, participants were randomly assigned to receive nitroglycerin (800 mcg metered spray) and a 20-minute tilt table test or no nitroglycerin and a standard 40-minute tilt table test [17]. Nitroglycerin increased the frequency of a positive tilt table test from 11 to 36 percent in all patients, although the results are nonspecific as the rate of positive tests increased in both patients with prior syncope and control patients. Comparison of isoproterenol and nitroglycerin Isoproterenol and nitroglycerin have been compared as adjuncts to tilt table testing [18,19]: In one study of 71 patients with unexplained syncope and 30 controls who underwent tilt table testing twice on separate days, with all patients receiving isoproterenol and nitroglycerin on separate days, rates of test positivity were similar in patients receiving nitroglycerin and isoproterenol (49 and 41 percent, respectively) [18]. However, sublingual nitroglycerin was simpler to use and better tolerated than isoproterenol. In a study of 96 patients with unexplained syncope who underwent three separate tilt table tests on the same day (passive, once with isoproterenol, once with nitroglycerin), sublingual nitroglycerin with tilt table testing led to a higher number of positive responses than isoproterenol (55 versus 42 percent), especially among patients with a positive tilt table test without pharmacologic agents (94 versus 67 percent) [19]. TILT TABLE TEST RESULTS Test interpretation General approach The tilt table test findings should be interpreted in the context of all relevant clinical data, particularly information about the patient s spontaneous events and other potential causes of events (eg, structural heart disease). On the other hand, while the tilt table test is frequently positive in patients with vasovagal syncope, it is not the gold standard for the diagnosis of vasovagal syncope, as it has limited sensitivity, specificity, and reproducibility. Although isoproterenol and nitroglycerin increase the sensitivity of the test, these drug interventions also decrease test specificity (ie, increase the number of false positives). Thus, a positive test (with or without drug provocation) does not definitively establish that the patient s clinical events were caused by the type of syncope induced by the test (eg, vasovagal syncope). After a positive test, the patient is asked if symptoms during the test were the same as those https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 8/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate experienced during spontaneous events. It is crucial to interpret the test result in light of the patient s spontaneous symptoms. The vasovagal reflex seen on a tilt table test may reflect a given patient's predisposition to vasovagal syncope; however, the specific physiologic response to the tilt table test may differ from the physiology of clinical episodes. Also, the response to tilt table testing can be highly variable, and even the severity of cardioinhibitory versus vasodepressor components may differ from one test to another. Additionally, factors such as age and the use of medications during the protocol may affect the likelihood of a positive test. Older adults are less likely to have a cardioinhibitory response and more likely to have a vasodepressor response [20]. Ultimately, in all patients with syncope, obtaining a thorough history as part of the initial evaluation is the most important component of the diagnostic evaluation. In patients with structural heart disease, other causes of syncope should be evaluated before attributing the syncope to a vasovagal or orthostatic response. (See "Syncope in adults: Clinical manifestations and initial diagnostic evaluation", section on 'Approach to initial evaluation'.) Patterns of response to head-up tilt include those with or without associated syncope [11]: Patterns without syncope The head-up tilt test is considered negative for syncope if the patient is able to maintain an upright position and/or does not experience complete loss of consciousness (LOC). The following hemodynamic responses to head-up tilt are observed: Normal result In a normal response, there is no change or a slight increase ( 10 percent) in systemic blood pressure (BP) and slight increase ( 10 percent) in HR until the patient is returned to the baseline position [11]. Postural tachycardia syndrome (POTS) Tilt table testing may not be as useful as active standing for detection of POTS. Key features of POTS include symptoms of orthostatic intolerance (eg, lightheadedness or palpitations) with a sustained increase in heart rate (HR) 30 beats per minute (bpm; 40 bpm for individuals <20 years old) within 10 minutes after the start of head-up tilt with no decline in BP. However, other common clinical factors (eg, dehydration, concomitant inflammatory conditions, anemia, hyperthyroidism, etc) should generally be excluded before tilt table testing, and should be excluded before a POTS diagnosis is made. (See "Postural tachycardia syndrome", section on 'Diagnostic approach'.) Possible vasovagal response If a patient experiences symptoms suggestive of presyncope without LOC with a significant fall in BP ( 40 mmHg decline in systolic BP) or HR ( 60 bpm decline in HR), the patient is returned to the baseline position, and the test is considered suggestive of vasovagal syncope. (See "Reflex syncope in adults and https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 9/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate adolescents: Clinical presentation and diagnostic evaluation", section on 'Upright tilt table test'.) Nonspecific response After a variable period of time after head-up tilt there is commonly a mild decrease in BP (generally <15 mmHg decline in systolic BP) and mild increase in HR (by 10 percent). The patient may or may not experience dizziness during this nondiagnostic response. The clinical significance of such responses without induction of syncope is not clear [2,4]. Patterns with syncope or apparent syncope The head-up tilt response is considered positive for syncope if the patient experiences complete LOC and/or dizziness or lightheadedness with inability to maintain an upright posture. Among patients experiencing syncope in response to head-up tilt, the associated physiologic features suggest the cause. Features of vasovagal syncope not present with orthostatic hypotension (OH) include latency (delay) in the BP fall after head-up tilt, an accelerating decline in BP, and a decline in HR. Vasovagal response Key characteristics of the vasovagal response are a delayed accelerating fall in BP with mild to severe fall in HR. After a variable period of time after head-up tilt, there may be a gradual slight decline in BP and a gradual slight increase in HR. The rate of fall in BP then accelerates (convex curve), the rate of fall in HR also accelerates, and in some cases the HR falls to a period of asystole. LOC generally occurs within three minutes of onset of the vasovagal reaction [11]. After return to the baseline position, HR and BP quickly increase. Variations in the vasovagal response include: only a mild HR decrease, an initial brief slight HR increase followed by a greater HR decrease, and minimal change in BP and HR before accelerating declines in BP and HR ( figure 1). Responses to tilt table testing appear to vary with patient age. Younger subjects are more likely to have a bradycardic response, whereas older subjects are more likely to have a vasodepressive response (ie, minimal decline in HR) [21-23]. Orthostatic hypotension Key features of OH are either an immediate fall in BP with or without an increase in HR ("immediate OH") or a delayed ("classic") hypotensive response occurring within three to five minutes after assuming upright posture; some patients may exhibit both forms. Further, patients with severe autonomic failure syndromes (eg, pure autonomic failure, Parkinson disease) may exhibit an abrupt drop of pressure with upright posture that does not recover and may become sufficiently severe to necessitate test termination. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 10/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Immediately after head-up tilt, the BP declines at a decelerating rate (concave curve) [11]. After the first three minutes of head-up tilt, the BP may continue to decline considerably. The HR may increase in response to the fall in BP but if HR control is impaired there may be no or only slight increase in HR. The latter complicates prevention of OH, which typically demands therapies that further increase supine BP. Diagnosis of orthostatic hypotension by comparing supine and standing blood pressure is discussed separately. (See "Mechanisms, causes, and evaluation of orthostatic hypotension".) Pseudosyncope During head-up tilt, if the patient appears to lose consciousness or is unable to maintain posture without a significant fall in BP or HR, the patient is returned to a horizontal supine position, and the test is considered positive for psychogenic pseudosyncope. Additional supportive observations include tightly closed eyes and a prolonged period of apparent LOC (typically >2 to 3 minutes even after return to supine posture). If an electroencephalogram is recorded during the test, it does not show the typical slowing that occurs in true syncope. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis".) It is important to be aware that many patients with pseudosyncope may also be experiencing true syncope, and the presence of pseudosyncope does not eliminate the need for a careful assessment of all symptoms. Test performance The sensitivity of tilt table testing is difficult to determine given the lack of a clinical gold standard as well as varying protocols and patient selection [4]. Using clinical diagnosis as the standard for comparison, reported sensitivity rates for passive phase testing have ranged from 13 to 75 percent [4,24]. Thus, the false negative rate may be 25 percent depending upon the protocol and patient population. For this reason, vasovagal syncope cannot be excluded by a negative tilt table test. Although the specificity of passive phase tilt testing has been reported as greater than 90 percent in some studies of patients with syncope [24], high rates of passive tilt test positivity have been observed in patients with likely tachyarrhythmic syncope (45 percent) [25] and in healthy individuals with no history of syncope (13 percent) [26]. Drug provocation (with isoproterenol or nitroglycerin) yields higher sensitivity (eg, 42 to 87 percent) but this higher sensitivity is at the expense of lower specificity (70 to 94 percent) [24]. Among patients with cardiac syncope, 43 percent had a positive nitroglycerin tilt test [27]. Among healthy volunteers, a positive response is seen in as many as 45 percent who undergo a https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 11/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate tilt table test with isoproterenol [28] and in as many as 28 percent who undergo tilt table test with nitroglycerin [17]. COMPLICATIONS AND SIDE EFFECTS Complications of tilt table testing are rare, but prolonged asystole or symptomatic hypotension occasionally occurs. If either occurs, the patient should be placed in a horizontal supine position until recovery. Atrial fibrillation is infrequently induced during or after a positive tilt table test with or without isoproterenol infusion [29]. While most cases spontaneously convert to sinus rhythm within 48 hours, atrial fibrillation commonly recurs during the next few years [29]. Ventricular fibrillation has been rarely reported in patients with ischemic heart disease or other structural heart disease undergoing tilt table testing with administration of isoproterenol [30]. (See 'Contraindications' above.) Frequent minor side effects include palpitations in patients receiving isoproterenol and headache in patients treated with nitroglycerin [11]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Syncope".) SUMMARY AND RECOMMENDATIONS Indications for tilt table testing The upright tilt table test is a component of the evaluation of selected patients with syncope. The role for tilt table testing is limited since the initial diagnostic evaluation (without tilt testing) is often diagnostic in patients with vasovagal syncope, and tilt table testing has limited reproducibility and diagnostic accuracy. (See 'Test performance' above.) However, a positive test that reproduces patient symptoms may not only be helpful diagnostically but may also increase patient confidence that an accurate diagnosis has been made. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 12/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate With the understanding that tilt table testing is an imperfect diagnostic test requiring experienced interpretation and that clinical practice varies, tilt table testing may be included as part of the complete syncope evaluation for selected patients in the following settings: Syncope of unknown cause For recurrent syncope (or a single episode with high risk of physical injury should syncope recur) with unknown cause after initial evaluation. If structural heart disease is present, cardiac causes of syncope should be excluded before tilt table testing is performed. Suspected vasovagal or orthostatic syncope To help confirm the diagnosis if the diagnosis is uncertain after the initial evaluation and to identify the mechanism of syncope (eg, cardioinhibitory and/or vasodepressor) in selected patients with suspected vasovagal or orthostatic syncope, which influences therapy. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Upright tilt table test' and "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Diagnostic evaluation' and "Reflex syncope in adults and adolescents: Treatment" and "Reflex syncope in adults and adolescents: Treatment", section on 'Additional measures'.) Evaluation of autonomic system function Tilt table testing may be a component of evaluation of the autonomic system. (See "Diabetic autonomic neuropathy" and "Hereditary sensory and autonomic neuropathies" and "Mechanisms, causes, and evaluation of orthostatic hypotension" and "Immune-mediated neuropathies".) Contraindications Tilt table testing should not be performed in patients who have severe coronary or cerebrovascular disease or are pregnant. (See 'Contraindications' above.) Equipment and procedure Upright tilt table testing is typically performed in an electrophysiology laboratory or dedicated procedure room using a special motorized tilt table that raises to 60 to 70 degrees with rapid return to a horizontal position. The passive (drug-free) phase is 20 to 45 minutes long. If the initial passive phase is negative, a drug provocation phase using isoproterenol or nitroglycerin may be performed. (See 'Tilt table testing procedure' above.) Interpretation The tilt table test findings should be interpreted in the context of all relevant clinical data, particularly information about the patient s spontaneous events and other potential causes of events (eg, structural heart disease). Although the tilt table test is frequently positive in patients with vasovagal syncope, it is not the gold standard for the diagnosis of vasovagal syncope, as it has limited sensitivity, specificity, and reproducibility. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 13/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate (See 'Test interpretation' above and 'Test performance' above and "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Diagnosis'.) Symptomatic response without syncope (see 'Patterns without syncope' above): Postural tachycardia syndrome (POTS) Key features include symptoms of orthostatic intolerance (lightheadedness, palpitations, fading vision, presyncope, difficulty concentrating, or headache) with a sustained increase in heart rate (HR) 30 beats per minute (bpm; 40 bpm for individuals <20 years old) within 10 minutes after the start of head-up tilt with no decline in blood pressure (BP). However, other factors such as dehydration should be excluded before tilt table testing. (See "Postural tachycardia syndrome", section on 'Diagnostic approach'.) Possible vasovagal response If a patient experiences symptoms suggestive of presyncope without loss of consciousness (LOC) with a significant fall in BP ( 40 mmHg decline in systolic BP) or HR ( 60 bpm decline in HR), the patient is returned to the baseline position, and the test is considered suggestive of vasovagal syncope. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Upright tilt table test'.) Nonspecific response After a variable period of time after head-up tilt there is commonly a mild decrease in BP (generally <10 mm Hg decline in systolic BP) and mild increase in HR (by 10 percent). The patient may or may not experience dizziness during this nondiagnostic response. Patterns with apparent syncope (see 'Patterns with syncope or apparent syncope' above): Vasovagal response Key characteristics of the vasovagal response are an initial sinus tachycardia with onset of upright posture followed by a delayed accelerating fall in BP with mild to severe fall in HR ( figure 1). Orthostatic hypotension Key features of orthostatic hypotension (OH) are one or both of the following: an immediate fall in BP with or without an increase in HR [11] or a delayed hypotensive response at three to five minutes after onset of upright posture. Pseudosyncope During head-up tilt, if the patient appears to lose consciousness or is unable to maintain posture without a significant fall in BP or HR, the test is considered positive for psychogenic pseudosyncope. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis".) https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 14/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Test performance The sensitivity and specificity of tilt table testing are uncertain given the lack of a clinical gold standard. Reported sensitivity rates for passive phase testing have ranged from 13 to 75 percent and specificity may be greater than 90 percent. Drug provocation yields higher sensitivity but at the expense of a lower specificity. Complications Tilt table testing is rarely complicated by prolonged asystole or hypotension. Atrial fibrillation is infrequently induced. Ventricular fibrillation is a rare complication of isoproterenol administration in patients with heart disease. (See 'Complications and side effects' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Brian Olshansky, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Sutton R, Fedorowski A, Olshansky B, et al. Tilt testing remains a valuable asset. Eur Heart J 2021; 42:1654. 2. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 3. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015; 12:e41. 4. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018; 39:1883.

evaluation of selected patients with syncope. The role for tilt table testing is limited since the initial diagnostic evaluation (without tilt testing) is often diagnostic in patients with vasovagal syncope, and tilt table testing has limited reproducibility and diagnostic accuracy. (See 'Test performance' above.) However, a positive test that reproduces patient symptoms may not only be helpful diagnostically but may also increase patient confidence that an accurate diagnosis has been made. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 12/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate With the understanding that tilt table testing is an imperfect diagnostic test requiring experienced interpretation and that clinical practice varies, tilt table testing may be included as part of the complete syncope evaluation for selected patients in the following settings: Syncope of unknown cause For recurrent syncope (or a single episode with high risk of physical injury should syncope recur) with unknown cause after initial evaluation. If structural heart disease is present, cardiac causes of syncope should be excluded before tilt table testing is performed. Suspected vasovagal or orthostatic syncope To help confirm the diagnosis if the diagnosis is uncertain after the initial evaluation and to identify the mechanism of syncope (eg, cardioinhibitory and/or vasodepressor) in selected patients with suspected vasovagal or orthostatic syncope, which influences therapy. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Upright tilt table test' and "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Diagnostic evaluation' and "Reflex syncope in adults and adolescents: Treatment" and "Reflex syncope in adults and adolescents: Treatment", section on 'Additional measures'.) Evaluation of autonomic system function Tilt table testing may be a component of evaluation of the autonomic system. (See "Diabetic autonomic neuropathy" and "Hereditary sensory and autonomic neuropathies" and "Mechanisms, causes, and evaluation of orthostatic hypotension" and "Immune-mediated neuropathies".) Contraindications Tilt table testing should not be performed in patients who have severe coronary or cerebrovascular disease or are pregnant. (See 'Contraindications' above.) Equipment and procedure Upright tilt table testing is typically performed in an electrophysiology laboratory or dedicated procedure room using a special motorized tilt table that raises to 60 to 70 degrees with rapid return to a horizontal position. The passive (drug-free) phase is 20 to 45 minutes long. If the initial passive phase is negative, a drug provocation phase using isoproterenol or nitroglycerin may be performed. (See 'Tilt table testing procedure' above.) Interpretation The tilt table test findings should be interpreted in the context of all relevant clinical data, particularly information about the patient s spontaneous events and other potential causes of events (eg, structural heart disease). Although the tilt table test is frequently positive in patients with vasovagal syncope, it is not the gold standard for the diagnosis of vasovagal syncope, as it has limited sensitivity, specificity, and reproducibility. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 13/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate (See 'Test interpretation' above and 'Test performance' above and "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Diagnosis'.) Symptomatic response without syncope (see 'Patterns without syncope' above): Postural tachycardia syndrome (POTS) Key features include symptoms of orthostatic intolerance (lightheadedness, palpitations, fading vision, presyncope, difficulty concentrating, or headache) with a sustained increase in heart rate (HR) 30 beats per minute (bpm; 40 bpm for individuals <20 years old) within 10 minutes after the start of head-up tilt with no decline in blood pressure (BP). However, other factors such as dehydration should be excluded before tilt table testing. (See "Postural tachycardia syndrome", section on 'Diagnostic approach'.) Possible vasovagal response If a patient experiences symptoms suggestive of presyncope without loss of consciousness (LOC) with a significant fall in BP ( 40 mmHg decline in systolic BP) or HR ( 60 bpm decline in HR), the patient is returned to the baseline position, and the test is considered suggestive of vasovagal syncope. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Upright tilt table test'.) Nonspecific response After a variable period of time after head-up tilt there is commonly a mild decrease in BP (generally <10 mm Hg decline in systolic BP) and mild increase in HR (by 10 percent). The patient may or may not experience dizziness during this nondiagnostic response. Patterns with apparent syncope (see 'Patterns with syncope or apparent syncope' above): Vasovagal response Key characteristics of the vasovagal response are an initial sinus tachycardia with onset of upright posture followed by a delayed accelerating fall in BP with mild to severe fall in HR ( figure 1). Orthostatic hypotension Key features of orthostatic hypotension (OH) are one or both of the following: an immediate fall in BP with or without an increase in HR [11] or a delayed hypotensive response at three to five minutes after onset of upright posture. Pseudosyncope During head-up tilt, if the patient appears to lose consciousness or is unable to maintain posture without a significant fall in BP or HR, the test is considered positive for psychogenic pseudosyncope. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis".) https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 14/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Test performance The sensitivity and specificity of tilt table testing are uncertain given the lack of a clinical gold standard. Reported sensitivity rates for passive phase testing have ranged from 13 to 75 percent and specificity may be greater than 90 percent. Drug provocation yields higher sensitivity but at the expense of a lower specificity. Complications Tilt table testing is rarely complicated by prolonged asystole or hypotension. Atrial fibrillation is infrequently induced. Ventricular fibrillation is a rare complication of isoproterenol administration in patients with heart disease. (See 'Complications and side effects' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Brian Olshansky, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Sutton R, Fedorowski A, Olshansky B, et al. Tilt testing remains a valuable asset. Eur Heart J 2021; 42:1654. 2. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 3. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015; 12:e41. 4. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018; 39:1883. 5. Adkisson WO, Benditt DG. Head-up tilt table testing. In: Cardiac Electrophysiciology: from Ce ll to Bedside, 7th ed, Zipes DP, Jalife J, Stevenson WG (Eds), Elsevier Saunders, Philadelphia 2 017. p.630. 6. Thijs RD, Brignole M, Falup-Pecurariu C, et al. Recommendations for tilt table testing and other provocative cardiovascular autonomic tests in conditions that may cause transient loss of consciousness : Consensus statement of the European Federation of Autonomic https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 15/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Societies (EFAS) endorsed by the American Autonomic Society (AAS) and the European Academy of Neurology (EAN). Clin Auton Res 2021; 31:369. 7. Brignole M, Russo V, Arabia F, et al. Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole. Eur Heart J 2021; 42:508. 8. Kochiadakis GE, Papadimitriou EA, Marketou ME, et al. Autonomic nervous system changes in vasovagal syncope: is there any difference between young and older patients? Pacing Clin Electrophysiol 2004; 27:1371. 9. Sheldon R, Rose S, Koshman ML. Isoproterenol tilt-table testing in patients with syncope and structural heart disease. Am J Cardiol 1996; 78:700. 10. Leman RB, Clarke E, Gillette P. Significant complications can occur with ischemic heart disease and tilt table testing. Pacing Clin Electrophysiol 1999; 22:675. 11. Brignole M, Moya A, de Lange FJ, et al. Practical Instructions for the 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018; 39:e43. 12. Claffey P, P rez-Denia L, Rivasi G, et al. Near-infrared spectroscopy in evaluating psychogenic pseudosyncope-a novel diagnostic approach. QJM 2020; 113:239. 13. Mallat Z, Vicaut E, Sangar A, et al. Prediction of head-up tilt test result by analysis of early heart rate variations. Circulation 1997; 96:581. 14. Shen WK, Jahangir A, Beinborn D, et al. Utility of a single-stage isoproterenol tilt table test in adults: a randomized comparison with passive head-up tilt. J Am Coll Cardiol 1999; 33:985. 15. Aerts AJ, Dendale P, Daniels C, et al. Intravenous nitrates for pharmacological stimulation during head-up tilt testing in patients with suspected vasovagal syncope and healthy controls. Pacing Clin Electrophysiol 1999; 22:1593. 16. Gisolf J, Westerhof BE, van Dijk N, et al. Sublingual nitroglycerin used in routine tilt testing provokes a cardiac output-mediated vasovagal response. J Am Coll Cardiol 2004; 44:588. 17. Parry SW, Gray JC, Newton JL, et al. 'Front-loaded' head-up tilt table testing: validation of a rapid first line nitrate-provoked tilt protocol for the diagnosis of vasovagal syncope. Age Ageing 2008; 37:411. 18. Raviele A, Giada F, Brignole M, et al. Comparison of diagnostic accuracy of sublingual nitroglycerin test and low-dose isoproterenol test in patients with unexplained syncope. Am J Cardiol 2000; 85:1194. 19. Del pine S, Prunier F, Lefth riotis G, et al. Comparison between isoproterenol and nitroglycerin sensitized head-upright tilt in patients with unexplained syncope and negative or positive passive head-up tilt response. Am J Cardiol 2002; 90:488. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 16/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate 20. van Dijk JG, van Rossum IA, van Houwelingen M, et al. Influence of Age on Magnitude and Timing of Vasodepression and Cardioinhibition in Tilt-Induced Vasovagal Syncope. JACC Clin Electrophysiol 2022; 8:997. 21. Moya A, Brignole M, Menozzi C, et al. Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope. Circulation 2001; 104:1261. 22. Brignole M, Menozzi C, Del Rosso A, et al. New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification. Analysis of the pre-syncopal phase of the tilt test without and with nitroglycerin challenge. Vasovagal Syncope International Study. Europace 2000; 2:66. 23. Kurbaan AS, Bowker TJ, Wijesekera N, et al. Age and hemodynamic responses to tilt testing in those with syncope of unknown origin. J Am Coll Cardiol 2003; 41:1004. 24. Macedo P, Leite LR, Asirvatham SJ, et al. Head Up Tilt Testing: An Appraisal of Its Current Role in the Management of Patients with Syncope. J Atr Fibrillation 2011; 4:333. 25. Brignole M, Gianfranchi L, Menozzi C, et al. Role of autonomic reflexes in syncope associated with paroxysmal atrial fibrillation. J Am Coll Cardiol 1993; 22:1123. 26. Petersen ME, Williams TR, Gordon C, et al. The normal response to prolonged passive head up tilt testing. Heart 2000; 84:509. 27. Ungar A, Sgobino P, Russo V, et al. Diagnosis of neurally mediated syncope at initial evaluation and with tilt table testing compared with that revealed by prolonged ECG monitoring. An analysis from the Third International Study on Syncope of Uncertain Etiology (ISSUE-3). Heart 2013; 99:1825. 28. Kapoor WN, Brant N. Evaluation of syncope by upright tilt testing with isoproterenol. A nonspecific test. Ann Intern Med 1992; 116:358. 29. Kim JH, Lee SH, Park SJ, et al. Atrial fibrillation occurring during head-up tilt testing: Once detected, atrial fibrillation should be monitored, regardless of how it is detected. Heart Rhythm 2019; 16:520. 30. Shenthar J, Pujar D, Aravind Prabhu M, Sadashivappa Surhynne P. Ventricular fibrillation a rare complication during head-up tilt test. HeartRhythm Case Rep 2015; 1:363. Topic 1016 Version 29.0 https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 17/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate GRAPHICS Algorithm for syncope/collapse This algorithm poses key questions about a collapse episode, including whether and when LOC occurred. However, in the absence of a credible witness, information about such episodes is often limited, as the affected individual may not have accurate recall of the event. Some causes have more than one possible type of presentation. LOC: loss of consciousness; BLS: basic life support; ACLS: advanced cardiac life support; SAH: subarachnoid hemorrhage; TIA: transient ischemic attack. This includes actual LOC as well as apparent LOC. Accidental falls without LOC often have multiple causes, including gait, posture, or balance impairment, environmental hazard, vertigo, focal seizure, TIA, stroke, and presyncope. https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 18/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate These conditions result in apparent transient LOC, although consciousness may be preserved. Other causes of collapse may cause secondary head trauma. Most TIAs and strokes are not associated with LOC. An SAH may cause transient or prolonged LOC. A rare cause of LOC is a brainstem stroke. Graphic 131146 Version 1.0 https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 19/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Heart rate and blood pressure patterns observed in head-up tilt table testing Shown are the heart rate and blood pressure responses seen during tilt table testing in patients with various etiologies of syncope including classic neurocardiogenic syncope, pure autonomic failure, or POTS. HR: heart rate; BP: blood pressure; POTS: postural orthostatic tachycardia syndrome. Reproduced with permission from: Grubb BP. Neurocardiogenic syncope. In: Syncope: Mechanisms and Management, Grubb BP, Olshansky B (Eds), Furtura https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 20/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Publishing Co., Armonk, NY, 1997. p. 73-166. Copyright 1997 Futura Publishing Co. Graphic 55504 Version 4.0 https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 21/22 7/6/23, 2:38 PM Upright tilt table testing in the evaluation of syncope - UpToDate Contributor Disclosures David Benditt, MD Equity Ownership/Stock Options: Medtronic [Pacemakers/event recorders and defibrillators]. Grant/Research/Clinical Trial Support: Medtronic [Pacemakers/event recorders and defibrillators]; St Jude Medical [Pacemakers/event recorders and defibrillators]. Consultant/Advisory Boards: Medtronic [Pacemakers/event recorders and defibrillators]; Zoll [Pacemakers/event recorders and defibrillators]. Other Financial Interest: Advanced CPR Solutions [Outside director]. All of the relevant financial relationships listed have been mitigated. Peter Kowey, MD, FACC, FAHA, FHRS Equity Ownership/Stock Options: VuMedi [Arrhythmias]. Consultant/Advisory Boards: Abbvie [Arrhythmias]; Acesion Pharma [Arrhythmias]; Allergan [Arrhythmias, cardiac safety of non-cardiac drugs]; Anthos [Anticoagulants]; Boehringer-Ingelheim [Arrhythmias]; Bristol-Meyers-Squibb [Arrhythmias]; Daiichi Sankyo [Arrhythmias]; Gilead [Arrhythmias]; Huya [Arrhythmias]; InCarda Therapeutics [Arrhythmias]; INSTA [Arrhythmias]; Johnson & Johnson [Arrhythmias]; Medtronic [Arrhythmias]; Milestone [Arrhythmias]; Novartis [Arrhythmias, cardiac safety of non-cardiac drugs]; Pfizer [Arrhythmias]; Sanofi [Arrhythmias]; Takeda [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/upright-tilt-table-testing-in-the-evaluation-of-syncope/print 22/22

7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Amiodarone: Clinical uses : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA, Rod Passman, MD, MSCE : Samuel L vy, MD, Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 30, 2022. INTRODUCTION Amiodarone is an iodinated benzofuran derivative that was synthesized and tested as an antianginal agent in the 1960s but was later discovered to have antiarrhythmic properties. Amiodarone is widely prescribed, largely due to its efficacy in the management of both supraventricular and ventricular arrhythmias. In addition to the superior efficacy compared with most other antiarrhythmic drugs, amiodarone has very little negative inotropic activity and a low rate of ventricular proarrhythmia, making it advantageous for use in patients with heart failure [1]. Despite these advantages, the use of amiodarone is associated with a relatively high incidence of side effects, making it a complicated drug to use safely. This topic will review the electrophysiologic properties of amiodarone, clinical indications, and dosing recommendations for oral and intravenous amiodarone. The side effects of amiodarone are discussed in detail elsewhere. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Amiodarone and thyroid dysfunction".) PHARMACOKINETICS Slow and wide distribution of amiodarone to tissue (fat, muscle, highly perfused organs) results in a requirement of long loading periods in an effort to accelerate the onset of drug activity. Oral amiodarone is markedly lipophilic, resulting in a very large volume of distribution (average approximately 66 L/kg) and a prolonged time to reach stable plasma levels [1]. It is incompletely absorbed (approximately 30 to 70 percent) after oral administration and is taken up very https://www.uptodate.com/contents/amiodarone-clinical-uses/print 1/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate extensively by tissue, with marked interindividual variation [2]. Because of these characteristics, even with loading, arrhythmia recurrence during the first months of therapy does not necessarily predict long-term efficacy. Conversely, intravenous (IV) amiodarone begins to act within one hour, with rapid onset of action within minutes following an IV bolus. Estimates of the elimination half-life of amiodarone vary, depending on how the half-life has been measured and the route of amiodarone administration. After long-term oral therapy, amiodarone has a true elimination half-life between 60 and 142 days [2,3]. The relatively short half-life for disappearance of amiodarone from plasma after a single- dose or short-term IV administration is likely a measure of drug redistribution from vascular space into tissue and not true body elimination. There is little correlation between the plasma concentration of amiodarone or its major active metabolite, desethylamiodarone, and drug efficacy or toxicity [1]. ELECTROPHYSIOLOGIC PROPERTIES The electrophysiologic properties of amiodarone are complex and incompletely understood. Though classified as a Vaughan-Williams class III antiarrhythmic agent due to its inhibition of outward potassium channels, the drug also has class I sodium channel blocking effects, class II antiadrenergic effects, and class IV calcium channel blocking effects ( table 1). The oral and intravenous (IV) forms of amiodarone have important electrophysiologic differences that have an impact on their clinical use ( table 2). Oral amiodarone Oral amiodarone is classified as a class III antiarrhythmic agent since it prolongs the duration of the action potential and the refractory period of both atrial and ventricular tissue ( figure 1). This effect is primarily mediated by blockade of the rapid component of the delayed rectifier current (IKr) that is responsible for phase 3 repolarization of the action potential ( figure 2). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Like other class III agents (sotalol, dofetilide, ibutilide, dronedarone), amiodarone prolongs the QT interval. However, by contrast to most other class III agents, amiodarone has very little proarrhythmic activity. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 2/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Oral amiodarone has several other effects that may contribute to its therapeutic efficacy: It inhibits inactivated (phase 0) sodium channels, an effect that is primarily seen at rapid heart rates It has some class II antiarrhythmic drug activity, inhibiting sympathetic activity, primarily by causing noncompetitive beta receptor blockade It also has some class IV antiarrhythmic drug activity by blocking L-type (slow) calcium channels Intravenous amiodarone IV amiodarone has a number of important electrophysiologic differences from chronically administered oral amiodarone [4,5]: IV amiodarone produces a much smaller increase in the action potential duration in atrial and ventricular myocardium and a minimal increase in the atrial and ventricular refractory periods. As a result, there is little or no increase in QRS duration or the QT interval, respectively. IV amiodarone has little effect on sinus cycle length. It has vasodilator activity that triggers an increase in sympathetic activity, and as a result, there is little or no slowing of the sinus rate. IV amiodarone may have more potent and more rapid antiadrenergic activity. Like oral amiodarone, IV amiodarone inhibits inactivated sodium channels, though to a lesser degree than the oral form [4]. This property may account for the efficacy of the agent in the suppression of ventricular tachyarrhythmias [6]. IV amiodarone also prolongs atrioventricular (AV) nodal conduction and refractoriness and may be effective in slowing the ventricular rate in critically ill patients with atrial tachyarrhythmias [7]. Effects on the ECG The multiple actions of chronically administered oral amiodarone therapy can produce a variety of changes in the electrocardiogram (ECG). These include: Slowing of the sinus rate. Both calcium channel blockade and beta blockade may contribute to this effect, which can lead to sinus bradycardia [5]. Prolongation of the PR interval and the AV nodal refractory period. Thus, AV conduction block may occur, an effect that may also be related to calcium channel blockade since the AV node is a "slow response" tissue that relies on an inward calcium current for depolarization. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Action potential in slow response tissues'.) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 3/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Widening of the QRS complex (typically less than 10 percent), as conduction is slowed in ventricular muscle by the blocking effect on the inactivated sodium channel, thereby slowing phase 0 depolarization ( figure 1) [8]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Prolongation of the QT interval (typically less than 10 percent) due to blockade of IKr, the delayed rectifier potassium current that is responsible for phase 3 depolarization of the action potential ( figure 1) [8,9]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.) ORAL AMIODARONE FOR THE TREATMENT OF ATRIAL ARRHYTHMIAS Amiodarone can be used to treat most types of atrial arrhythmias but is used primarily to maintain normal sinus rhythm in patients with atrial fibrillation (AF). However, oral amiodarone is not FDA approved in the United States for rhythm control in AF, despite common usage for this indication. It is commonly used for several reasons: Amiodarone is the most effective medical therapy available for maintaining sinus rhythm There is a low risk of ventricular proarrhythmia based on the electrophysiologic properties of amiodarone Amiodarone does not increase mortality in heart failure patients Therapy can be easily initiated on an outpatient basis In addition, if AF recurs, amiodarone usually slows the ventricular response at rest and with exercise. It also may reduce symptoms associated with rapid ventricular response to AF, though amiodarone is not recommended solely as a rate-controlling agent. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Amiodarone'.) Amiodarone can be used to treat other atrial arrhythmias such as atrial flutter or atrial tachycardia, but the availability of other antiarrhythmic drugs with lower toxicity rates, and the high success rates of ablative approaches to atrial flutter or atrial tachycardia, often favors these alternatives. The major limiting factor in the use of oral amiodarone for the treatment of AF and other atrial arrhythmias is long-term organ toxicity (eg, thyroid, lung, etc) ( table 3). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Prevention of recurrent paroxysmal atrial fibrillation The decision to pursue a strategy of rhythm control in any patient with AF is complex and depends on: https://www.uptodate.com/contents/amiodarone-clinical-uses/print 4/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate The presence or absence of symptoms Potential adverse effects of persistent AF (ie, uncontrolled ventricular rate) Adverse effects of alternative therapies for AF The choice of which antiarrhythmic drug to use for paroxysmal AF is also complex and based on a variety of factors, most notably the presence and type of structural heart disease. Unlike many other antiarrhythmic drugs, amiodarone has a low risk of ventricular proarrhythmia and does not increase mortality when administered to patients with coronary disease, left ventricular (LV) hypertrophy, LV dysfunction, or congestive heart failure. While there is no universally accepted dosing regimen, oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used ( table 4) [10]. Gastrointestinal side effects may limit loading doses. The usual maintenance dose should be the lowest effective dose, which for AF is usually 200 mg daily but can sometimes be as low as 100 mg daily. Doses up to 400 mg/day may also be used but are not recommended for routine maintenance given the higher risk of adverse events. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Pharmacologic cardioversion of atrial fibrillation Amiodarone is not a first-line therapy for pharmacologic cardioversion given its limited efficacy and long onset of action. If amiodarone is used in this setting, American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines recommend oral loading and maintenance doses to be the same as those described for amiodarone use to prevent recurrence and maintain sinus rhythm in patients with paroxysmal AF. (See 'Prevention of recurrent paroxysmal atrial fibrillation' above.) Oral amiodarone can result in pharmacologic cardioversion of AF in approximately 25 percent of patients with high ventricular rates from either acute or recent-onset AF [10-12]. Because of the potential for cardioversion following administration of amiodarone, standard precautions need to be considered to prevent thromboembolic events. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Amiodarone and other pharmacologic agents for cardioversion are reviewed separately. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.) Pretreatment before elective cardioversion or catheter ablation for persistent atrial fibrillation In patients who did not remain in sinus rhythm following cardioversion or in patients at high risk for recurrent AF after planned cardioversion, we often pretreat with an antiarrhythmic drug, including amiodarone [13]. Given the prolonged half-life of oral https://www.uptodate.com/contents/amiodarone-clinical-uses/print 5/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate amiodarone, the loading time is extended, so the drug should be started two to six weeks prior to elective cardioversion to reduce the risk of recurrence. Dosing regimens vary ( table 4) but generally aim for an oral load of 6 to 10 grams over a period of two to six weeks prior to cardioversion, with a decrease in dose to maintenance levels (usually 100 to 200 mg daily) following cardioversion or shortly thereafter. Given the unique pharmacologic properties of amiodarone, AF recurrences in the first two to three months following cardioversion do not necessarily predict long-term failure of the drug. (See "Atrial fibrillation: Cardioversion", section on 'Preprocedural antiarrhythmic drugs'.) Oral amiodarone has also been investigated in patients undergoing catheter ablation for persistent AF. In the AMIO-CAT trial, in which 212 patients undergoing AF ablation were randomized to begin therapy with amiodarone or placebo for eight weeks following catheter ablation, there was a nonsignificant trend toward fewer recurrences of AF in the amiodarone group (39 versus 48 percent), but significantly fewer patients receiving amiodarone required hospitalization or cardioversion for recurrent AF [14]. In the SPECULATE trial, in which 112 patients with long-standing persistent AF were randomized to discontinuation of chronic amiodarone therapy four months prior to ablation or continuation of therapy and then followed for an average of 32 months, significantly more patients who continued amiodarone had successful termination of AF at the time of ablation (79 versus 57 percent); however, late AF recurrence was significantly greater in the group who continued amiodarone [15]. Further investigation is needed to determine the optimal role for amiodarone in patients undergoing AF ablation. Prophylaxis against atrial fibrillation following cardiac surgery Amiodarone lowers the incidence of postoperative AF in patients undergoing cardiac surgery [10]. Various dosing regimens for oral amiodarone have been used in clinical trials [16,17]. In general, however, we recommend beta blockers rather than amiodarone; however, for patients who cannot take beta blockers, amiodarone may be used. The approach to prevention of AF following cardiac surgery is discussed in detail separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Amiodarone'.) INTRAVENOUS AMIODARONE FOR THE TREATMENT OF ATRIAL ARRHYTHMIAS https://www.uptodate.com/contents/amiodarone-clinical-uses/print 6/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Intravenous (IV) amiodarone is primarily used for the treatment of atrial arrhythmias in two settings: Restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable atrial fibrillation (AF). Rate control in critically ill patients with AF with rapid ventricular response in whom the tachycardia is contributing to hemodynamic compromise. The administration of IV amiodarone requires attention to a specific dosing schedule to minimize side effects, which are largely different from those seen with chronic oral therapy. In addition, there is substantial interindividual variability in response time; as a result, careful patient observation and dose adjustment are recommended as necessary. Amiodarone should be mixed in a 5 percent dextrose solution and the amiodarone concentration kept below 2 mg/mL if given through a peripheral vein to minimize the development of local phlebitis. Higher drug concentrations must be delivered through an indwelling catheter in a central vein. Amiodarone is physically incompatible with a number of drugs, including heparin, which should not be given in the same solution. (See 'Side effects with IV administration' below.) Restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable atrial fibrillation AF is common in critically ill patients and may contribute to hemodynamic instability. IV amiodarone can be used in this situation but has not been sufficiently studied in this population to allow for specific recommendations. When administered ( table 4), an initial IV loading dose of 150 mg is given over a minimum of 10 minutes. More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter [1]. This regimen delivers 1050 mg of amiodarone in the first 24 hours. In general, the reported efficacy of IV amiodarone in restoring and maintaining sinus rhythm is inconsistent, though professional society guidelines list IV amiodarone as an option for pharmacologic cardioversion [10]. (See "Atrial fibrillation: Cardioversion", section on 'Indications'.) Several meta-analyses have been published evaluating the efficacy of IV amiodarone in restoration of normal sinus rhythm in critically ill patients [18-20]. The meta-analyses have included studies with widely varying methodologies, leading to some conflicting results. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 7/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate The largest meta-analysis included studies comparing amiodarone with other antiarrhythmic drugs or placebo [19]. IV amiodarone was as efficacious as other antiarrhythmic drugs and more effective than placebo, but amiodarone was associated with a higher rate of adverse events compared with placebo. Another meta-analysis, which included only studies comparing amiodarone with placebo or class Ic antiarrhythmic drugs, determined that conversion from AF to sinus rhythm was greater at 8 and 24 hours, but not at one or two hours [20]. Conversion rates from AF to sinus rhythm following IV amiodarone are higher when the bolus (3 to 7 mg/kg) is followed by continuous infusion (900 to 3000 mg daily) [18]. Ventricular rate control in critically ill patients with atrial fibrillation and rapid ventricular response IV amiodarone may be used as a rate-controlling agent in critically ill individuals with hemodynamically destabilizing AF who cannot be maintained in sinus rhythm and in whom standard rate-controlling therapies have been either unsuccessful or are contraindicated due to hypotension. An initial IV loading dose of 150 mg is given over a minimum of 10 minutes ( table 4). More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter [1]. This regimen delivers 1050 mg of amiodarone in the first 24 hours. Repeated 150 mg boluses can be given over 10 to 30 minutes, but no more than six to eight additional boluses should be administered in any 24-hour period. AF with rapid ventricular response may contribute to hemodynamic compromise. Furthermore, ventricular rates >120 beats/minute for prolonged periods of time may contribute to left ventricular dysfunction. In a retrospective study, intensive care unit patients with hemodynamically destabilizing AF or atrial flutter resistant to conventional therapy experienced a significant 37 beat/minute decrease in ventricular rate and an increase in systolic blood pressure of 24 mmHg with no associated adverse effects [7]. IV amiodarone may also be used for rate control in patients with congestive heart failure [10]. AMIODARONE FOR VENTRICULAR ARRHYTHMIAS Amiodarone is useful in a variety of ventricular arrhythmias including ventricular premature beats (VPBs), nonsustained ventricular tachycardia (VT), and sustained VT or ventricular fibrillation (VF). Most commonly, amiodarone is used for the secondary prevention of recurrent ventricular arrhythmias in patients with an implantable cardioverter-defibrillator (ICD) to reduce the frequency of ICD shocks. Typically, a beta blocker is co-administered with amiodarone. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 8/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Treatment of ventricular arrhythmias Amiodarone suppresses VPBs and episodes of nonsustained VT. This is clearly demonstrated in several of the primary prevention trials of amiodarone in post-myocardial infarction (MI) and congestive heart failure patients in whom baseline and follow-up 24-hour ambulatory ECGs were performed. As examples: The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) pilot study enrolled patients with frequent or repetitive asymptomatic ventricular premature depolarizations (VPDs) [21]. When compared with placebo, patients receiving amiodarone had much greater suppression of VPDs and nonsustained VT (86 compared with 50 percent of placebo patients). The CHF-STAT trial compared amiodarone versus placebo in patients with heart failure, left ventricular (LV) ejection fraction of 40 percent or less, and frequent VPBs (more than 10/hour) [22]. Following two weeks of treatment, significantly fewer patients on amiodarone had VT on Holter monitor (33 versus 76 percent). Despite the reduction in ventricular arrhythmias and ectopy, amiodarone did not reduce mortality. Additional trials are reviewed in detail elsewhere. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Amiodarone is also one of the few antiarrhythmic drugs that does not increase mortality when given to patients with moderate to severe LV dysfunction. The apparent efficacy and safety of amiodarone for the treatment of ventricular tachyarrhythmias in patients with structural heart disease have led to several studies evaluating the impact of amiodarone on survival in patients at high risk of arrhythmic death. Primary prevention of sudden cardiac death Amiodarone for primary prevention of sudden cardiac death (SCD) is generally considered only for patients with LV dysfunction who are not candidates for, or refuse to have, ICD implantation [23]. When administered ( table 4), the recommended loading dose for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams [1]. Higher loading dose regimens have been evaluated but do not appear to provide greater efficacy. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects. Ventricular arrhythmias are responsible for a large proportion of SCDs, especially in those individuals with underlying structural heart disease. The ability of amiodarone to suppress ventricular arrhythmias led to several trials designed to assess its effect on patients deemed high risk for ventricular arrhythmias either because they have already survived a sustained ventricular tachyarrhythmia or were believed to be at high risk of developing such arrhythmias due to the presence of LV dysfunction. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 9/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Earlier studies comparing amiodarone with standard medical therapy generally enrolled patients with either recent MI or congestive heart failure [2]. A 2015 Cochrane systematic review and meta-analysis (based on low to moderate quality evidence) concluded that, compared with placebo or no intervention, amiodarone reduced SCD (risk ratio [RR] 0.76, 95% CI 0.66-0.88), total cardiac death (RR 0.86, 95% CI 0.77-0.96), and all-cause mortality (RR 0.88, 95% CI 0.78-1.00) [24]. In trials comparing amiodarone with ICD therapy, ICD therapy was superior in the primary prevention of SCD [25,26]. Because of this, amiodarone for primary prevention of SCD is rarely used without concurrent use of an ICD. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Secondary prevention of sudden cardiac death In view of the superiority of ICD compared with antiarrhythmic drugs, including amiodarone, for the secondary prevention of SCD, amiodarone should not be used alone for secondary prevention except in those who do not meet ICD criteria, or in those who meet criteria but cannot receive a device or refuse device implantation. When administered ( table 4), the recommended loading dose for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams [1]. Higher loading dose regimens have been evaluated but do not appear to provide greater efficacy. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects. Survivors of SCD due to arrhythmia carry a high risk of recurrence. With the possible exception of amiodarone, attempts to significantly reduce SCD rates by using antiarrhythmic drugs have yielded disappointing results, most likely related to the proarrhythmic effects of many antiarrhythmic drugs. The recognition of the limitations of antiarrhythmic drugs for secondary prevention was paralleled by the development of smaller, transvenous ICDs with tiered therapies, bradycardia pacing, and success rates of >95 percent in terminating VT and VF. Several randomized trials and meta-analyses have compared ICDs with antiarrhythmic drugs for secondary prevention of SCD in patients with resuscitated VF, sustained VT with syncope, or sustained VT with ejection fraction 40 percent, and evidence of hemodynamic compromise. All showed superior efficacy of ICD compared with antiarrhythmic drugs. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Prevention of ventricular arrhythmias in patients with ICDs Shocks delivered by an ICD, especially when repetitive, can be painful and impact quality of life [27]. Amiodarone may be used to decrease the risk of ICD shocks. When administered ( table 4), the recommended loading dose for the prevention of ICD shocks is 400 to 1200 mg/day (usually in divided doses) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 10/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate for a total of 6 to 10 grams [23,28]. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects. The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) Study evaluated amiodarone plus beta blocker, sotalol alone, and beta blocker alone for the prevention of ICD shocks in 412 patients [29]. Amiodarone plus beta blocker significantly reduced the risk of shock compared with beta blocker alone (hazard ratio [HR] 0.27, 95% CI 0.14- 0.52) or sotalol alone (HR 0.43, 95% CI 0.22-0.85). In the SURVIVE-VT trial, patients with ischemic cardiomyopathy and appropriate ICD shocks who were randomly assigned antiarrhythmic drugs, including amiodarone, were more likely to experience the composite endpoint (including cardiovascular death, appropriate ICD shock, heart failure hospitalization, or severe treatment- related complications), compared with those treated with ablation (HR 0.52, 95%CI 0.30-0.90). (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Antiarrhythmic drugs'.) When using amiodarone in patients with ICDs, reassessment of defibrillation threshold may be necessary in those individuals with marginally acceptable defibrillation threshold prior to drug initiation [30]. Additionally, care must be taken in device programming as amiodarone may slow the rate of VT such that the cycle length of spontaneous VT falls outside of the programmed limits (heart rate or cycle length) for detection of VT. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Increased defibrillation threshold'.) IV amiodarone for the treatment of electrical storm and incessant ventricular tachycardia The use of IV amiodarone in the treatment of electrical storm and incessant VT is discussed separately. (See "Electrical storm and incessant ventricular tachycardia".) IV amiodarone during resuscitation from cardiac arrest The administration of IV amiodarone as part of the advanced cardiac life support protocol for resuscitation of cardiac arrest is discussed separately. (See "Advanced cardiac life support (ACLS) in adults".) SPECIAL CONSIDERATIONS Side effects with IV administration A major problem noted with the intravenous (IV) preparation is hypotension, which occurs in as many as 26 percent of patients and has been attributed to faster loading rates as well as the solvents used in the preparation [6,31]. Hypotension does not appear to occur with a preparation of amiodarone that employs an aqueous base [32]. Patients who develop hypotension may benefit from a decrease in the infusion rate, while additional IV boluses may be beneficial in patients with recurrent arrhythmias during the early phase of therapy [1,7]. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 11/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Proarrhythmia has been noted in 2 to 3 percent of patients treated with intravenous amiodarone; it usually manifests as torsades de pointes, but ventricular fibrillation can occur [4,6]. In a multicenter study in which 6 of 342 patients developed proarrhythmia, all had an exacerbating factor such as acute ischemia or an electrolyte imbalance [6]. Other cardiac side effects (bradycardia, asystole, heart failure, and shock), nausea, vomiting, and abnormal liver function tests occurred in 1 to 5 percent of patients each [4,6]. When given through peripheral intravenous lines, amiodarone may cause local phlebitis [33,34]. The risk of amiodarone-induced phlebitis increases with higher infusion rates and higher concentrations (eg, >2 mg/mL). The risk of phlebitis can be reduced by using lower infusion rates (when possible), lower concentrations (<2 mg/mL), or an in-line filter [35]. Transition from IV to oral therapy The bioavailability of oral compared with intravenous amiodarone ranges from 30 to 70 percent and is increased in the presence of food. Additionally, an increase in plasma levels may not be seen for four to five hours after the ingestion of oral amiodarone. We suggest the following approach to converting IV to oral amiodarone dosing: Patients who have been on IV therapy for more than two weeks can be started on maintenance oral amiodarone at a dose of 200 to 400 mg/day. Patients who have been on IV therapy for one to two weeks can be started on an intermediate amiodarone dose of 400 to 800 mg/day. This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day. Patients who have been on IV therapy for one week or less should probably receive the usual oral amiodarone loading dose of 400 to 1200 mg/day (typically in two divided doses). This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day. Both oral and IV therapy can be given concurrently for a few days if there is a concern about gastrointestinal tract function. Dose adjustment Amiodarone is metabolized in the liver. The major metabolite is desethylamiodarone, which is active and has a longer elimination half-life than amiodarone [1]. Dose reduction is probably necessary in patients with significant hepatic disease. By comparison, there is minimal elimination of both amiodarone and desethylamiodarone by the kidneys due both to the large volume of distribution and extensive protein binding; the latter effect also minimizes drug removal by dialysis. As a result, the dose of amiodarone does not have to be reduced in patients with renal disease or in patients undergoing dialysis. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 12/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Drug interactions Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Interactions with other drugs, such as digoxin and warfarin, must be considered. A few key drug interactions are discussed separately in UpToDate. Additionally, specific interactions of amiodarone with other medications may be determined using the Lexicomp drug interactions tool. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse drug interactions'.) Use in children The overall safety and efficacy of amiodarone in children have not been fully established. Use of amiodarone in the treatment of tachyarrhythmias in children has been reported in several small series and one small clinical trial [36]. Although amiodarone is effective for number of arrhythmias, its use in children is often limited by toxicities. Adverse events are common with IV amiodarone use in children and may be severe. Consultation with a pediatric cardiologist is advised. Severe adverse effects may include cardiovascular collapse, hypotension, bradycardia, and AV block. Nausea and vomiting are also common. ECG and blood pressure monitoring should be performed during administration of IV amiodarone. Amiodarone appears to be effective in the following circumstances: Supraventricular tachycardia (SVT) In children with refractory SVT, IV amiodarone is an option as second-line therapy for conversion to sinus rhythm. Use of IV amiodarone in this setting is generally limited to treatment of SVT that is refractory to other agents (adenosine, procainamide), and oral amiodarone is a second-line therapy for the prevention of recurrent arrhythmia. In children with frequent or symptomatic SVT episodes, oral amiodarone is sometimes used for chronic management if there is a poor response to first- and second-line agents (eg, beta blockers, digoxin, and sotalol). (See "Management of supraventricular tachycardia (SVT) in children".) Wide QRS complex tachycardia IV amiodarone has also been used, alone or in combination with other antiarrhythmic drugs, in infants and children with resistant, life- threatening ventricular tachyarrhythmias [37,38]. (See "Management and evaluation of wide QRS complex tachycardia in children", section on 'Shock-resistant tachyarrhythmia'.) Optimal dosing of amiodarone in children is not well established. For oral therapy, dosing is based upon body weight or, in children less than one year of age, upon body surface area. The loading dose, which can be given in one or two divided 2 doses per day, is 10 to 15 mg/kg per day or 600 to 800 mg/1.73 m per day for 4 to 14 days or until adequate control of the arrhythmia is attained or prominent adverse effects occur. 2 The dose should then be reduced to 5 mg/kg per day or 200 to 400 mg/1.73 m per day https://www.uptodate.com/contents/amiodarone-clinical-uses/print 13/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate once daily for several weeks. If the arrhythmia does not recur, the lowest effective dose should be used for maintenance. The usual minimal dose is 2.5 mg/kg per day. For IV therapy in critically ill children with tachyarrhythmias who have not responded to standard therapy, a variety of regimens have been used. We typically give a slow bolus infusion of 5 mg/kg (maximum dose 300 mg) IV over 20 to 60 minutes. If the patient does not convert to sinus rhythm, additional bolus doses of 1 to 5 mg/kg (up to a total of 15 mg/kg) can be given if there are no signs of toxicity (eg, hypotension, prolonged QT interval). This can be followed, if necessary, by a continuous infusion at a rate of 5 to 10 mcg/kg per minute. Use in pregnancy Amiodarone has unique characteristics that mandate cautious use in pregnancy. The complications that can occur with the use of amiodarone during pregnancy are: Hypothyroidism or hyperthyroidism in the mother or fetus because of the iodine in amiodarone Fetal bradycardia Fetal QT interval prolongation Premature labor Low birth weight In addition, amiodarone is found in fetal tissue and breast milk. For these reasons, the use of amiodarone in pregnancy should be reserved for maternal and fetal arrhythmias not responding to agents with known safety. Concomitant beta-blocker therapy should be avoided. Breast feeding is not recommended when the mother is taking amiodarone. (See "Supraventricular arrhythmias during pregnancy" and "Maternal conduction disorders and bradycardia during pregnancy".) Neonates of mothers taking amiodarone should have complete thyroid function tests and developmental follow-up. (See "Clinical features and detection of congenital hypothyroidism".) SIDE EFFECTS While amiodarone does have many potential benefits, side effects are a serious concern. Of greatest concern are potential toxicities involving the lungs, thyroid, liver, eyes, and skin ( table 3). The potential side effects related to amiodarone use are discussed in detail separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 14/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Electrocardiographic actions Amiodarone has various electrophysiologic properties that are favorable in the treatment of tachyarrhythmias. There are important differences in these properties between the oral and intravenous (IV) preparations. (See 'Electrophysiologic properties' above.) Amiodarone can slow the sinus heart rate, prolong the PR interval, widen the QRS complex, and prolong the QT interval on surface electrocardiogram. (See 'Effects on the ECG' above.) Treatment of atrial arrythmias Oral amiodarone This can be used to treat most types of atrial arrhythmias but is used primarily to maintain normal sinus rhythm in patients with atrial fibrillation (AF). However, oral amiodarone is not FDA approved in the United States for rhythm control in AF, despite common usage for this indication. While there is no universally accepted dosing regimen ( table 4), oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used. The usual maintenance dose should be the lowest effective dose, which for AF is usually 200 mg daily but can

usual oral amiodarone loading dose of 400 to 1200 mg/day (typically in two divided doses). This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day. Both oral and IV therapy can be given concurrently for a few days if there is a concern about gastrointestinal tract function. Dose adjustment Amiodarone is metabolized in the liver. The major metabolite is desethylamiodarone, which is active and has a longer elimination half-life than amiodarone [1]. Dose reduction is probably necessary in patients with significant hepatic disease. By comparison, there is minimal elimination of both amiodarone and desethylamiodarone by the kidneys due both to the large volume of distribution and extensive protein binding; the latter effect also minimizes drug removal by dialysis. As a result, the dose of amiodarone does not have to be reduced in patients with renal disease or in patients undergoing dialysis. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 12/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Drug interactions Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Interactions with other drugs, such as digoxin and warfarin, must be considered. A few key drug interactions are discussed separately in UpToDate. Additionally, specific interactions of amiodarone with other medications may be determined using the Lexicomp drug interactions tool. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse drug interactions'.) Use in children The overall safety and efficacy of amiodarone in children have not been fully established. Use of amiodarone in the treatment of tachyarrhythmias in children has been reported in several small series and one small clinical trial [36]. Although amiodarone is effective for number of arrhythmias, its use in children is often limited by toxicities. Adverse events are common with IV amiodarone use in children and may be severe. Consultation with a pediatric cardiologist is advised. Severe adverse effects may include cardiovascular collapse, hypotension, bradycardia, and AV block. Nausea and vomiting are also common. ECG and blood pressure monitoring should be performed during administration of IV amiodarone. Amiodarone appears to be effective in the following circumstances: Supraventricular tachycardia (SVT) In children with refractory SVT, IV amiodarone is an option as second-line therapy for conversion to sinus rhythm. Use of IV amiodarone in this setting is generally limited to treatment of SVT that is refractory to other agents (adenosine, procainamide), and oral amiodarone is a second-line therapy for the prevention of recurrent arrhythmia. In children with frequent or symptomatic SVT episodes, oral amiodarone is sometimes used for chronic management if there is a poor response to first- and second-line agents (eg, beta blockers, digoxin, and sotalol). (See "Management of supraventricular tachycardia (SVT) in children".) Wide QRS complex tachycardia IV amiodarone has also been used, alone or in combination with other antiarrhythmic drugs, in infants and children with resistant, life- threatening ventricular tachyarrhythmias [37,38]. (See "Management and evaluation of wide QRS complex tachycardia in children", section on 'Shock-resistant tachyarrhythmia'.) Optimal dosing of amiodarone in children is not well established. For oral therapy, dosing is based upon body weight or, in children less than one year of age, upon body surface area. The loading dose, which can be given in one or two divided 2 doses per day, is 10 to 15 mg/kg per day or 600 to 800 mg/1.73 m per day for 4 to 14 days or until adequate control of the arrhythmia is attained or prominent adverse effects occur. 2 The dose should then be reduced to 5 mg/kg per day or 200 to 400 mg/1.73 m per day https://www.uptodate.com/contents/amiodarone-clinical-uses/print 13/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate once daily for several weeks. If the arrhythmia does not recur, the lowest effective dose should be used for maintenance. The usual minimal dose is 2.5 mg/kg per day. For IV therapy in critically ill children with tachyarrhythmias who have not responded to standard therapy, a variety of regimens have been used. We typically give a slow bolus infusion of 5 mg/kg (maximum dose 300 mg) IV over 20 to 60 minutes. If the patient does not convert to sinus rhythm, additional bolus doses of 1 to 5 mg/kg (up to a total of 15 mg/kg) can be given if there are no signs of toxicity (eg, hypotension, prolonged QT interval). This can be followed, if necessary, by a continuous infusion at a rate of 5 to 10 mcg/kg per minute. Use in pregnancy Amiodarone has unique characteristics that mandate cautious use in pregnancy. The complications that can occur with the use of amiodarone during pregnancy are: Hypothyroidism or hyperthyroidism in the mother or fetus because of the iodine in amiodarone Fetal bradycardia Fetal QT interval prolongation Premature labor Low birth weight In addition, amiodarone is found in fetal tissue and breast milk. For these reasons, the use of amiodarone in pregnancy should be reserved for maternal and fetal arrhythmias not responding to agents with known safety. Concomitant beta-blocker therapy should be avoided. Breast feeding is not recommended when the mother is taking amiodarone. (See "Supraventricular arrhythmias during pregnancy" and "Maternal conduction disorders and bradycardia during pregnancy".) Neonates of mothers taking amiodarone should have complete thyroid function tests and developmental follow-up. (See "Clinical features and detection of congenital hypothyroidism".) SIDE EFFECTS While amiodarone does have many potential benefits, side effects are a serious concern. Of greatest concern are potential toxicities involving the lungs, thyroid, liver, eyes, and skin ( table 3). The potential side effects related to amiodarone use are discussed in detail separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 14/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Electrocardiographic actions Amiodarone has various electrophysiologic properties that are favorable in the treatment of tachyarrhythmias. There are important differences in these properties between the oral and intravenous (IV) preparations. (See 'Electrophysiologic properties' above.) Amiodarone can slow the sinus heart rate, prolong the PR interval, widen the QRS complex, and prolong the QT interval on surface electrocardiogram. (See 'Effects on the ECG' above.) Treatment of atrial arrythmias Oral amiodarone This can be used to treat most types of atrial arrhythmias but is used primarily to maintain normal sinus rhythm in patients with atrial fibrillation (AF). However, oral amiodarone is not FDA approved in the United States for rhythm control in AF, despite common usage for this indication. While there is no universally accepted dosing regimen ( table 4), oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used. The usual maintenance dose should be the lowest effective dose, which for AF is usually 200 mg daily but can sometimes be as low as 100 mg daily. (See 'Oral amiodarone for the treatment of atrial arrhythmias' above.) IV amiodarone This is primarily used for the treatment of atrial arrhythmias in two settings: restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable AF, and rate control in critically ill patients with AF with rapid ventricular response in whom the tachycardia is contributing to hemodynamic compromise. An initial IV loading dose of 150 mg is given over a minimum of 10 minutes ( table 4). More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter. (See 'Intravenous amiodarone for the treatment of atrial arrhythmias' above.) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 15/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Treatment of ventricular arrythmias Amiodarone is useful in a variety of ventricular arrhythmias but is most commonly used for the secondary prevention of recurrent ventricular arrhythmias in patients, including patients with an implantable cardioverter- defibrillator (ICD) to reduce the frequency of ICD shocks. The recommended loading dose ( table 4) for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams (except for secondary prevention of ICD shocks, when the loading dose is typically 8 to 10 grams). Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects. (See 'Amiodarone for ventricular arrhythmias' above.) In the context of implantable cardioverter-defibrillators Despite its effectiveness in reducing ventricular tachyarrhythmias, amiodarone has been shown to be inferior to ICDs in reducing mortality in both primary and secondary prevention studies of patients at high risk for sudden cardiac death. Thus, the use of amiodarone in this setting should be reserved for patients who are candidates for an ICD but who cannot or refuse to have an ICD implanted. (See 'Primary prevention of sudden cardiac death' above and 'Secondary prevention of sudden cardiac death' above.) Transition from IV to oral dosing The dosing of amiodarone following conversion from IV to oral administration varies according to the duration of IV treatment prior to conversion. (See 'Transition from IV to oral therapy' above.) Drug interactions and side effects Amiodarone has the potential for numerous drug interactions and side effects ( table 3) that require monitoring. (See 'Drug interactions' above and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Goldschlager N, Epstein AE, Naccarelli GV, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4:1250. 2. Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety. Circulation 1999; 100:2025. 3. Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA 2007; 298:1312. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 16/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate 4. Desai AD, Chun S, Sung RJ. The role of intravenous amiodarone in the management of cardiac arrhythmias. Ann Intern Med 1997; 127:294. 5. Gomes JA, Kang PS, Hariman RJ, et al. Electrophysiologic effects and mechanisms of termination of supraventricular tachycardia by intravenous amiodarone. Am Heart J 1984; 107:214. 6. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995; 92:3264. 7. Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Intravenous amiodarone for acute heart rate control in the critically ill patient with atrial tachyarrhythmias. Am J Cardiol 1998; 81:594. 8. Aiba T, Shimizu W, Inagaki M, et al. Excessive increase in QT interval and dispersion of repolarization predict recurrent ventricular tachyarrhythmia after amiodarone. Pacing Clin Electrophysiol 2004; 27:901. 9. Kamiya K, Nishiyama A, Yasui K, et al. Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K(+) current. Circulation 2001; 103:1317. 10. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 11. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 12. Lei LY, Chew DS, Lee W, et al. Pharmacological Cardioversion of Atrial Tachyarrhythmias Using Single High-Dose Oral Amiodarone: A Systematic Review and Meta-Analysis. Circ Arrhythm Electrophysiol 2021; 14:e010321. 13. Um KJ, McIntyre WF, Mendoza PA, et al. Pre-treatment with antiarrhythmic drugs for elective electrical cardioversion of atrial fibrillation: a systematic review and network meta-analysis. Europace 2022; 24:1548. 14. Darkner S, Chen X, Hansen J, et al. Recurrence of arrhythmia following short-term oral AMIOdarone after CATheter ablation for atrial fibrillation: a double-blind, randomized, placebo-controlled study (AMIO-CAT trial). Eur Heart J 2014; 35:3356. 15. Mohanty S, Di Biase L, Mohanty P, et al. Effect of periprocedural amiodarone on procedure outcome in patients with longstanding persistent atrial fibrillation undergoing extended pulmonary vein antrum isolation: results from a randomized study (SPECULATE). Heart Rhythm 2015; 12:477. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 17/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate 16. Daoud EG, Strickberger SA, Man KC, et al. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med 1997; 337:1785. 17. Giri S, White CM, Dunn AB, et al. Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): a randomised placebo- controlled trial. Lancet 2001; 357:830. 18. Khan IA, Mehta NJ, Gowda RM. Amiodarone for pharmacological cardioversion of recent- onset atrial fibrillation. Int J Cardiol 2003; 89:239. 19. Hilleman DE, Spinler SA. Conversion of recent-onset atrial fibrillation with intravenous amiodarone: a meta-analysis of randomized controlled trials. Pharmacotherapy 2002; 22:66. 20. Chevalier P, Durand-Dubief A, Burri H, et al. Amiodarone versus placebo and class Ic drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis. J Am Coll Cardiol 2003; 41:255. 21. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 1997; 349:675. 22. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995; 333:77. 23. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 24. Claro JC, Candia R, Rada G, et al. Amiodarone versus other pharmacological interventions for prevention of sudden cardiac death. Cochrane Database Syst Rev 2015; :CD008093. 25. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996; 335:1933. 26. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999; 341:1882. 27. Passman R, Subacius H, Ruo B, et al. Implantable cardioverter defibrillators and quality of life: results from the defibrillators in nonischemic cardiomyopathy treatment evaluation study. Arch Intern Med 2007; 167:2226. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 18/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate 28. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 29. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta- blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006; 295:165. 30. Hohnloser SH, Dorian P, Roberts R, et al. Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial. Circulation 2006; 114:104. 31. Podrid PJ. Amiodarone: reevaluation of an old drug. Ann Intern Med 1995; 122:689. 32. Gallik DM, Singer I, Meissner MD, et al. Hemodynamic and surface electrocardiographic effects of a new aqueous formulation of intravenous amiodarone. Am J Cardiol 2002; 90:964. 33. Boyce BA, Yee BH. Incidence and severity of phlebitis in patients receiving peripherally infused amiodarone. Crit Care Nurse 2012; 32:27. 34. Norton L, Ottoboni LK, Varady A, et al. Phlebitis in amiodarone administration: incidence, contributing factors, and clinical implications. Am J Crit Care 2013; 22:498. 35. Oragano CA, Patton D, Moore Z. Phlebitis in Intravenous Amiodarone Administration: Incidence and Contributing Factors. Crit Care Nurse 2019; 39:e1. 36. Saul JP, Scott WA, Brown S, et al. Intravenous amiodarone for incessant tachyarrhythmias in children: a randomized, double-blind, antiarrhythmic drug trial. Circulation 2005; 112:3470. 37. Perry JC, Fenrich AL, Hulse JE, et al. Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol. J Am Coll Cardiol 1996; 27:1246. 38. Figa FH, Gow RM, Hamilton RM, Freedom RM. Clinical efficacy and safety of intravenous Amiodarone in infants and children. Am J Cardiol 1994; 74:573. Topic 926 Version 43.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 19/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/amiodarone-clinical-uses/print 20/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 21/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Oral versus intravenous amiodarone Effect Variable Oral Intravenous amiodarone amiodarone Prolongation of action potential duration in atrial and ventricular myocardium +++ + Blockage of inactivated sodium channels +++ ++ Slowing of phase 4 depolarization in the sinus node +++ + Calcium channel blockade +++ +++ Noncompetetive blockade of alpha and beta adrenoreceptors + + (faster) AV node effective refractory period Ventricular effective refractory period / Heart rate QRS interval / QTc duration A-H interval H-V interval Block conversion of thyroxine to trilodothyronine +++ AV: atrioventricular; A-H interval: time from initial rapid deflection of the atrial wave to the initial rapid deflection of the His bundle potential; H-V interval: time from initial deflection of the His bundle potential to the onset of ventricular activity; +: yes or present; -: no or absent; : increase; : decrease. Comparison of the electropharmacologic effects of oral and intravenous amiodarone. Compared with oral amiodarone, the intravenous preparation produces a much lesser increase in the action potential duration in atrial and ventricular myocardium and a minimal increase in the atrial and ventricular refractory periods. As a result, there is little or no increase in QRS duration and the QT interval, respectively. Intravenous amiodarone also has little effect on sinus cycle length and has vasodilator activity that triggers an increase in sympathetic activity; both of these effects result in little or no slowing of the sinus rate. Lastly, the intravenous preparation may have more potent and more rapid antiadrenergic activity. Data from: Desai AD, Chun S, Sung RJ. Ann Intern Med 1997; 127:294. Graphic 79689 Version 4.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 22/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Relationship between fast sodium-mediated myocardial action potential and surface electrocardiogram Each phase of the myocardial action potential (numbers, upper panel) corresponds to a deflection or interval on the surface ECG (lower panel). Phase 4, the resting membrane potential, is responsible for the TQ segment; this segment has a prominent role in the ECG manifestations of ischemia during exercise testing. ECG: electrocardiogram. Graphic 64133 Version 4.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 23/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 24/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Amiodarone baseline testing and monitoring for side effects Monitoring Area of interest for monitoring Possible adverse effect Baseline testing Follow-up testing Cardiac ECG (at baseline and during loading dose) Yearly QT prolongation; torsades de pointes After adding medications that Symptomatic sinoatrial interact with amiodarone or prolong or conduction system impairment the QT interval Implantable Defibrillation threshold As needed for Increased defibrillation cardioverter- testing (if clinically signs/symptoms threshold defibrillators indicated) Dermatologic Physical examination As needed for Photosensitivity to UV signs/symptoms light Blue-gray skin discoloration Endocrine TSH (with reflex testing if abnormal) 3 to 4 months after starting drug, then Hyperthyroidism, hypothyroidism yearly As needed for signs/symptoms Hepatic AST and ALT 6 months after starting AST or ALT elevation 2 upper limit of reference range drug, then yearly Ophthalmologic Eye examination Yearly Corneal microdeposits Optic neuropathy Pulmonary Chest radiograph, Yearly for surveillance Pulmonary toxicity PFTs* (cough, fever, dyspnea) Along with PFTs (including DLCO) and chest computed tomography for signs/symptoms Refer to UpToDate topics on pulmonary toxicity, thyroid toxicity, and clinical uses of amiodarone for additional information. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 25/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate ECG: electrocardiogram; UV: ultraviolet; TSH: thyroid-stimulating hormone; AST: aspartate aminotransferase; ALT: alanine transaminase; PFTs: pulmonary function tests; DLCO: diffusing capacity of the lungs for carbon monoxide. There are differing opinions, and no concensus, of obtaining formal PFTs with assessment of diffusion capacity (ie, DLCO) as baseline testing in all patients. Some experts obtain baseline PFTs with DLCO prior to starting amiodarone, particularly among patients with underlying lung disease, while other experts rarely or never obtain baseline PFTs. Graphic 126072 Version 4.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 26/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Amiodarone dosing in adults by indication Indications Loading dose Maintenance dose Atrial arrhythmias Prevention of recurrent Total loading dose: 6 to 10 Lowest effective dose, PAF grams usually 100 to 200 mg orally once per day Pharmacologic Outpatient: Given as 400 to cardioversion of PAF 600 mg orally per day in divided doses with meals Maximum 200 mg orally per day Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals Pretreatment before Total loading dose: 6 to 10 Lowest effective dose, elective cardioversion or catheter ablation of AF grams orally over 2 to 6 weeks usually 100 to 200 mg orally once per day Given as 400 to 1200 mg orally per day in divided Maximum 400 mg orally per day in most circumstances doses Restoration and maintenance of NSR in Total IV loading dose: 1050 mg critically ill patients with AF Given as 150 mg IV bolus over 10 to 30 minutes, Ventricular rate control in critically ill patients with followed by continuous IV infusion at 1 mg per minute AF and rapid ventricular response for 6 hours, then 0.5 mg per minute for 18 hours* IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy If amiodarone will be used chronically: Following IV infusion, give 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams; consider overlapping IV and oral amiodarone for 24 to 48 hours Ventricular arrhythmias https://www.uptodate.com/contents/amiodarone-clinical-uses/print 27/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Primary and secondary Total oral loading dose: 6 to Maximum 400 mg orally per prevention of SCD in patients with LV 10 grams day in most circumstances Outpatient: 400 to 600 mg Lowest effective dose, ideally dysfunction who are not candidates for or refuse orally per day in divided doses with meal 200 mg or less orally once per day or in divided doses ICD implantation Inpatient: 400 to 1200 mg orally per day in divided doses with meals for 1 to 2 weeks Prevention of ventricular arrhythmias in patients Total loading dose: 6 to 10 grams Maximum 400 mg orally per day in most circumstances with ICDs to decrease risk Outpatient: Given as 400 to 600 mg orally per day in Lowest effective dose, ideally 200 mg or less orally per day of shocks divided doses with meals Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals until desired dose is achieved Cardiac arrest associated 300 mg IV or IO rapid bolus with VF or pulseless VT with a repeat dose of 150 mg as indicated Upon return of spontaneous circulation follow with an infusion of 1 mg per minute for 6 hours and then 0.5 mg per minute for 18 hours* Electrical (VT) storm and incessant VT in Total IV loading dose: 1050 mg If amiodarone is used chronically: Lowest effective hemodynamically stable patients dose, ideally 200 mg or less orally per day; maximum 400 150 mg IV bolus over 10 minutes, followed by mg orally per day in most continuous IV infusion at 1 mg per minute for 6 hours, circumstances then 0.5 mg per minute for 18 hours IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy Additional 150 mg boluses may be given if VT storm recurs https://www.uptodate.com/contents/amiodarone-clinical-uses/print 28/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate If amiodarone will be used chronically: Following IV infusion 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams. Consider overlapping IV and oral amiodarone for 24-48 hours PAF: paroxysmal atrial fibrillation; AF: atrial fibrillation; NSR: normal sinus rhythm; IV: intravenous; SCD: sudden cardiac death; LV: left ventricular; ICD: implantable cardioverter-defibrillator; VF: ventricular fibrillation; VT: ventricular tachycardia; IO: intraosseous. When administered to critically ill patients with atrial fibrillation and rapid ventricular response, repeated 150 mg boluses can be given over 10 to 30 minutes if needed, but no more than six to eight additional boluses should be administered in any 24-hour period. Typically, patients are given 1 or 2 doses of oral amiodarone prior to discontinuation of the IV infusion. Graphic 117524 Version 5.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 29/30 7/6/23, 2:49 PM Amiodarone: Clinical uses - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/amiodarone-clinical-uses/print 30/30

7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials : Kapil Kumar, MD, Peter J Zimetbaum, MD : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 09, 2023. INTRODUCTION Long-term outcomes, such as survival or rate of thromboembolism, are similar with either rhythm or rate control strategies in patients with atrial fibrillation (AF) ( figure 1A-B). In addition, anticoagulation is required with both in most patients [1,2]. Thus, the main goal of therapy is to reduce symptoms by decreasing the frequency and duration of episodes [3,4]. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1) [3,5]. Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia [6-8]. Most patients for whom rhythm control is chosen will require rate control, both prior to its initiation and after, as many patients will have breakthrough episodes of AF. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) The studies describing the efficacy and toxicity (including proarrhythmia) of the different antiarrhythmic drugs used to maintain sinus rhythm in patients with AF will be reviewed here. Recommendations concerning the use of pharmacologic therapy, the choice between a rhythm and a rate control strategy, and the role of alternative methods to maintain sinus rhythm in selected patients who are refractory to conventional therapy, including surgery and radiofrequency ablation, are discussed separately. (See "Antiarrhythmic drugs to maintain sinus https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 1/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate rhythm in patients with atrial fibrillation: Recommendations" and "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".) This topic will also address the issue of whether other medications are associated with a decreased frequency of recurrent AF. (See 'Other therapies' below.) META-ANALYSIS The safety and efficacy of a number of antiarrhythmic drugs was assessed in a 2019 meta- analysis, which included 59 trials (n = 20,981) in which an antiarrhythmic drug for the treatment of atrial fibrillation (AF) was compared against a placebo, another antiarrhythmic, or untreated controls [9]. The following findings were noted: Compared with controls, disopyramide, quinidine, flecainide, propafenone, amiodarone, dofetilide, dronedarone, and sotalol lowered the recurrence rate of AF (risk ratios [RR] 0.77, 0.83, 0.65, 0.67, 0.52, 0.72, 0.85, and 0.83, respectively). Metoprolol also lowered the risk (RR 0.83). All-cause mortality was increased (compared with controls) with sotalol (2.23, 95% CI 1.03- 4.81). Mortality may be increased with other antiarrhythmic drugs, but the evidence was of moderate certainty or weak. These data support the general observation (as summarized in the following sections) that antiarrhythmics can reduce AF recurrences, but their overall value is limited by adverse effects. All of the antiarrhythmic drugs used to maintain sinus rhythm in AF have the potential to provoke ventricular arrhythmias. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Drugs'.) CLASS IA ANTIARRHYTHMIC DRUGS Quinidine, disopyramide, and procainamide are class IA antiarrhythmic drugs ( table 2). These drugs act by modifying the sodium channel and inhibiting the outward potassium current resulting in QT prolongation. They also have important vagolytic effects. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Quinidine is the most widely studied class IA agent for the maintenance of sinus rhythm in AF [10,11]. Although studies have shown that quinidine can reduce the rate of recurrent AF https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 2/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate compared to placebo, it is associated with an increase in mortality, particularly in patients with heart failure [7,8,12,13]. The use of quinidine for the maintenance of sinus rhythm has declined largely because other drugs are both more effective and safer. Disopyramide also seems to have some benefit in the prevention of recurrent AF [14], although it must be used with caution since it can significantly worsen underlying heart failure. The efficacy of oral procainamide has been evaluated in older and poorly controlled trials or in patients who recently underwent coronary artery bypass surgery [15-17]. Oral procainamide is not readily available in the US. CLASS IC ANTIARRHYTHMIC DRUGS Flecainide and propafenone are classified as class IC antiarrhythmic agents, although they are known to have significantly different electrophysiologic and other properties. The following observations have been made regarding their efficacy: Compared to placebo, both are more effective in maintaining sinus rhythm at six months and in prolonging the time to atrial fibrillation (AF) recurrence [18-26]. Flecainide and propafenone appear to have equal efficacy [27,28]. In a randomized, open- label study of 200 patients, for example, the probability of a safe and effective response (maintenance of sinus rhythm or fewer episodes of paroxysmal AF) at one year was 77 and 75 percent with flecainide and propafenone, respectively [27]. A meta-analysis evaluated trials of patients with AF resistant to class I drugs or sotalol who were treated with flecainide or amiodarone after cardioversion [29]. Maintenance of sinus rhythm at 12 months was significantly more likely with amiodarone (60 versus 34 percent with flecainide). Despite the apparent benefit for the prevention of recurrent AF, the toxicity associated with these drugs has restricted their use. The cardiac complications of the class IC drugs include worsening of heart failure, bradycardia, and presumably drug-induced atrial and ventricular arrhythmias in 7 to 27 percent of cases. In up to 13 percent of patients AF recurs as, or converts to, persistent atrial flutter [30]. Radiofrequency ablation of the atrial flutter, with continuation of the antiarrhythmic agent, is an effective approach for reducing arrhythmia recurrence and duration [30,31]. (See 'Hybrid therapy in patients who develop atrial flutter' below and "Atrial flutter: Maintenance of sinus rhythm".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 3/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The use of flecainide is restricted to those patients who have no structural heart disease, particularly coronary heart disease. The concern about the use of the class IC agents is primarily the result of the Cardiac Arrhythmia Suppression Trial (CAST), which showed that flecainide increased the number of deaths among patients with drug-suppressible ventricular premature beats in the year following a myocardial infarction ( figure 2) [32]. It is not known if these findings can be extrapolated to other types of heart disease. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'Class I agents'.) Propafenone has some mild beta-blocking activity in addition to its effects on the sodium channel. Thus, its toxicity may not be identical to that of flecainide and, in patients with ventricular arrhythmia, propafenone appears to be less proarrhythmic. In a study of 480 patients with supraventricular arrhythmia treated with propafenone for 14 months, 59 percent of patients experienced at least one side effect; the drug was discontinued due to an adverse reaction in only 15 percent, while 17 percent required a reduction in dose [33]. Arrhythmia aggravation occurred in 2 percent of patients; the incidence was higher in those with structural heart disease compared to those without (3 versus 1 percent). CLASS III ANTIARRHYTHMIC AGENTS Amiodarone, dronedarone, sotalol, dofetilide, and ibutilide are classified as class III antiarrhythmic agents. There are, however, many dissimilarities among these drugs, and they should be considered separately. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Amiodarone Amiodarone is the most effective antiarrhythmic drug for the prevention of atrial fibrillation (AF), as demonstrated in the following randomized trials [34-39]: The Canadian Trial of Atrial Fibrillation (CTAF) randomly assigned 403 patients who had at least one episode of AF within six months of entry to low-dose amiodarone, sotalol, or propafenone [34]. After a mean follow-up of 16 months, amiodarone was associated with a significantly greater likelihood of being free from recurrent AF (65 versus 37 percent for sotalol and propafenone) and a longer median time to recurrence (>468 versus 98 days) ( figure 3). There was no difference among the three therapies in mortality, but there was an almost significant trend toward an increased incidence of side effects resulting in drug discontinuation with amiodarone (18 versus 11 percent for sotalol or propafenone). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Similar relative efficacies were noted in a substudy from the AFFIRM trial [37]. Patients in the rhythm control arm were randomly assigned to amiodarone or sotalol (256 patients), https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 4/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate amiodarone or a class I drug (222 patients), or sotalol and a class I drug (183 patients). The one-year endpoint was defined as the patient being alive, being in sinus rhythm at follow- up visits, still taking the drug (ie, no discontinuation for episodes of highly symptomatic AF), and needing no electrical or pharmacologic cardioversions. The likelihood of achieving the endpoint was significantly higher with amiodarone compared to sotalol (60 versus 38 percent) or a class I drug (62 versus 23 percent). In comparison to CTAF, amiodarone was not associated with a higher risk than sotalol of cessation of therapy for adverse effects (13 versus 16 percent). The SAFE-T trial compared amiodarone, sotalol, and placebo in patients with persistent AF for both conversion to sinus rhythm and maintenance of sinus rhythm [35]. The rate of maintenance of sinus rhythm was significantly higher at one year with amiodarone than sotalol or placebo and with sotalol than placebo (52 versus 32 and 13 percent on intention to treat analysis and 65 versus 40 and 18 percent on treatment received analysis). The primary endpoint, the median time to recurrence beginning after day 28, was 487, 74, and 6 days in the three groups. However, among the approximately 25 percent of patients with ischemic heart disease, the median time to recurrence with amiodarone was not significantly different from sotalol (569 versus 428 days). There was no difference among the study groups in terms of adverse effects except for a small increase in minor bleeding among patients treated with amiodarone. The mortality rate was not significantly higher with amiodarone and sotalol combined compared to placebo (4.36 versus 2.84 per 100 person-years), but trials of patients with heart failure or myocardial infarction have not shown an increase in mortality with amiodarone [40,41]. Nonrandomized studies of patients with chronic or paroxysmal AF refractory to most other antiarrhythmic agents have shown that amiodarone maintained sinus rhythm in 53 to 79 percent of cases during a 15 to 27 month follow-up [42-45]. Amiodarone is less effective in patients who have AF for over one year or who have an enlarged LA. However, even in this group, the success rate with amiodarone may be as high as 50 to 60 percent [42,43]. Amiodarone has also been evaluated as a prophylactic therapy to prevent AF after cardiac surgery. This issue is discussed separately. (See "Early noncardiac complications of coronary artery bypass graft surgery".) Sotalol Sotalol is not very effective in converting AF to sinus rhythm, but is useful in preventing recurrent episodes [46-48]. As an example, one study randomly assigned 253 patients with AF or atrial flutter to placebo or three doses of sotalol (80, 120, or 160 mg BID); the recurrence rate at one year was 72, 70, 60, and 55 percent, respectively, and the median times to https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 5/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate recurrence were 27, 106, 119, and 175 days, respectively [48]. As noted with other drugs, predictors of AF recurrence were the presence of coronary disease, duration of AF >2 months before reversion, LA size >60 mm, and older age. A number of studies have compared the efficacy of sotalol to other antiarrhythmic drugs for preventing recurrent AF. As noted above, randomized controlled trials and a substudy analysis from AFFIRM demonstrated that sotalol was less effective than amiodarone [34-37]. After a mean follow- up of 16 months in CTAF, for example, amiodarone was associated with a significantly greater likelihood of being free from recurrent AF (65 versus 37 percent for sotalol and propafenone) and a longer median time to recurrence (>468 versus 98 days) ( figure 3) [34]. Similar findings were noted in SAFE-T [35]. (See 'Amiodarone' above.) Sotalol appears to have equal efficacy to propafenone [34,49,50]. The best data come from CTAF, which randomly assigned 403 patients who had at least one episode of AF within six months of entry to low-dose amiodarone, sotalol, or propafenone [34]. After a mean follow-up of 16 months, the proportion of patients free from recurrent AF was 37 percent with both sotalol and propafenone ( figure 3). (See 'Amiodarone' above.) Dofetilide Dofetilide is a class III antiarrhythmic drug ( table 2). The SAFIRE-D trial evaluated 204 patients with AF who were successfully cardioverted electrically or pharmacologically with dofetilide and maintained on a dose of 125, 250, or 500 g twice daily or placebo [51]. The probability of remaining in sinus rhythm at one year was significantly greater for dofetilide compared to placebo (40, 37, and 58 versus 25 percent). The all-cause mortality was the same in the four groups. (See "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) The results were similar in the EMERALD trial, which randomly assigned patients who were pharmacologically or electrically cardioverted to therapy with one of three doses of dofetilide (125, 250, or 500 g twice daily), sotalol (80 mg twice daily), or placebo [52]. After 12 months of therapy, AF recurred in 79 percent of placebo patients, 34 percent of those receiving the highest dose of dofetilide, and between 48 and 60 percent in the other groups. (See "Clinical use of dofetilide".) It is of concern that nonfatal torsades de pointes (TdP) or sudden death occurred in four patients in the high-dose dofetilide group [52]. However, a pooled analysis of 1346 patients receiving dofetilide and 677 treated with placebo in randomized clinical trials of the treatment of supraventricular arrhythmias found that dofetilide was not associated with an increase in mortality (adjusted hazard ratio 1.1) [53]. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 6/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The lack of an increase in mortality with dofetilide is reassuring. However, because drug-induced TdP is relatively rare and can be treated if it occurs in a monitored setting, the impact of this complication may not be seen in analyses limited to overall survival. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Dronedarone Dronedarone is a derivative of amiodarone. In patients with AF, randomized trials with up to 12 months of follow-up have found that dronedarone prevents recurrent AF and was safe (including no increased risk of serious arrhythmias) [54-56]. However, in the ANDROMEDA trial in patients with advanced heart failure from LV systolic dysfunction, there was an increased risk of death with dronedarone and the trial was stopped early [57]. As a result, dronedarone is contraindicated in this population of patients. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) In the ATHENA trial 4628 patients with AF were randomly assigned to either dronedarone or placebo [58]. Patients with New York Heart Association (NYHA) class II or III heart failure comprised 21 percent of the study population, but patients with NYHA class IV heart failure were excluded. After a mean follow-up period of 21 months, dronedarone significantly reduced the primary outcome of death or cardiovascular hospitalization (31.9 versus 39.4 percent, hazard ratio 0.76, 95% CI 0.69-0.84) and the secondary outcome of cardiovascular death (2.7 versus 3.9 percent, hazard ratio 0.71, 95% CI 0.51-0.98). Dronedarone is the only antiarrhythmic drug that has shown a salutary effect on mortality. Maintenance of sinus rhythm was not one of the endpoints in ATHENA. The DIONYSOS study was a short-term (median duration of seven months) comparison between amiodarone and dronedarone to assess the differences in drug tolerability and AF recurrence in 504 patients [59]. Sixty percent of the patients had persistent AF. The authors found that the composite primary endpoint of AF recurrence or premature study drug discontinuation occurred in 75.5 percent of patients taking dronedarone, but only 58.8 percent of patients taking amiodarone. This endpoint was primarily driven by AF recurrence on dronedarone compared to amiodarone (63.5 versus 42.0 percent, respectively). Drug discontinuation and the main safety endpoints of extra-cardiac toxicity only tended to be less with dronedarone, but did not reach statistical significance. It is possibly that with longer follow-up periods there would have been a greater difference in noncardiac side effects, since the toxicity with amiodarone is typically manifest after several months to years of use. In a meta-analysis of dronedarone trials prior to the DIONYSOS study, where the effect of amiodarone versus dronedarone was estimated with the use of indirect comparison and normal logistic meta-analysis models, a similar conclusion was reached [60]. Amiodarone was found to https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 7/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate be more effective in maintaining sinus rhythm, but at the expense of greater drug discontinuation secondary to adverse events. The PALLAS trial, which was stopped early due to an increase in adverse events in patients taking dronedarone, evaluated the potential use of dronedarone to improve cardiovascular outcomes in patients with permanent AF. This trial is discussed elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Concerns about dronedarone'.) Ibutilide Ibutilide is only available for intravenous use and therefore is useful for the acute reversion of AF, not for long-term prevention [61]. (See "Atrial fibrillation: Cardioversion".) Vernakalant Vernakalant is considered a relatively atrially-selective antiarrhythmic agent since one of its main actions is to inhibit the ultrarapid potassium current (IKur) and the acetylcholine potassium current (IKAch), both of which are predominantly found in the atria. Vernakalant also mildly inhibits other potassium channels and, to a much lesser extent, the sodium current. The program for vernakalant drug development in the US has been terminated. The drug is available in an intravenous form to terminate AF in Europe. BETA BLOCKERS There is no evidence to support the use of beta blockers (aside for sotalol), in the absence of other antiarrhythmic drugs, for the prevention of atrial fibrillation (AF). In patients with heart failure (HF) due to systolic dysfunction, chronic treatment with certain beta blockers reduces mortality. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) There is evidence that beta blockers may also reduce the likelihood of the development of AF in patients with HF. A systematic review including seven randomized trials of 11,952 patients evaluated the efficacy of beta blockers for this purpose [62]. Among patients who were in sinus rhythm at baseline and were followed for six months to two years, the incidence of new onset AF was significantly lower in patients treated with beta blockers than those assigned to placebo (28 versus 39 per 1000 patient years). (See "The management of atrial fibrillation in patients with heart failure".) A separate issue is whether beta blockers, which are felt to have some antiarrhythmic properties ( table 2), are effective for preventing recurrent atrial fibrillation in patients with no heart disease. The evidence to support their use for this purpose is scant, and any reduction in the https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 8/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate reported frequency of AF may be attributable to improved rate control that may render recurrent AF silent. VERAPAMIL The calcium channel blocking agents verapamil and diltiazem impair conduction and prolong refractoriness in the AV node. They have been used both acutely and chronically to slow the ventricular response in atrial fibrillation (AF). Verapamil has also been investigated for its effectiveness in maintaining sinus rhythm after cardioversion. The rationale for this approach is the observation that the electrical remodeling that occurs during AF is thought to be due, at least in part, to abnormal calcium loading during rapid atrial rates. In studies in animals and humans, verapamil has been shown to prevent electrical remodeling [63,64]. (See "Mechanisms of atrial fibrillation", section on 'Electrical remodeling'.) Verapamil as a single agent was not effective in preventing AF recurrence in the VERDICT trial, in which 97 patients with persistent AF were randomly assigned to either verapamil or digoxin [65]. There was no difference in AF recurrence rates at one month. It was suggested that verapamil may be effective only when given with a sodium or potassium channel blocking agent [66]. Verapamil with another agent Based upon the observations cited above, several studies evaluated the benefit of verapamil with another agent in preventing recurrences of AF. In the small VEPARAF trial, the addition of verapamil to either amiodarone or flecainide significantly reduced the incidence of recurrent AF within three months of cardioversion compared with either agent alone [67]. The larger PAFAC and SOPAT trials found the combination of verapamil and quinidine to be comparable to sotalol, and superior to placebo, in preventing AF recurrence. In PAFAC, 848 patients with persistent AF were cardioverted and then randomly assigned to sotalol, quinidine and verapamil, or placebo [68]. Patients used an event recorder to record and transmit at least one ECG daily during a mean of nine months of follow-up. The incidence of death or any AF recurrence was significantly lower for both sotalol and for quinidine plus verapamil than for placebo (67 and 65 versus 83 percent). Serious adverse events were not more common with quinidine plus verapamil than with sotalol, and the only episodes of torsades de pointes occurred with sotalol. In the SOPAT trial, 1033 patients with recurrent symptomatic paroxysmal AF were randomly assigned to placebo, sotalol, or one of two dose combinations of quinidine plus verapamil [69]. As in the PAFAC trial, patients recorded and transmitted at least one ECG daily with an event https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 9/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate recorder. The mean time to first AF recurrence was prolonged significantly in all three active treatment groups compared to placebo. At a mean of eight months of follow-up, the number of days of symptomatic AF was reduced significantly for all three active treatment arms compared to placebo. There was no difference between the sotalol and the two quinidine plus verapamil treatment groups in either of these efficacy endpoints or in the incidence of serious adverse side effects. OTHER THERAPIES In addition to conventional antiarrhythmic drugs, a number of other agents have been investigated for the purpose of suppressing atrial fibrillation (AF). ACE inhibitors, angiotensin II receptor blockers Both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) reduce the incidence of atrial fibrillation in selected patient populations. In a recent meta-analysis of 26 randomized trials that evaluated the effect of ACE inhibitors and ARBs on the prevention of AF, it was demonstrated that both classes of drugs had a similar beneficial effect on AF [70]. The effect was more potent for recurrent AF compared to primary prevention of AF (OR 0.45 versus 0.80, respectively). ACE inhibitor or ARB effect on AF was additive to that of amiodarone when used concurrently and endured even in patients with depressive LV function. This issue is discussed in further detail separately. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation".) Magnesium Although not a primary antiarrhythmic agent, magnesium affects atrial electrophysiologic properties. Some studies, particularly those in patients undergoing coronary artery bypass surgery, have found that magnesium deficiency is associated with AF and that magnesium supplementation reduces its incidence. (See "Significance of hypomagnesemia in cardiovascular disease" and "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.) The role of oral magnesium therapy in the prevention of recurrent AF after cardioversion was evaluated in one study of 301 patients who were followed for at least six months after the restoration of sinus rhythm; magnesium therapy alone or in combination with sotalol was ineffective for preventing recurrent AF [71]. Statins There is some evidence that statins may prevent recurrences in patients with lone AF [72,73], ischemic heart disease [73,74] and after cardiac bypass surgery [73,75]. Aldosterone Blockers These drugs have been useful in the treatment of heart failure. Spironolactone and eplerenone have effects on atrial electrophysiologic properties in https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 10/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate experimental animals, but no studies in patients with AF have been done. DRUG-REFRACTORY ATRIAL FIBRILLATION Some patients are refractory to individual antiarrhythmic agents plus an AV nodal blocker or develop side effects on doses necessary for arrhythmia prevention. There are limited data to support the use of combination antiarrhythmic drug therapy, and this approach may expose the patient to a greater risk of proarrhythmia and other side effects. As a result, combination therapy is not recommended. Such patients can be treated with a rate control strategy or referred for nonpharmacologic therapy of atrial fibrillation (AF). These options include: Radiofrequency catheter ablation (RFA), which is the most common of these approaches. (See "Atrial fibrillation: Catheter ablation".) Surgical procedures such as the maze operation, particularly for patients undergoing cardiac surgery for another indication. Some centers also offer mini-maze operations using limited bilateral thoracotomies as standalone procedures as well. (See "Atrial fibrillation: Surgical ablation".) HYBRID THERAPY IN PATIENTS WHO DEVELOP ATRIAL FLUTTER Atrial flutter can occur after the initiation of antiarrhythmic drug therapy in patients with atrial fibrillation (AF), especially with the use of class IC agents or amiodarone. One approach to managing this situation has been a hybrid approach that involves ablation of atrial flutter by creating a block across the cavotricuspid isthmus and then continuation of the antiarrhythmic drug. Although this approach may be helpful in maintaining sinus rhythm in the short term, data (articles below) suggest that in the long term, there is a high recurrence of AF [76,77]. Therefore, the development of atrial flutter on an antiarrhythmic drug may be considered failure of therapy. SUMMARY Recommendations for the use drug therapy to maintain sinus rhythm in patients with atrial fibrillation (AF) are found elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 11/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The following are the important points made in this topic: The main goal of drug therapy to maintain sinus rhythm is to reduce symptoms by decreasing the frequency and duration of episodes. The primary endpoint of many clinical trials involving antiarrhythmic drugs has been time to first recurrence of AF. However, there is great variation in efficacy of antiarrhythmic drugs from patient to patient. Although a drug may be shown to significantly prolong the time to recurrence of AF in a clinical trial, some patients will experience no benefit and others will experience a dramatic reduction in AF frequency. Other outcomes are also important. These include the effect of the drug on overall AF burden, AF episode duration, symptoms, ventricular rate control, and hospitalizations. A single recurrence of AF on a drug does not necessarily indicate treatment failure or require a change in therapy. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1). Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia. Amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective in the maintenance of sinus rhythm. Of these, amiodarone is the most effective, but is associated with the development of more frequent side effects. Dronedarone is also associated with the development of significant side effects as well as worse outcomes in some groups of patients with AF. (See 'Amiodarone' above and 'Dronedarone' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 2. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 3. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. 4. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 12/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 5. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57:223. 6. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 7. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82:1106. 8. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20:527. 9. Valembois L, Audureau E, Takeda A, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2019; 9:CD005049. 10. S dermark T, Jonsson B, Olsson A, et al. Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm. Br Heart J 1975; 37:486. 11. Lloyd EA, Gersh BJ, Forman R. The efficacy of quinidine and disopyramide in the maintenance of sinus rhythm after electroconversion from atrial fibrillation. A double-blind study comparing quinidine, disopyramide and placebo. S Afr Med J 1984; 65:367. 12. Reimold SC, Chalmers TC, Berlin JA, Antman EM. Assessment of the efficacy and safety of antiarrhythmic therapy for chronic atrial fibrillation: observations on the role of trial design and implications of drug-related mortality. Am Heart J 1992; 124:924. 13. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 14. Karlson BW, Torstensson I, Abj rn C, et al. Disopyramide in the maintenance of sinus rhythm after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study. Eur Heart J 1988; 9:284. 15. Szekely P, Sideris DA, Batson GA. Maintenance of sinus rhythm after atrial defibrillation. Br Heart J 1970; 32:741. 16. Madrid AH, Moro C, Mar n-Huerta E, et al. Comparison of flecainide and procainamide in cardioversion of atrial fibrillation. Eur Heart J 1993; 14:1127. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 13/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 17. Hjelms E. Procainamide conversion of acute atrial fibrillation after open-heart surgery compared with digoxin treatment. Scand J Thorac Cardiovasc Surg 1992; 26:193. 18. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. Am J Cardiol 1989; 64:1317. 19. Anderson JL, Gilbert EM, Alpert BL, et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group. Circulation 1989; 80:1557. 20. Pritchett EL, McCarthy EA, Wilkinson WE. Propafenone treatment of symptomatic paroxysmal supraventricular arrhythmias. A randomized, placebo-controlled, crossover trial in patients tolerating oral therapy. Ann Intern Med 1991; 114:539. 21. A randomized, placebo-controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. UK Propafenone PSVT Study Group. Circulation 1995; 92:2550. 22. Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Propafenone Atrial Fibrillation Trial Investigators. Am J Cardiol 1997; 79:418. 23. Antman EM, Beamer AD, Cantillon C, et al. Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs. J Am Coll Cardiol 1990; 15:698. 24. Geller JC, Geller M, Carlson MD, Waldo AL. Efficacy and safety of moricizine in the maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Am J Cardiol 2001; 87:172. 25. Meinertz T, Lip GY, Lombardi F, et al. Efficacy and safety of propafenone sustained release in the prophylaxis of symptomatic paroxysmal atrial fibrillation (The European Rythmol/Rytmonorm Atrial Fibrillation Trial [ERAFT] Study). Am J Cardiol 2002; 90:1300. 26. Pritchett EL, Page RL, Carlson M, et al. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. Am J Cardiol 2003; 92:941. 27. Chimienti M, Cullen MT Jr, Casadei G. Safety of long-term flecainide and propafenone in the management of patients with symptomatic paroxysmal atrial fibrillation: report from the Flecainide and Propafenone Italian Study Investigators. Am J Cardiol 1996; 77:60A. 28. Aliot E, Denjoy I. Comparison of the safety and efficacy of flecainide versus propafenone in hospital out-patients with symptomatic paroxysmal atrial fibrillation/flutter. The Flecainide AF French Study Group. Am J Cardiol 1996; 77:66A.

decreasing the frequency and duration of episodes. The primary endpoint of many clinical trials involving antiarrhythmic drugs has been time to first recurrence of AF. However, there is great variation in efficacy of antiarrhythmic drugs from patient to patient. Although a drug may be shown to significantly prolong the time to recurrence of AF in a clinical trial, some patients will experience no benefit and others will experience a dramatic reduction in AF frequency. Other outcomes are also important. These include the effect of the drug on overall AF burden, AF episode duration, symptoms, ventricular rate control, and hospitalizations. A single recurrence of AF on a drug does not necessarily indicate treatment failure or require a change in therapy. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1). Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia. Amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective in the maintenance of sinus rhythm. Of these, amiodarone is the most effective, but is associated with the development of more frequent side effects. Dronedarone is also associated with the development of significant side effects as well as worse outcomes in some groups of patients with AF. (See 'Amiodarone' above and 'Dronedarone' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 2. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 3. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. 4. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 12/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 5. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57:223. 6. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 7. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82:1106. 8. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20:527. 9. Valembois L, Audureau E, Takeda A, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2019; 9:CD005049. 10. S dermark T, Jonsson B, Olsson A, et al. Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm. Br Heart J 1975; 37:486. 11. Lloyd EA, Gersh BJ, Forman R. The efficacy of quinidine and disopyramide in the maintenance of sinus rhythm after electroconversion from atrial fibrillation. A double-blind study comparing quinidine, disopyramide and placebo. S Afr Med J 1984; 65:367. 12. Reimold SC, Chalmers TC, Berlin JA, Antman EM. Assessment of the efficacy and safety of antiarrhythmic therapy for chronic atrial fibrillation: observations on the role of trial design and implications of drug-related mortality. Am Heart J 1992; 124:924. 13. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 14. Karlson BW, Torstensson I, Abj rn C, et al. Disopyramide in the maintenance of sinus rhythm after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study. Eur Heart J 1988; 9:284. 15. Szekely P, Sideris DA, Batson GA. Maintenance of sinus rhythm after atrial defibrillation. Br Heart J 1970; 32:741. 16. Madrid AH, Moro C, Mar n-Huerta E, et al. Comparison of flecainide and procainamide in cardioversion of atrial fibrillation. Eur Heart J 1993; 14:1127. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 13/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 17. Hjelms E. Procainamide conversion of acute atrial fibrillation after open-heart surgery compared with digoxin treatment. Scand J Thorac Cardiovasc Surg 1992; 26:193. 18. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. Am J Cardiol 1989; 64:1317. 19. Anderson JL, Gilbert EM, Alpert BL, et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group. Circulation 1989; 80:1557. 20. Pritchett EL, McCarthy EA, Wilkinson WE. Propafenone treatment of symptomatic paroxysmal supraventricular arrhythmias. A randomized, placebo-controlled, crossover trial in patients tolerating oral therapy. Ann Intern Med 1991; 114:539. 21. A randomized, placebo-controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. UK Propafenone PSVT Study Group. Circulation 1995; 92:2550. 22. Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Propafenone Atrial Fibrillation Trial Investigators. Am J Cardiol 1997; 79:418. 23. Antman EM, Beamer AD, Cantillon C, et al. Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs. J Am Coll Cardiol 1990; 15:698. 24. Geller JC, Geller M, Carlson MD, Waldo AL. Efficacy and safety of moricizine in the maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Am J Cardiol 2001; 87:172. 25. Meinertz T, Lip GY, Lombardi F, et al. Efficacy and safety of propafenone sustained release in the prophylaxis of symptomatic paroxysmal atrial fibrillation (The European Rythmol/Rytmonorm Atrial Fibrillation Trial [ERAFT] Study). Am J Cardiol 2002; 90:1300. 26. Pritchett EL, Page RL, Carlson M, et al. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. Am J Cardiol 2003; 92:941. 27. Chimienti M, Cullen MT Jr, Casadei G. Safety of long-term flecainide and propafenone in the management of patients with symptomatic paroxysmal atrial fibrillation: report from the Flecainide and Propafenone Italian Study Investigators. Am J Cardiol 1996; 77:60A. 28. Aliot E, Denjoy I. Comparison of the safety and efficacy of flecainide versus propafenone in hospital out-patients with symptomatic paroxysmal atrial fibrillation/flutter. The Flecainide AF French Study Group. Am J Cardiol 1996; 77:66A. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 14/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 29. Zarembski DG, Nolan PE Jr, Slack MK, Caruso AC. Treatment of resistant atrial fibrillation. A meta-analysis comparing amiodarone and flecainide. Arch Intern Med 1995; 155:1885. 30. Schumacher B, Jung W, Lewalter T, et al. Radiofrequency ablation of atrial flutter due to administration of class IC antiarrhythmic drugs for atrial fibrillation. Am J Cardiol 1999; 83:710. 31. Nabar A, Rodriguez LM, Timmermans C, et al. Radiofrequency ablation of "class IC atrial flutter" in patients with resistant atrial fibrillation. Am J Cardiol 1999; 83:785. 32. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 33. Podrid PJ, Anderson JL. Safety and tolerability of long-term propafenone therapy for supraventricular tachyarrhythmias. The Propafenone Multicenter Study Group. Am J Cardiol 1996; 78:430. 34. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913. 35. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 36. Kochiadakis GE, Igoumenidis NE, Marketou ME, et al. Low dose amiodarone and sotalol in the treatment of recurrent, symptomatic atrial fibrillation: a comparative, placebo controlled study. Heart 2000; 84:251. 37. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003; 42:20. 38. Dorian P, Mangat I. Restoring sinus rhythm in atrial fibrillation: a Pyrrhic victory? J Am Coll Cardiol 2003; 42:30. 39. Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007; 356:935. 40. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators. Lancet 1997; 350:1417. 41. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225. 42. Brodsky MA, Allen BJ, Walker CJ 3rd, et al. Amiodarone for maintenance of sinus rhythm after conversion of atrial fibrillation in the setting of a dilated left atrium. Am J Cardiol 1987; 60:572. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 15/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 43. Gold RL, Haffajee CI, Charos G, et al. Amiodarone for refractory atrial fibrillation. Am J Cardiol 1986; 57:124. 44. Horowitz LN, Spielman SR, Greenspan AM, et al. Use of amiodarone in the treatment of persistent and paroxysmal atrial fibrillation resistant to quinidine therapy. J Am Coll Cardiol 1985; 6:1402. 45. Skoularigis J, R thlisberger C, Skudicky D, et al. Effectiveness of amiodarone and electrical cardioversion for chronic rheumatic atrial fibrillation after mitral valve surgery. Am J Cardiol 1993; 72:423. 46. Gallik DM, Kim SG, Ferrick KJ, et al. Efficacy and safety of sotalol in patients with refractory atrial fibrillation or flutter. Am Heart J 1997; 134:155. 47. Alt E, Ammer R, Lehmann G, et al. Patient characteristics and underlying heart disease as predictors of recurrent atrial fibrillation after internal and external cardioversion in patients treated with oral sotalol. Am Heart J 1997; 134:419. 48. Benditt DG, Williams JH, Jin J, et al. Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. d,l-Sotalol Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1999; 84:270. 49. Reimold SC, Cantillon CO, Friedman PL, Antman EM. Propafenone versus sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol 1993; 71:558. 50. Bellandi F, Simonetti I, Leoncini M, et al. Long-term efficacy and safety of propafenone and sotalol for the maintenance of sinus rhythm after conversion of recurrent symptomatic atrial fibrillation. Am J Cardiol 2001; 88:640. 51. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000; 102:2385. 52. Ferguson JJ. Meeting highlights. Highlights of the 71st scientific sessions of the American Heart Association. Circulation 1999; 99:2486. 53. Pritchett EL, Wilkinson WE. Effect of dofetilide on survival in patients with supraventricular arrhythmias. Am Heart J 1999; 138:994. 54. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 2003; 24:1481. 55. Kathofer S, Thomas D, Karle CA. The novel antiarrhythmic drug dronedarone: comparison with amiodarone. Cardiovasc Drug Rev 2005; 23:217. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 16/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 56. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987. 57. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 58. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668. 59. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21:597. 60. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089. 61. Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation 1996; 94:1613. 62. Nasr IA, Bouzamondo A, Hulot JS, et al. Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis. Eur Heart J 2007; 28:457. 63. Tieleman RG, De Langen C, Van Gelder IC, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997; 95:1945. 64. Daoud EG, Knight BP, Weiss R, et al. Effect of verapamil and procainamide on atrial fibrillation-induced electrical remodeling in humans. Circulation 1997; 96:1542. 65. Van Noord T, Van Gelder IC, Tieleman RG, et al. VERDICT: the Verapamil versus Digoxin Cardioversion Trial: A randomized study on the role of calcium lowering for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2001; 12:766. 66. Knight BP. Calcium channel blockade for prevention of recurrent atrial fibrillation: have we reached a VERDICT? J Cardiovasc Electrophysiol 2001; 12:770. 67. De Simone A, De Pasquale M, De Matteis C, et al. VErapamil plus antiarrhythmic drugs reduce atrial fibrillation recurrences after an electrical cardioversion (VEPARAF Study). Eur Heart J 2003; 24:1425. 68. Fetsch T, Bauer P, Engberding R, et al. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur Heart J 2004; 25:1385. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 17/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 69. Patten M, Maas R, Bauer P, et al. Suppression of paroxysmal atrial tachyarrhythmias results of the SOPAT trial. Eur Heart J 2004; 25:1395. 70. Zhang Y, Zhang P, Mu Y, et al. The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Clin Pharmacol Ther 2010; 88:521. 71. Frick M, Darp B, Ostergren J, Rosenqvist M. The effect of oral magnesium, alone or as an adjuvant to sotalol, after cardioversion in patients with persistent atrial fibrillation. Eur Heart J 2000; 21:1177. 72. Siu CW, Lau CP, Tse HF. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol 2003; 92:1343. 73. Fauchier L, Pierre B, de Labriolle A, et al. Antiarrhythmic effect of statin therapy and atrial fibrillation a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2008; 51:828. 74. Young-Xu Y, Jabbour S, Goldberg R, et al. Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol 2003; 92:1379. 75. Dotani MI, Elnicki DM, Jain AC, Gibson CM. Effect of preoperative statin therapy and cardiac outcomes after coronary artery bypass grafting. Am J Cardiol 2000; 86:1128. 76. Garc a Seara J, Raposeiras Roubin S, Gude Sampedro F, et al. Failure of hybrid therapy for the prevention of long-term recurrence of atrial fibrillation. Int J Cardiol 2014; 176:74. 77. Anastasio N, Frankel DS, Deyell MW, et al. Nearly uniform failure of atrial flutter ablation and continuation of antiarrhythmic agents (hybrid therapy) for the long-term control of atrial fibrillation. J Interv Card Electrophysiol 2012; 35:57. Topic 1038 Version 37.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 18/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate GRAPHICS Rate control versus rhythm control in AFFIRM Results of the AFFIRM trial in which 4060 patients with atrial fibrillation (AF) that was likely to be recurrent were randomly assigned to rhythm or rate control. The primary end point was overall mortality. There was an almost significant trend toward lower mortality with rate control (21.3 versus 23.8 percent, hazard ratio 0.87, 95 percent CI 0.75 to 1.01). Data from Wyse DG, Waldo AL, DiMarco JP, et al. N Engl J Med 2002; 347:1825. Graphic 61608 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 19/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Rate control versus rhythm control in RACE Results of the RACE trial in which 522 patients with recurrent persistent atrial fibrillation (AF) were randomly assigned to rhythm or rate control. The primary end point was a composite of cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker placement, and antiarrhythmic drug side effects. There was an almost significant trend toward a lower incidence of the primary end point with rate control (17.2 versus 22.6 percent with rhythm control, hazard ratio 0.73, 90 percent CI 0.53 to 1.01). Data from Van Gelder IC, Hagens VE, Bosker HA, et al. N Engl J Med 2002; 347:1834. Graphic 74434 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 20/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate ACC/AHA/ESC guideline summary: Maintenance of sinus rhythm in atrial fibrillation (AF) Class I - There is evidence and/or general agreement that the following approach is effective for the maintenance of sinus rhythm in patients with AF Treatment of precipitating or reversible causes of AF before initiating therapy with antiarrhythmic drugs. Class IIa - The weight of evidence or opinion is in favor of the usefulness of the following approaches for the maintenance of sinus rhythm in patients with AF Antiarrhythmic drug therapy to maintain sinus rhythm and prevent tachycardia-induced cardiomyopathy. Infrequent, well tolerated recurrent episodes of recurrent AF is reasonable as a successful outcome of antiarrhythmic drug therapy. Outpatient initiation of therapy in patients with no associated heart disease when the antiarrhythmic drug is well tolerated. In patients with lone AF and no structural heart disease, outpatient initiation of propafenone or flecainide therapy in patients with paroxysmal AF who are in sinus rhythm at the time of drug initiation. Sotalol in outpatients in sinus rhythm who have little or no heart disease, are prone to paroxysmal AF, a baseline uncorrected QT interval less than 460 msec, normal serum electrolytes, and no risk factors for class III drug-related proarrhythmia. Catheter ablation as an alternative to antiarrhythmic drug therapy to prevent recurrent AF in symptomatic patients with little or no left atrial enlargement. Class III - There is evidence and/or general agreement that the following approaches are not useful or may be harmful for the maintenance of sinus rhythm in patients with AF Use of a particular antiarrhythmic drug is not recommended in patients with well-defined risk factors for proarrhythmia with that drug. Antiarrhythmic drug therapy is not recommended in patients with advanced sinus node disease or atrioventricular node dysfunction unless they have a functioning electronic cardiac pacemaker. Data from Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial brillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to revise the 2001 guidelines for the management of patients with atrial brillation). J Am Coll Cardiol 2006; 48:e149. Graphic 78424 Version 2.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 21/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Maintenance of sinus rhythm Therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation. Drugs are listed alphabetically and not in order of suggested use. The seriousness of heart disease progresses from left to right, and selection of therapy in patients with multiple conditions depends on the most serious condition present. LVH: left ventricular hypertrophy. Reproduced from: Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial brillation: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2011; 57:223. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 83173 Version 2.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 22/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 23/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 24/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 25/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The rate of recurrent atrial fibrillation is lowest with amiodarone The Canadian Trial of Atrial Fibrillation randomized 403 patients with at least one episode of atrial fibrillation (AF) during the prior six months to low-dose amiodarone, propafenone, or sotalol. After a mean follow-up of 16 months, the likelihood of being free from recurrent AF was highest with amiodarone (65 versus 37 percent for sotalol and propafenone) and the median time to recurrence was longer (>468 versus 98 days). Data from: Roy D, Talajic M, Dorian P, et al. N Engl J Med 2000; 342:913. Graphic 69285 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 26/27 7/6/23, 2:49 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 27/27

7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations : Kapil Kumar, MD : Peter J Zimetbaum, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 24, 2021. INTRODUCTION For patients with atrial fibrillation (AF), there are two main strategies to manage the irregular rhythm and its impact on symptoms: rhythm control (restoration followed by maintenance of sinus rhythm with either antiarrhythmic drugs or catheter ablation); and rate control with atrioventricular (AV) nodal blockers. (See 'Initial management decisions' below.) For those patients in whom a rhythm control strategy is chosen, the main goal of therapy is to reduce symptoms by decreasing the frequency and duration of episodes as well as the symptoms during recurrences [1,2]. As antiarrhythmic drugs are associated with a potential for serious adverse side effects, particularly the induction of proarrhythmia, they should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risks associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' below.) Rhythm control can be achieved with either antiarrhythmic drug therapy or nonpharmacologic methods. This topic provides recommendations for the former. The clinical trials describing the efficacy and toxicity (including proarrhythmia) of the different antiarrhythmic drugs are presented separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Nonpharmacologic methods to maintain sinus rhythm (including surgery and radiofrequency ablation or cryoballoon ablation) in selected patients who are refractory to conventional therapy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 1/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".) INDICATIONS There are three settings in which a rhythm control strategy for the maintenance of sinus rhythm should be considered [3]: Persistent symptoms (palpitations, dyspnea, lightheadedness, angina, syncope, and heart failure) despite adequate rate control. An inability to attain adequate rate control (to prevent tachycardia-mediated cardiomyopathy). (See "Arrhythmia-induced cardiomyopathy".) Patient preference. Some patients will strongly prefer to avoid either paroxysmal or persistent AF. We consider cardioversion to sinus rhythm in most patients, particularly younger patients, with a first-detected episode of atrial fibrillation (AF) in whom the arrhythmia is of recent onset and the risk for recurrence appears to be low. Maintenance antiarrhythmic drug therapy is not routinely used after cardioversion in patients with newly detected AF [3]. These issues are discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) INITIAL MANAGEMENT DECISIONS Prior to selecting and initiating antiarrhythmic drug therapy, the following issues should be considered. Rhythm versus rate control: The choice between a rhythm- or a rate-control strategy is determined by many factors, including patient age, the degree to which symptoms interfere with the quality of life, and concerns about antiarrhythmic drug therapy or catheter ablation. There is no evidence that long-term outcomes, such as rates of survival or thromboembolism, are improved by rhythm control ( figure 1 and figure 2) [4,5]. Our recommendations for the use of these two strategies are found elsewhere. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 2/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Precipitating factors: Before initiating a rhythm control strategy, any risk factors for atrial fibrillation (AF) should be addressed. Examples include hyperthyroidism, hypertension, heart failure, sleep apnea, and excess alcohol intake. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Chronic disease associations'.) Maintenance antiarrhythmic drug therapy is not recommended after cardioversion in a patient with a transient or reversible cause (such as cardiac surgery, pericarditis, or pulmonary embolism). An option in such patients is beta blocker therapy after restoration of sinus rhythm, which may provide modest protection against recurrent AF [6]. However, short-term antiarrhythmic therapy can be considered in this situation as the underlying cause is treated in patients who are highly symptomatic. Anticoagulation: The proper use of anticoagulation in the period surrounding conversion to sinus rhythm is discussed separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Rate control: An atrioventricular (AV) nodal blocker, such as a beta blocker or a rate- slowing calcium channel blocker, is usually started before, or simultaneously with, antiarrhythmic drug therapy in patients who have demonstrated a moderate to rapid ventricular rate ( 110 beats per minute) during AF. Slowing of the rate generally improves symptoms prior to the restoration of sinus rhythm. This therapy is continued while the patient is in sinus rhythm to protect against a rapid ventricular rate should AF recur. This issue is discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) Restoration of sinus rhythm: Many patients with AF in whom a rhythm control strategy is chosen will need sinus rhythm restored prior to the initiation of long-term antiarrhythmic drug therapy. The restoration of sinus rhythm is discussed in detail elsewhere. (See "Atrial fibrillation: Cardioversion".) Some patients with relatively infrequent episodes of paroxysmal atrial fibrillation can be managed with antiarrhythmic therapy given only at the time of the episode. This form of outpatient "pill-in-the-pocket" therapy for recurrent AF is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.) SELECTING AN ANTIARRHYTHMIC DRUG https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 3/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Once the issues discussed above have been addressed, an antiarrhythmic agent can be chosen. The choice of drug is significantly influenced both by drug and patient characteristics. As with all therapeutic interventions, the choice of agent should take into account the benefit to risk ratio of the therapy chosen. (See 'Proarrhythmia' below.) Amiodarone, dofetilide, flecainide, propafenone, sotalol, and less commonly dronedarone are the drugs we recommend to maintain sinus rhythm. (See 'Concerns about dronedarone' below.) For additional information regarding the therapeutic use of these drugs, including information regarding dosing and side effects, the reader is referred to individual UpToDate topics on these drugs or to the individual drug monographs in our drug database. The following points regarding antiarrhythmic drugs should be kept in mind in choosing therapy: Compared to other agents, amiodarone is associated with the greatest likelihood of maintaining sinus rhythm, but also with the highest risk of long-term complications [7,8]. In addition, a 2014 report raises the possibility that amiodarone use in patients taking warfarin is associated with an increased risk of stroke compared to those not taking the drug [9]. In this study, there was a lower time in the therapeutic range (of the international normalized ratio) in patients receiving amiodarone. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Quinidine, procainamide, and disopyramide are no longer recommended for patients with AF, except perhaps in patients with vagally mediated atrial fibrillation (AF), as there are more effective drugs and due to extracardiac side effects as well as the concern about proarrhythmia [10]. (See 'Proarrhythmia' below.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia [6,11,12]. Of course beta blockers may have already been initiated to slow the ventricular rate in AF. (See 'Proarrhythmia' below and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Beta blockers'.) The following patient characteristics may influence decision making: The clinical features of the patient, such as presence or absence of clinical heart disease. We believe it is prudent to obtain a two-dimensional echocardiogram to screen for structural heart disease (eg, left ventricular systolic dysfunction, left ventricular https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 4/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate hypertrophy, or valvular heart disease). An exercise or nuclear stress imaging test may be used to screen for coronary heart disease and is typically done before starting a class IC agent. (See 'Atrial fibrillation without structural heart disease' below and 'Atrial fibrillation associated with structural heart disease' below.) The presence of paroxysmal compared to persistent AF [1,13]. As examples, our experts rarely use dofetilide for paroxysmal AF and infrequently choose dronedarone for persistent AF due to reduced efficacy compared with amiodarone. The presence of vagally-mediated AF [14,15]. The 2016 European Society of Cardiology AF guideline suggest that, because of its long-lasting anticholinergic activity, disopyramide may be considered in patients with vagally-induced AF (eg, occurring most often in athletic young men with slow heart rates during rest or sleep), as long as the patient does not have prostatism or glaucoma [13,16]. The combination of disopyramide and either a beta blocker or a calcium channel blocker must be used cautiously because of the additive negative inotropic effects. If disopyramide cannot be given or is not tolerated, flecainide and amiodarone represent the sequential alternatives. Our experts use disopyramide cautiously due to concern for proarrhythmia. For patients with adrenergically-mediated AF (eg, occurring during exercise or other activity), we suggest beta blockers as first-line therapy, followed by sotalol and amiodarone. Antiarrhythmic drugs are associated with a potential for serious adverse side effects, particularly the induction of proarrhythmia. Thus, they should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risk associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' below.) As the expectation of antiarrhythmic therapy is to reduce the frequency and duration of episodes, improve quality of life, and prevent hospitalization, a recurrence of AF does not necessarily denote a failure of the medication or mandate a change to a different antiarrhythmic drug. Atrial fibrillation without structural heart disease Patients without structural heart disease include those with hypertension who do not have left ventricular hypertrophy. The author and reviewers of this topic generally select flecainide or propafenone as the first antiarrhythmic drug for these patients due to its relatively good side effect profile, efficacy, and ease of use. The use of these drugs in patients >70 years of age should be considered more cautiously, given the higher likelihood of underlying coronary artery disease. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 5/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate In these patients, flecainide, propafenone, amiodarone, dronedarone, sotalol, and dofetilide are superior to placebo for maintaining sinus rhythm. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) For those patients in whom flecainide or propafenone will not be used as the preferred agent, the following points can influence the choice of antiarrhythmic drug in patients without structural heart disease: In the Canadian Trial of Atrial fibrillation, AFFIRM, and the SAFE-T randomized trials, amiodarone was more effective than flecainide, propafenone, or sotalol (which have nearly equivalent efficacy to each other), but has a significantly higher rate of adverse side effects. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Amiodarone'.) In a meta-analysis of trials where the effect of amiodarone versus dronedarone was estimated with the use of indirect comparison and normal logistic meta-analysis models, amiodarone was found to be more effective in maintaining sinus rhythm, but at the expense of greater drug discontinuation secondary to adverse events [17]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Both amiodarone and dronedarone are associated with significant side effects. We suggest carefully discussing these with the patient prior to initiating therapy. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of dronedarone".)In the EMERALD trial, Dofetilide had a somewhat better efficacy than sotalol. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dofetilide'.) Some cardiologists prefer to use low-dose amiodarone (100 to 200 mg per day), particularly in older patients, in preference to flecainide, sotalol, or dronedarone for two principal reasons: greater efficacy than sotalol and dronedarone ( figure 3) [18-20], and a very low incidence of torsades de pointes [21,22]. In addition, since amiodarone has beta blocking and calcium channel blocking activity, the ventricular rate is usually slower and better tolerated if AF does recur. If amiodarone is used for rhythm control, the need for additional medications to control rate (eg, beta blockers or calcium channel blockers) may be decreased. Despite these advantages, low-dose amiodarone still has appreciable toxicity, including thyroid disease, hepatic dysfunction, lung disease, neurologic abnormalities, and bradycardia [21,22]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 6/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Atrial fibrillation associated with structural heart disease Amiodarone, sotalol, and dofetilide are the most commonly recommended first-line drugs in patients with structural heart disease ( algorithm 1) [13]. Our authors and reviewers prefer either dronedarone or sotalol to amiodarone and dofetilide. Dronedarone is easier to use than sotalol (continuous monitoring of initiation required), but is less efficacious. (See "Clinical uses of sotalol".) These drugs (with the exception of dronedarone) were used for initial therapy in almost 70 percent of patients in AFFIRM, 88 percent of whom had organic heart disease and/or hypertension [4]. Amiodarone was significantly more effective than sotalol in the CTAF, AFFIRM, and SAFE-T trials [18-20]. However, in SAFE-T, sotalol was as effective as amiodarone in the subgroup of patients with coronary heart disease [19]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Coronary heart disease In patients with coronary heart disease who do not have heart failure, sotalol, dronedarone, dofetilide, and amiodarone are acceptable choices ( table 1 and algorithm 1) [13,23,24]. We prefer sotalol due to its better extracardiac side effect profiles. Flecainide and propafenone are contraindicated in this population. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Major side effects of class I antiarrhythmic drugs".) In the Cardiac Arrhythmia Suppression Trial (CAST) of patients with drug-suppressible ventricular premature beats in the year following a myocardial infarction, flecainide increased mortality compared to placebo ( figure 4) [25]. Although propafenone was not used in CAST and may not have the same potential for proarrhythmia as flecainide and encainide [26], it cannot be recommended in patients with underlying heart disease [27]. The extension of this concern to structural heart disease other than coronary artery disease stems in part from the flecainide clinical and safety database, which was used in a retrospective study demonstrating that the presence of structural heart disease including valvular heart disease, congenital heart disease, and cardiomyopathies lead to an alarming increase in proarrhythmia and death [28]. Heart failure Amiodarone and dofetilide, are used in patients with AF and heart failure (HF) or those with a left ventricular ejection fraction less than 35 percent. Our authors and reviewers are more comfortable using dofetilide in this setting with an implantable defibrillator in place or in younger patients with less severe impairment of left ventricular systolic function. This issue is discussed in detail elsewhere. (See "The management of atrial fibrillation in patients with heart failure".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 7/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Sotalol, propafenone, dronedarone, and flecainide should not be used in patients with heart failure, due to studies showing an increase in mortality with these agents. (See "Clinical uses of sotalol" and "Amiodarone: Clinical uses" and "Major side effects of class I antiarrhythmic drugs".) Left ventricular hypertrophy Patients with significant left ventricular hypertrophy (defined as left ventricular wall thickness greater 1.4 cm for the purposes of this discussion) due to hypertension, hypertrophic cardiomyopathy, or aortic stenosis have underlying subendocardial ischemia and electrophysiologic abnormalities. These increase the risk for proarrhythmia with antiarrhythmic agents. (See "Left ventricular hypertrophy and arrhythmia" and 'Proarrhythmia' below and "Left ventricular hypertrophy: Clinical findings and ECG diagnosis".) Sotalol, flecainide and propafenone are thought to have a significant arrhythmic risk in patients with left ventricular hypertrophy (LVH). Dronedarone has been evaluated in patients with LVH and is thought to be relatively safe [24], although our experts rarely use it. Amiodarone is another therapeutic option. (See "Clinical uses of dronedarone".) Drug-resistant atrial fibrillation Some patients are refractory to individual antiarrhythmic agents plus an AV nodal blocker or develop side effects on doses necessary for arrhythmia prevention. Although some have suggested that combination antiarrhythmic drug therapy (eg, a class IC agent with sotalol or amiodarone, often in lower doses, or the combination of dronedarone plus ranolazine) may be an alternative, there are limited data to support such an approach and the patient may be exposed to a greater risk of proarrhythmia and other side effects [29]. As a result, combination antiarrhythmic drug therapy is not recommended. Such patients can be treated with a rate control strategy or referred for nonpharmacologic therapy to prevent recurrent AF including surgery (such as the maze operation) or catheter ablation (such as pulmonary vein isolation). (See "Atrial fibrillation: Catheter ablation" and "The role of pacemakers in the prevention of atrial fibrillation" and "Atrial fibrillation: Surgical ablation".) INPATIENT VERSUS OUTPATIENT INITIATION Many patients begun on antiarrhythmic drug therapy should be hospitalized for continuous electrocardiographic monitoring due to a 10 to 15 percent incidence of adverse cardiac events during the initiation of therapy [30]. (See 'Proarrhythmia' below and "Arrhythmia management for the primary care clinician", section on 'Antiarrhythmic drugs'.) The two complications of greatest concern are bradycardia and proarrhythmia. Other adverse cardiac events can include significant QT prolongation, heart failure, rapid ventricular rate, https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 8/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate conduction abnormalities, hypotension, and stroke. The risk is greatest in the first 24 hours and in patients with a prior myocardial infarction. Outpatient initiation of antiarrhythmic drug therapy with the following agents may be considered: Flecainide or propafenone in patients in sinus rhythm who have no underlying structural heart disease, normal baseline QT intervals, and no profound bradycardia or suspected sinus or atrioventricular (AV) node dysfunction [13]. Amiodarone or dronedarone in selected patients who have no other risk factors for torsades de pointes (eg, hypokalemia, hypomagnesemia) or sinus node dysfunction or AV conduction disease. Dronedarone and amiodarone are the only two drugs that can be initiated in outpatients while in atrial fibrillation. Patients with an implantable cardioverter-defibrillator (ICD) represent another group in which outpatient initiation of therapy can be tried, since the ICD provides protection against the risks associated with bradyarrhythmias and tachyarrhythmias. However, one should be cognizant of the potential effects of antiarrhythmic drugs on ventricular defibrillation threshold and ventricular tachycardia cycle length, which could influence the efficacy of ICD therapy. The initiation of antiarrhythmic drugs in patients with paroxysmal AF while they are in sinus rhythm is also associated with some risk. In a review of 409 outpatient initiation trials for a history of recurrent AF or atrial flutter, adverse cardiac events occurred in 17 (4.5 percent); these included three deaths, three permanent pacemakers for bradycardia, and 11 dose reductions for bradycardia [31]. Inpatient initiation with continuous telemetry of higher-risk drugs such as dofetilide and sotalol is typically done over a course of three days, which encompasses five half-lives allowing for achievement of steady-state plasma concentrations. In highly selected patients (eg, normal renal function, no bradycardia, and normal QT interval), sotalol can be loaded as outpatient with event monitor and closely following electrocardiogram for QT interval while in sinus rhythm. LONG-TERM ISSUES AF recurrence Recurrent atrial fibrillation (AF) should not necessarily be labeled as treatment failure. Some patients will elect to continue drug therapy (and, in some cases, occasional cardioversion) because the arrhythmia burden has been substantially reduced as evidenced by episodes that are less frequent, shorter, or associated with milder symptoms. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 9/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nonpharmacologic therapies are another option in such patients. (See "Atrial fibrillation: Atrioventricular node ablation" and "Atrial fibrillation: Catheter ablation".) If a patient has unacceptable recurrent AF on one antiarrhythmic drug, the drug is discontinued and another (and on rare occasion a third) agent is tried. Dosing The starting and maintenance doses for amiodarone, dronedarone, propafenone, flecainide, sotalol, disopyramide, and dofetilide are found in respective LexiComp drug monographs available in UpToDate. Many factors including age, sex, weight, renal or hepatic function, and characteristics on the electrocardiogram influence the starting dose for many of these. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Drug-related arrhythmias and mortality The use of antiarrhythmic drugs is associated with possible life-threatening side effects. The greatest concerns with these agents are proarrhythmia (and consequent tachyarrhythmia) and bradycardia. Patients should be instructed to report symptoms suggestive of the development of drug related arrhythmias, such as syncope, lightheadedness or dizzy spells, or worsening exercise intolerance. (See "Arrhythmia management for the primary care clinician", section on 'Antiarrhythmic drugs' and "Arrhythmia management for the primary care clinician", section on 'Symptoms'.) A 2012 meta-analysis of 56 studies (20,771 patients) compared one or more antiarrhythmic drugs to control or to each other [32]. Compared to controls, the use of the class IA antiarrhythmics quinidine and disopyramide (odds ratio 2.39, 95% CI 1.03-5.59) or sotalol (2.47, 95% CI 1.2-5.05) was associated with increased all-cause mortality, whereas the use of amiodarone, dronedarone, and dofetilide was not (odds ratios were not calculated for flecainide or propafenone). All antiarrhythmics studied showed increased pro-arrhythmic effects (counting both bradyarrhythmias and tachyarrhythmias attributable to treatment), with the exceptions of amiodarone, dronedarone, and propafenone. Proarrhythmia All of the antiarrhythmic drugs used to maintain sinus rhythm have the potential to increase ectopy or induce or aggravate monomorphic ventricular tachycardia (VT), torsades de pointes, or ventricular fibrillation (VF); this is referred to as proarrhythmia ( table 1). In addition to its baseline potential to predispose the patient to proarrhythmia, a drug that is initially safe may become proarrhythmic when the patient develops coronary heart disease or heart failure or is treated with other medications that in combination may be arrhythmogenic. Thus, the patient should be alerted to the potential significance of symptoms such as syncope https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 10/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate and dyspnea and warned about the use of noncardiac drugs that can prolong the QT interval ( table 2). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) We agree with the following recommendations made according to drug class in the American College of Cardiology/American Heart Association/European Society of Cardiology guideline [13]: With type IC drugs, QRS widening should not be permitted to exceed 150 percent of the baseline QRS duration. Exercise testing may detect QRS widening that occurs only at rapid heart rates (use-dependent conduction slowing). Exercise testing is also a useful way to screen for exercise-induced proarrhythmia and is typically performed one to two weeks after drug initiation. For type IA or type III drugs ( table 3), with the possible exception of amiodarone, the corrected QT interval in sinus rhythm should remain below 520 milliseconds. More specific and conservative recommendations are available for dofetilide in the package insert. During follow-up, serum creatinine, potassium, and magnesium concentrations should be monitored periodically because proarrhythmia is increased by renal insufficiency, which can lead to drug accumulation, hyperkalemia, and hypermagnesemia. The presence of renal insufficiency warrants dose reduction or cessation of sotalol and dofetilide. In comparison, amiodarone is metabolized in the liver and dose adjustment is probably necessary in patients with hepatic dysfunction. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse hepatic effects'.) Bradyarrhythmia Amiodarone and dronedarone can cause both sinus bradycardia and AV nodal block, with an overall incidence of bradycardic events of about 5 percent. Sotalol, like other beta blockers, can also cause bradycardia. In some cases, permanent pacemaker placement is necessary to permit continued use of these agents. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol".) Ambulatory monitoring Our authors and reviewers have differing thresholds for the use of ambulatory monitoring to screen for proarrhythmia and bradycardia, ranging from screening in the highest risk cases only to screening in everyone. Some experts suggest screening all patients with an ambulatory event monitor for at least two weeks after initiation of therapy, looking for QT interval prolongation or bradyarrhythmias. The basis for this recommendation is that many events occur after three days [31]. For those experts who are more selective based on patient risk, high-risk is defined as baseline bradycardia or borderline QT prolongation, heart failure, or systolic left ventricular dysfunction. Others perform routine monitoring when sotalol, flecainide, or propafenone are chosen. Dofetilide must be initiated in a setting with continuous monitoring. (See "Clinical use of dofetilide".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 11/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate For those patients who are not referred for ambulatory monitoring, we suggest that a 12-lead electrocardiogram be obtained after the initiation of antiarrhythmic drug therapy. Short- versus long-term therapy Based on concerns about drug related arrhythmias and the observation that the atrial action potential normalizes after two to four weeks of sinus rhythm (after AF), the concept that short-term therapy might be as effective and safer than long-term therapy has been proposed. This concept was tested in the Flec-SL non-inferiority trial, which randomly assigned 554 patients with persistent AF and who were intended to undergo cardioversion to either four weeks or six months of flecainide (200 to 300 mg per day) [33]. All patients had successful restoration of sinus rhythm and were then followed with daily telemetric electrocardiography (and Holter monitoring whenever AF was noted on two ECGs) for six months. The primary outcome of time to persistent AF or death occurred in 46 and 39 percent of patients, respectively, which did not meet the criteria of non-inferiority. In addition, a post-hoc analysis of patients who had not reached the primary endpoint in the first month found long- term therapy to be superior (Kaplan-Meier estimate of difference 14.3 percent; hazard ratio 0.3; p = 0.0001). We do not consider short-term therapy appropriate for most patients with persistent AF. Concerns about dronedarone Patients with severe heart failure (HF) (generally those with NYHA class III or IV HF, or those who have been hospitalized with HF in the past four weeks) or those with an ejection fraction of <35 percent should not receive dronedarone. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) The Permanent Atrial fibriLLAtion outcome Study (PALLAS) was designed to test the hypothesis that dronedarone would improve major outcomes in 10,000 patients with permanent AF, over 70 percent of whom had New York Heart Association heart failure class I to III or left ventricular systolic dysfunction at baseline. The rationale was that patients with permanent AF, which affects up to 50 percent of patients with AF, have an increased risk of adverse cardiovascular outcomes including death and myocardial infarction as well as systemic embolization. The ATHENA trial showed a significant reduction in cardiovascular events with dronedarone in patients with paroxysmal or persistent AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled), after a significantly increased risk (Hazard Ratio 2.29, 95% CI 1.34-3.94) of cardiovascular events https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 12/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [34]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. (See 'Summary and recommendations' below.) The European Medicines Agency and the United States Food and Drug Agency (USFDA) have advised against the use of dronedarone in patients with permanent AF [35,36]. In addition, the USFDA now recommends that people taking the drug should have an electrocardiogram every three months to make sure that AF has not become permanent. For patients taking dronedarone, routine monitoring of lung and liver function is not mandated by the USFDA; however, periodic monitoring may be reasonable [37]. (See "Clinical uses of dronedarone", section on 'Maintenance of sinus rhythm'.) Follow-up We consider the following approach to follow-up reasonable: We perform an ECG one week after initiation of any antiarrhythmic drug. We typically see patients within three months of initiating a new antiarrhythmic drug to assess efficacy and side effects. This is in addition to commonly performing ambulatory monitoring after drug initiation. Patients are typically seen every 6 to 12 months unless there are particular concerns regarding QT interval prolongation, bradycardia, or other issues identified on the ECG. Specific follow-up recommendations for individual drugs are presented separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol", section on 'Major side effects' and "Clinical use of dofetilide", section on 'Safety' and "Major side effects of class I antiarrhythmic drugs", section on 'Flecainide' and "Major side effects of class I antiarrhythmic drugs", section on 'Propafenone'.) RECOMMENDATIONS OF OTHERS Our recommendations for the use of antiarrhythmic drugs to maintain sinus rhythm in patients with AF are generally in agreement with recommendations from the American Heart Association/American College of Cardiology/Heart Rhythm Society (2014) and its 2019 focused update, as well as the European Society of Cardiology (2016) [15,38-40]. (See 'Summary and recommendations' below.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 13/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)") SUMMARY AND RECOMMENDATIONS For those patients with atrial fibrillation (AF) in whom a rhythm-control strategy is chosen, the principal goal is to reduce symptoms by decreasing the frequency and duration of episodes [1,2]. (See 'Initial management decisions' above.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia. (See 'Selecting an antiarrhythmic drug' above.) Compared to placebo, amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective for the maintenance of sinus rhythm, but maintenance rates at one year are significantly less than 75 percent. Amiodarone is consistently more effective than the other antiarrhythmic drugs. (See 'Selecting an antiarrhythmic drug' above.)

electrocardiogram be obtained after the initiation of antiarrhythmic drug therapy. Short- versus long-term therapy Based on concerns about drug related arrhythmias and the observation that the atrial action potential normalizes after two to four weeks of sinus rhythm (after AF), the concept that short-term therapy might be as effective and safer than long-term therapy has been proposed. This concept was tested in the Flec-SL non-inferiority trial, which randomly assigned 554 patients with persistent AF and who were intended to undergo cardioversion to either four weeks or six months of flecainide (200 to 300 mg per day) [33]. All patients had successful restoration of sinus rhythm and were then followed with daily telemetric electrocardiography (and Holter monitoring whenever AF was noted on two ECGs) for six months. The primary outcome of time to persistent AF or death occurred in 46 and 39 percent of patients, respectively, which did not meet the criteria of non-inferiority. In addition, a post-hoc analysis of patients who had not reached the primary endpoint in the first month found long- term therapy to be superior (Kaplan-Meier estimate of difference 14.3 percent; hazard ratio 0.3; p = 0.0001). We do not consider short-term therapy appropriate for most patients with persistent AF. Concerns about dronedarone Patients with severe heart failure (HF) (generally those with NYHA class III or IV HF, or those who have been hospitalized with HF in the past four weeks) or those with an ejection fraction of <35 percent should not receive dronedarone. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) The Permanent Atrial fibriLLAtion outcome Study (PALLAS) was designed to test the hypothesis that dronedarone would improve major outcomes in 10,000 patients with permanent AF, over 70 percent of whom had New York Heart Association heart failure class I to III or left ventricular systolic dysfunction at baseline. The rationale was that patients with permanent AF, which affects up to 50 percent of patients with AF, have an increased risk of adverse cardiovascular outcomes including death and myocardial infarction as well as systemic embolization. The ATHENA trial showed a significant reduction in cardiovascular events with dronedarone in patients with paroxysmal or persistent AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled), after a significantly increased risk (Hazard Ratio 2.29, 95% CI 1.34-3.94) of cardiovascular events https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 12/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [34]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. (See 'Summary and recommendations' below.) The European Medicines Agency and the United States Food and Drug Agency (USFDA) have advised against the use of dronedarone in patients with permanent AF [35,36]. In addition, the USFDA now recommends that people taking the drug should have an electrocardiogram every three months to make sure that AF has not become permanent. For patients taking dronedarone, routine monitoring of lung and liver function is not mandated by the USFDA; however, periodic monitoring may be reasonable [37]. (See "Clinical uses of dronedarone", section on 'Maintenance of sinus rhythm'.) Follow-up We consider the following approach to follow-up reasonable: We perform an ECG one week after initiation of any antiarrhythmic drug. We typically see patients within three months of initiating a new antiarrhythmic drug to assess efficacy and side effects. This is in addition to commonly performing ambulatory monitoring after drug initiation. Patients are typically seen every 6 to 12 months unless there are particular concerns regarding QT interval prolongation, bradycardia, or other issues identified on the ECG. Specific follow-up recommendations for individual drugs are presented separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol", section on 'Major side effects' and "Clinical use of dofetilide", section on 'Safety' and "Major side effects of class I antiarrhythmic drugs", section on 'Flecainide' and "Major side effects of class I antiarrhythmic drugs", section on 'Propafenone'.) RECOMMENDATIONS OF OTHERS Our recommendations for the use of antiarrhythmic drugs to maintain sinus rhythm in patients with AF are generally in agreement with recommendations from the American Heart Association/American College of Cardiology/Heart Rhythm Society (2014) and its 2019 focused update, as well as the European Society of Cardiology (2016) [15,38-40]. (See 'Summary and recommendations' below.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 13/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)") SUMMARY AND RECOMMENDATIONS For those patients with atrial fibrillation (AF) in whom a rhythm-control strategy is chosen, the principal goal is to reduce symptoms by decreasing the frequency and duration of episodes [1,2]. (See 'Initial management decisions' above.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia. (See 'Selecting an antiarrhythmic drug' above.) Compared to placebo, amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective for the maintenance of sinus rhythm, but maintenance rates at one year are significantly less than 75 percent. Amiodarone is consistently more effective than the other antiarrhythmic drugs. (See 'Selecting an antiarrhythmic drug' above.) In addition to less-than-optimal efficacy, serious drug-related adverse side effects limit the use of these drugs. Antiarrhythmic drug therapy should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risks https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 14/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' above.) Based upon the potential for drug toxicity in the form of induced bradycardia or tachycardia, many patients will need to be hospitalized for continuous electrocardiographic monitoring. Dofetilide must be initiated in a setting with continuous monitoring. (See 'Inpatient versus outpatient initiation' above.) For patients with no structural heart disease and no apparent risk for drug-induced bradycardia or tachycardia, we suggest flecainide or propafenone as the preferred antiarrhythmic drug (Grade 2B). Amiodarone, dofetilide, dronedarone, or sotalol may be used, with sotalol chosen more often by our authors and reviewers. Practitioners should choose only those agents with which they have significant familiarity. (See 'Atrial fibrillation without structural heart disease' above.) For patients with coronary artery disease who do not have advanced heart failure, we suggest dronedarone or sotalol in preference to amiodarone (Grade 2B). Amiodarone is a reasonable choice in patients who prefer its greater efficacy despite its worse extracardiac side-effect profile. (See 'Coronary heart disease' above.) For patients with heart failure, we suggest amiodarone in preference to dofetilide (Grade 2B). Flecainide, propafenone, dronedarone, and sotalol are contraindicated in these patients. (See 'Heart failure' above.) For patients with left ventricular hypertrophy, either amiodarone or dronedarone is generally preferred to other antiarrhythmic agents. Our authors and reviewers have differing approaches, with some choosing amiodarone more often and others choosing dronedarone more often. (See 'Left ventricular hypertrophy' above.) After the initiation of antiarrhythmic drug therapy, screening for drug-associated arrhythmia with ambulatory monitoring should be considered, particularly for patients at high risk of drug-induced arrhythmia. This includes those with baseline bradycardia or borderline QT prolongation, heart failure, or systolic left ventricular dysfunction. (See 'Ambulatory monitoring' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 15/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate 2. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. 3. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2003; 139:1009. 4. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 5. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 6. K hlkamp V, Schirdewan A, Stangl K, et al. Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2000; 36:139. 7. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 8. Lafuente-Lafuente C, Mouly S, Long s-Tejero MA, et al. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med 2006; 166:719. 9. Flaker G, Lopes RD, Hylek E, et al. Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. J Am Coll Cardiol 2014; 64:1541. 10. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82:1106. 11. Steeds RP, Birchall AS, Smith M, Channer KS. An open label, randomised, crossover study comparing sotalol and atenolol in the treatment of symptomatic paroxysmal atrial fibrillation. Heart 1999; 82:170. 12. Plewan A, Lehmann G, Ndrepepa G, et al. Maintenance of sinus rhythm after electrical cardioversion of persistent atrial fibrillation; sotalol vs bisoprolol. Eur Heart J 2001; 22:1504. 13. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57:223. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 16/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate 14. Herweg B, Dalal P, Nagy B, Schweitzer P. Power spectral analysis of heart period variability of preceding sinus rhythm before initiation of paroxysmal atrial fibrillation. Am J Cardiol 1998; 82:869. 15. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 16. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010; 12:1360. 17. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089. 18. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913. 19. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 20. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003; 42:20. 21. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 22. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30:791. 23. Zimetbaum P, Josephson ME. Is there a role for maintaining sinus rhythm in patients with atrial fibrillation? Ann Intern Med 2004; 141:720. 24. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 17/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate 25. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 26. Podrid PJ, Anderson JL. Safety and tolerability of long-term propafenone therapy for supraventricular tachyarrhythmias. The Propafenone Multicenter Study Group. Am J Cardiol 1996; 78:430. 27. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 28. Morganroth J, Anderson JL, Gentzkow GD. Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide. J Am Coll Cardiol 1986; 8:607. 29. Reiffel JA, Camm AJ, Belardinelli L, et al. The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism. Circ Arrhythm Electrophysiol 2015; 8:1048. 30. Maisel WH, Kuntz KM, Reimold SC, et al. Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med 1997; 127:281. 31. Hauser TH, Pinto DS, Josephson ME, Zimetbaum P. Safety and feasibility of a clinical pathway for the outpatient initiation of antiarrhythmic medications in patients with atrial fibrillation or atrial flutter. Am J Cardiol 2003; 91:1437. 32. Lafuente-Lafuente C, Longas-Tejero MA, Bergmann JF, Belmin J. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2012; :CD005049. 33. Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open- label, blinded endpoint assessment trial. Lancet 2012; 380:238. 34. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268. 35. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/09/new s_detail_001344.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac0 58004d5c1. 36. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPro ducts/ucm264204.htm. 37. http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm. 38. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 18/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 39. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 40. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1035 Version 60.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 19/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate GRAPHICS Rate control versus rhythm control in AFFIRM Results of the AFFIRM trial in which 4060 patients with atrial fibrillation (AF) that was likely to be recurrent were randomly assigned to rhythm or rate control. The primary end point was overall mortality. There was an almost significant trend toward lower mortality with rate control (21.3 versus 23.8 percent, hazard ratio 0.87, 95 percent CI 0.75 to 1.01). Data from Wyse DG, Waldo AL, DiMarco JP, et al. N Engl J Med 2002; 347:1825. Graphic 61608 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 20/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rate control versus rhythm control in RACE Results of the RACE trial in which 522 patients with recurrent persistent atrial fibrillation (AF) were randomly assigned to rhythm or rate control. The primary end point was a composite of cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker placement, and antiarrhythmic drug side effects. There was an almost significant trend toward a lower incidence of the primary end point with rate control (17.2 versus 22.6 percent with rhythm control, hazard ratio 0.73, 90 percent CI 0.53 to 1.01). Data from Van Gelder IC, Hagens VE, Bosker HA, et al. N Engl J Med 2002; 347:1834. Graphic 74434 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 21/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate The rate of recurrent atrial fibrillation is lowest with amiodarone The Canadian Trial of Atrial Fibrillation randomized 403 patients with at least one episode of atrial fibrillation (AF) during the prior six months to low-dose amiodarone, propafenone, or sotalol. After a mean follow-up of 16 months, the likelihood of being free from recurrent AF was highest with amiodarone (65 versus 37 percent for sotalol and propafenone) and the median time to recurrence was longer (>468 versus 98 days). Data from: Roy D, Talajic M, Dorian P, et al. N Engl J Med 2000; 342:913. Graphic 69285 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 22/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Strategies for rhythm control in patients with paroxysmal* and persistent AF AF: atrial fibrillation; CAD: coronary artery disease; HF: heart failure; LVH: left ventricular hypertrophy; AV: atrioventricular. Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (Class IIa recommendation). Drugs are listed alphabetically. Depending on patient preference when performed in experienced centers. Not recommended with severe LVH (wall thickness >1.5 cm). Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. Should be combined with AV nodal blocking agents. Reproduced from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. DOI: 10.1016/j.jacc.2014.03.021. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 95079 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 23/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Types of proarrhythmia during treatment with antiarrhythmic drugs (AADs) for atrial fibrillation or atrial flutter according to the Vaughan Williams Classification Ventricular proarrhythmia Torsade de pointes (Vaughan Williams class IA and type III drugs) Sustained monomorphic ventricular tachycardia (usually class IC drugs) Sustained polymorphic ventricular tachycardia/ventricular fibrillation without long QT interval (class IA, IC, and III drugs) Atrial proarrhythmia Provocation of recurrence (probably class IA, IC, and III drugs) Conversion of atrial fibrillation (AF) to atrial flutter (usually class IC drugs) with 1:1 conduction Increase of defibrillation threshold (a potential problem with class IC drugs) Abnormalities of conduction or impulse formation Accelerate ventricular rate during AF (class IA and type IC drugs) Accelerate conduction over accessory pathway (digoxin, type IV drugs) Sinus node dysfunction, atrioventricular block (almost all drugs) Vaughan Williams classification of AADs used for the treatment of atrial fibrillation or flutter Class IA - Disopyramide, procainamide, quinidine Class IC - Flecainide, propafenone Class III - Amiodarone, dofetilide, ibutilide, sotalol Class IV - Nondihydropyridine calcium channel blockers (diltiazem and verapamil) Data from Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial brillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to revise the 2001 guidelines for the management of patients with atrial brillation). J Am Coll Cardiol 2006; 48:e149. Graphic 66133 Version 4.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 24/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 25/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, especially with Hypocalcemia Diuretic therapy via electrolyte disorders Starvation particularly hypokalemia and hypomagnesemia prominent T-wave Anorexia nervosa Herbs inversions Liquid protein diets Cinchona (contains quinine), iboga Intracranial Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances disease Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine (intracoronary) Vandetanib Dofetilide Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 26/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine antimoniate Clarithromycin Flecainide Sparfloxacin Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil (systemic) Terbutaline Nilotinib Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate Dasatinib Vemurafenib oral) dimeglumine Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 27/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 28/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 29/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 30/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 31/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 28/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 29/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 30/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 31/32 7/6/23, 2:50 PM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 32/32

7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Arrhythmia management for the primary care clinician : Samuel L vy, MD, Brian Olshansky, MD : Hugh Calkins, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 03, 2021. INTRODUCTION Clinicians in many disciplines commonly face the problem of evaluating and treating patients with cardiac arrhythmias ( table 1). Carefully performed randomized trials, technological advances, and better understanding of arrhythmia mechanisms using intracardiac recordings and programmed electrical stimulation and mapping techniques have resulted in improved approaches to rhythm disturbances. Basic evaluation and management principles are key to the initial approach to the patient with an arrhythmia. There are several reasons to evaluate and treat arrhythmias: Eliminate symptoms and improve abnormal hemodynamics which can result from arrhythmias. Prevent imminent death and hemodynamic compromise due to a life-threatening arrhythmia. To assess the patient's risk of potentially developing a life-threatening arrhythmia, thereby allowing for possible preventive measures. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Reduce possible risks other than the direct effects of the arrhythmia (eg, reduce stroke in patients with atrial fibrillation). This topic will provide an overview of early diagnosis and management of rhythm disturbances in patients who present to primary care clinicians (PCCs). The reader will be referred to detailed https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 1/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate discussions of the individual arrhythmias. The role of the PCC in the evaluation of palpitations is discussed separately. (See "Evaluation of palpitations in adults".) DEFINITION An arrhythmia is any rhythm that is not normal sinus rhythm with normal atrioventricular (AV) conduction. Normal sinus rhythm originates from the sinus node in the upper portion of the right atrium. During sinus rhythm, the heart rate is in the normal range, the P waves are normal on the electrocardiogram (ECG), and the rate is stable. The normal sinus rate at rest has been considered to be between 60 and 100 beats per minute (bpm). However, the range (defined by two standard deviations from the mean) is between 43 and 93 bpm for men and 52 and 94 bpm for women. Sinus bradycardia or tachycardia may be physiologic (ie, normal) or nonphysiologic (ie, abnormal); each is discussed separately. (See "Sinus bradycardia" and "Sinus tachycardia: Evaluation and management".) Not uncommonly, the activation rate of the sinus node varies, leading to a variable P-P interval on the ECG. If the variation of the P-P interval is 0.12 sec (120 ms) or more in the presence of normal P waves, this is known as sinus arrhythmia. Sinus arrhythmia is usually physiologic and is related to respiratory cycles. It does not require treatment. (See "Normal sinus rhythm and sinus arrhythmia" and "Etiology of atrioventricular block".) ECG documentation, age of the patient, and the clinical context in which the arrhythmia occurs are critical to the proper management. COMMON ARRHYTHMIAS Common arrhythmias encountered in an office-based setting include: Premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat). Ventricular premature beats (VPBs) ( waveform 1). Bradycardias ( waveform 2), including sinus bradycardia ( waveform 2 and table 2). Ventricular tachycardia ( waveform 3A-B). Atrial fibrillation (AF) and atrial flutter ( waveform 4A-B). https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 2/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Supraventricular tachycardia (SVTs) ( waveform 5 and figure 1). AV block ( waveform 6). Nonsustained ventricular tachycardia (NSVT) ( waveform 7). Follow-up of already treated VT or ventricular fibrillation (VF). The diagnosis of these arrhythmias may be difficult, even for an experienced specialist in rhythm disturbances. As an example, the etiology of wide or narrow QRS tachycardias may be difficult to determine based upon the 12-lead ECG. (See "Wide QRS complex tachycardias: Approach to the diagnosis" and "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation".) Some rhythm disturbances, such as symptomatic bradycardia (with syncope or near syncope), rapid rates in atrial fibrillation, or sustained ventricular tachycardia, require urgent attention. Others, such as ectopic atrial and ventricular beats, may cause concern but do not need immediate management. In some cases, these concerning arrhythmias may be a sign of underlying cardiovascular pathology that requires attention more than the rhythm disturbance itself (eg, conditions like arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, etc). ROLE OF THE PCC IN LONG-TERM CARE The role of the primary care clinician (PCC) in the long-term care of patients with arrhythmias depends upon the particular arrhythmia diagnosis and treatment. All patients should be queried at each routine visit about changes in symptoms relevant to the arrhythmia and its treatment. Frequently, it becomes difficult to determine if a rhythm disturbance is benign or potentially serious and life-threatening. Furthermore, the association of symptoms with a rhythm disturbance can be confusing. As such, consultation with a cardiologist or an electrophysiologist may be required to help make the diagnosis and help with risk stratification. Commonly, the PCC can work in collaboration with long-term follow-up of the patient who has rhythm disturbances after the diagnosis is secured and an initial management has been undertaken. Patients with pacemakers, implantable cardioverter defibrillators, or cardiac resynchronization therapy are best followed periodically and evaluated by clinicians knowledgeable in device programming, device characteristics, and complications. Patients prescribed antiarrhythmic drug therapy, or those who have undergone an interventional procedure or catheter ablation therapy, are generally followed by a cardiologist https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 3/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate and/or cardiac electrophysiologist in collaboration with the PCC. APPROACH TO THE PATIENT Patients typically seek medical care for symptoms associated with an arrhythmia. In addition, some asymptomatic arrhythmias and findings require careful evaluation and management. An abnormal ECG that shows a rhythm disturbance different from sinus rhythm even in an asymptomatic patient requires careful assessment to determine long-term risks of symptoms and potential life-threatening outcomes. Occasionally, an asymptomatic patient who has an irregular pulse on examination, or who has an ECG, ambulatory monitor, or exercise test for another reason is found to have an arrhythmia or evidence that may indicate an arrhythmia may be present. Patients may also be referred for evaluation if they have a finding or condition associated with risk of arrhythmia, such as a short PR interval, a delta wave, a long QT interval on an ECG, or hypertrophic cardiomyopathy identified by an echocardiogram. Additionally, patients who have evidence of heart failure (HF) may be at risk for potentially serious and life-threatening rhythm disturbances that require more in-depth evaluation and assessment. In addition, individuals with family history of sudden death or heritable genetic syndromes (long QT syndrome, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy) are referred for arrhythmia evaluation, as discussed separately. (See "Congenital long QT syndrome: Diagnosis" and "Brugada syndrome or pattern: Management and approach to screening of relatives", section on 'Screening relatives' and "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Screening of family members'.) The initial evaluation of the patient with an arrhythmia consists of a complete history (aimed toward symptoms and timing of the arrhythmia and potential underlying diseases), physical examination, and 12-lead ECG, if possible, during the arrhythmia and without it. The ECG alone during the arrhythmia may determine the type of arrhythmia and whether a particular symptom is related to the arrhythmia. Symptoms The presence and type of symptoms may determine whether any action needs to be taken. Symptoms may be related to the arrhythmia (eg, palpitations) or due to the hemodynamic consequences of the arrhythmias (eg, dyspnea, dizziness, or syncope). Symptoms caused by cardiac arrhythmias can mimic those due to other medical disorders and include palpitations, dizziness, lightheadedness, syncope, chest discomfort, neck discomfort, https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 4/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate dyspnea, weakness, and anxiety. Secondary consequences of arrhythmias, often due to underlying heart disease, are an additional source of symptoms (eg, HF, ischemia, and thromboemboli). Cardiac arrhythmias can have unusual symptomatic presentations such as tinnitus, visual changes, increased urinary frequency, abdominal discomfort, and peripheral edema. Arrhythmias may cause a change in sympathetic and vagal tone, hormonal changes, elevation of venous pressure, and reduced cardiac output, all of which can lead to an even longer list of other symptoms. Symptom type and severity are related to the etiology and rate of the arrhythmia, and to the nature and severity of underlying cardiovascular disease and concurrent conditions. The symptom severity often dictates the urgency for therapy or even the need to evaluate and treat. The presence of structural heart disease is a key issue that determines the urgency of intervention, evaluation, therapy, and the prognostic importance of the arrhythmia. Arrhythmias commonly cause palpitations. The approach to the patient who presents with palpitations is found elsewhere. (See "Evaluation of palpitations in adults".) Diagnosis While the patient's age, medical history, and physical exam may strongly suggest the diagnosis, such as in a patient with lightheadedness and a rapid and irregularly irregular pulse (atrial fibrillation), the diagnosis requires documentation with an ECG or a monitor. (See "ECG tutorial: Atrial and atrioventricular nodal (supraventricular) arrhythmias" and "ECG tutorial: Atrioventricular block" and "ECG tutorial: Basic principles of ECG analysis" and "ECG tutorial: Intraventricular block" and "ECG tutorial: Rhythms and arrhythmias of the sinus node" and "ECG tutorial: Ventricular arrhythmias".) Many patients with a suspected arrhythmia have a paroxysmal pattern, so that the ECG recorded in the absence of symptoms is either normal or does not suggest a specific arrhythmia. Four types of outpatient monitoring systems are available (see "Ambulatory ECG monitoring"): Traditional Holter Continuous recording of ECG, usually for 24 or 48 hours. Event recorder Patient activated recorder, although some newer models have automatic arrhythmia detection software to store asymptomatic episodes. Data is transmitted over the phone to a monitoring station. Mobile continuous outpatient cardiac telemetry Continuous recording and analysis, with symptomatic or algorithm defined episodes transmitted automatically via cellular technology to monitoring station. https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 5/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Insertable cardiac monitor Patient and algorithm defined episodes stored in device, until interrogated either in office or remotely via home equipment and internet. Ambulatory monitoring to assess for arrhythmia is frequently indicated in the evaluation of patients with syncope [1]. An event recorder or transtelephonic monitor can help make the diagnosis in a patient with less frequent palpitations [2]. Transtelephonic ECG devices exist in several forms of recorders and transmitters capable of direct transmission of an ECG as an audio signal by telephone. These ECG signals are most commonly received at a base station equipped with a demodulator and an ECG strip chart recorder. Although such devices usually provide limited, noncontinuous sample ECG data, the device may be used in either a noncontinuous or continuous format. Transtelephonic devices with memory that record and are applied non-continuously are small (beeper size), lightweight instruments that are generally inexpensive. These devices are carried by the patient; they can be applied with temporary contact to the precordial area, or are attached by electrodes and worn continuously. The memory feature allows recording of data without the need for immediate access to telephone transmission. Transtelephonic monitoring includes wrist recorders whose circuitry is completed by contact of the index finger and thumb, or hand contact to the opposite wrist. This action results in the loop storage of a four- to five-minute ECG sample of lead I, and permits direct printout or transtelephonic transmission. The stored data may be transmitted by telephone directly to a facsimile machine. An implantable monitor (Reveal, Medtronic, Minneapolis, United States) is available in Europe and will be available soon in the United States. (See "Ambulatory ECG monitoring".) New patch monitors have become available that can record over a period of several weeks of data. Smartphone apps have been used to revolutionize external recording techniques and to detect atrial fibrillation. Other over-the-counter monitoring approaches (using certain types of watches) and other types of electrodes coupled to cell phones are now being used to detect atrial fibrillation and other rhythm disturbances. If episodes are associated with exercise or physical or mental stress or when an arrhythmia cannot be documented with ambulatory or transtelephonic monitoring, a treadmill or bicycle ergometer may be helpful to establish the presence and mechanism of the arrhythmia, particularly if the arrhythmia is triggered by exercise. In some instances, the rhythm disturbance is simply a lack of change in the heart rate with exercise or with excessive heart rates during exercise. https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 6/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate In some instances, such as in selected patients with unexplained syncope, an insertable cardiac monitor (sometimes referred to as an implantable cardiac monitor or an implantable loop recorder) may be indicated to detect the arrhythmia that may be responsible for patient symptoms based on the correlation between the symptoms and the recorded arrhythmias. (See "Ambulatory ECG monitoring", section on 'Insertable cardiac monitor'.) Patients identified with an arrhythmia For any patient with a diagnosed arrhythmia, several questions should be considered and hopefully answered in short order: Which arrhythmia(s) is present? Does the arrhythmia pose an immediate or long-term risk to the patient? Is the arrhythmia well-tolerated (based on symptoms and blood pressure)? Does the arrhythmia require immediate intervention, such as medical therapy or cardioversion? Does the patient require urgent hospitalization for the arrhythmia and/or associated underlying conditions (eg, underlying heart disease)? Is specialist consultation required, and if so, when? Should anticoagulation and/or other medical therapy be started and when? Asymptomatic patients Patients with asymptomatic arrhythmias rarely require urgent treatment, but evaluation of the arrhythmia is important to determine its clinical significance and appropriate management. In patients who have low risk for serious outcomes, a clinician may choose to refer the patient on an elective basis to a cardiologist or cardiac electrophysiologist. Additionally, the arrhythmias needs to be understood in light of any underlying medical diagnosis. For example, occasional asymptomatic PVCs may have little importance in young, otherwise healthy individuals but may portend a poor prognosis in patients with HF and cardiomyopathy. Symptomatic patients For patients who are symptomatic in the office, the testing strategy is based on an understanding of the suspected cause for the symptoms and symptom severity. The management strategy will depend both on the characteristics of the symptoms and the type of arrhythmia present if diagnosed. In the following clinical scenarios, we recommend urgent transfer to a facility with emergency care capabilities: Syncope or near syncope in patients with high degree AV block (ie, Mobitz type II second degree or third degree [complete] AV block) or bradycardia. https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 7/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Wide complex sustained rhythms (other than sinus with bundle branch block) including ventricular tachycardia especially if not well tolerated or associated with hypotension. Patients in whom the diagnosis is uncertain after examination and ECG, but for whom there is a concern about a life-threatening arrhythmia. Patients with a history of heart disease (including coronary artery disease, cardiomyopathy, or HF) who present with syncope, near syncope, and/or documented ventricular arrhythmia. Sustained supraventricular tachycardia (SVT). Atrial fibrillation or flutter with rapid or slow rates. Arrhythmias associated with chest pain, dyspnea or HF. Emergent cardioversion is not indicated for any conscious patient, including those with ventricular tachycardia, except if it is associated with hemodynamic compromise (systolic blood pressure [SBP] <80 mmHg). However, urgent cardioversion may be required if the rhythm is not tolerated well. Cardioversion has risks and should not be undertaken if there is a risk of a thromboembolic event that could be precipitated by electrical shock. Such may be the case for a patient who is not adequately anticoagulated and in atrial fibrillation for more than 24 hours. (See "Cardioversion for specific arrhythmias" and "Atrial fibrillation: Cardioversion".) Referral to a specialist Arrhythmias such as isolated PACs or ventricular premature beats (VPBs), or atrial fibrillation, are common in the general population and many primary care clinicians (PCC) are comfortable and capable of managing patients with these. We suggest elective referral to a cardiologist for the following patients: Any patient with an arrhythmia when the PCC is uncomfortable with either diagnosis or management. Candidates for permanent pacing. Those with an uncertain diagnosis, prognosis, or management strategy. Patients with wide QRS complex tachycardia of uncertain cause should generally be referred to a clinical electrophysiologist to define appropriate evaluation (such as an electrophysiologic study) and management. Patients with structural heart disease and ventricular arrhythmia should generally be referred to an electrophysiologist. Those who might benefit from implantation of a pacemaker, an implantable cardioverter defibrillator, or biventricular device (cardiac resynchronization therapy [CRT]). https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 8/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Those who might benefit from a catheter ablation procedure. Those who might benefit from antiarrhythmic drug therapy (eg, particularly patients with structural heart disease). Those who have a confusing picture, difficult to interpret ECG, or unusual findings on a monitor. THERAPEUTIC CONSIDERATIONS The goal of therapy for any arrhythmia is to improve symptoms and to prevent a potentially serious outcome, primarily a life-threatening arrhythmia and sudden death. Stroke prevention in patients with atrial fibrillation and atrial flutter is also an important treatment objective. The decision to initiate a long-term treatment strategy, whether it be with device or drug therapy, depends upon the severity and frequency of arrhythmia-related symptoms compared to the risks associated with the therapy itself. The need for long-term therapy must be carefully individualized to each patient since the severity and importance of symptoms are highly variable. The symptoms associated with any arrhythmia can have an impact on lifestyle, occupation, driving, and other important daily activities. In most cases, initiation of antiarrhythmic drug therapy will be guided by a cardiologist or cardiac electrophysiologist. Pacemakers, implantable cardioverter-defibrillators (ICDs), and biventricular devices are generally implanted by electrophysiologists or other clinicians with special training and certification in their placement. The ability to interrogate the devices long term is also necessary. The long-term follow-up of patients with implanted devices also requires special training and expertise. Antiarrhythmic drugs We suggest the involvement of a specialist (cardiologist or electrophysiologist) when initiation of any antiarrhythmic drug is considered. Antiarrhythmic drugs have the potential to increase premature ventricular contractions or induce or aggravate monomorphic ventricular tachycardia (VT), torsades de pointes, ventricular fibrillation (VF), conduction disturbances, or bradycardia. This phenomenon is known as proarrhythmia ( table 3). The potential for major adverse outcomes, including death, requires the expertise of a specialist who understands the use and risks of these drugs. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 9/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate The risk of proarrhythmia is higher for class I drugs ( table 4) in patients with structural heart disease, especially coronary heart disease and/or left ventricular dysfunction, than in patients with structurally normal heart disease. Class II drugs (beta blockers, except sotalol, which also has class III properties at higher dosing), have no proarrhythmic effects but can cause bradycardia. Class III drugs prolong repolarization and pose the specific risk of torsades de pointes or ventricular tachycardia. Although the exact incidence of proarrhythmia is not certain, it appears to be relatively low when antiarrhythmic drugs are used carefully and properly. The risk varies according to the type of arrhythmia treated, the presence of structural heart disease, the QT interval, pre-existing conduction disturbances, sinus node dysfunction, patient age, the presence of HF, and left and right ventricular function. The proarrhythmic risk is highest in patients with depressed left ventricular function (eg, ejection fraction [EF] <0.30), the group at highest risk for an arrhythmic event and sudden death and in case of ionic disturbance (hypokalemia); the risk is lowest in those with no organic heart disease. Proarrhythmia can be predictable and is most often idiosyncratic. However, it may be dose- related for specific drugs, including sotalol, dofetilide, class IC drugs, and the metabolite of procainamide, N-acetyl procainamide. Torsades de pointes is the most recognized form of drug proarrhythmia. It is characterized by a VT with a twisting of the peaks of the QRS complexes across an imaginary isoelectric line ( waveform 8A-C). The QT interval is prolonged, bradycardia is often present, and the arrhythmia is induced after a short-long cycle. Torsades de pointes was originally recognized as a complication of quinidine use, being the mechanism for "quinidine syncope." Many non- antiarrhythmic drugs, including some antibiotics, antipsychotics, and other classes of drugs, can increase the risk of torsades de pointes via prolongation of the QT interval ( table 5). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Initiation of therapy Therapy with some (but not all) antiarrhythmic drugs is best initiated in the hospital, primarily to monitor for early proarrhythmia. The decision to hospitalize depends upon several factors: The presence and severity of structural heart disease. The indication for treatment (eg, etiology of the arrhythmia and type and severity of associated symptoms). Treatment for ventricular tachycardia is usually started in the hospital. https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 10/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate The drug used. For example, the labeling information for dofetilide and sotalol specify inpatient initiation, while flecainide, propafenone, dronedarone, and amiodarone can generally be initiated outside the hospital in appropriate patients. Following the initiation of an antiarrhythmic drug, patients should have periodic monitoring with an ECG and laboratory tests. The frequency of such tests is higher at the time of initiation and dose adjustment. Careful monitoring of electrolytes may help reduce the risk of proarrhythmia. Assessment of renal and/or hepatic function is also important depending on the agent(s) being used. These drugs may interact with other drugs, which also require monitoring (for example, amiodarone tends to increase the International Normalized Ratio [INR] and digoxin level) Patients taking amiodarone should have assessment of hepatic, thyroid, and pulmonary function on a regular basis, or with any symptoms that suggest possible organ toxicity. Patients taking amiodarone should also be cautioned regarding skin photosensitivity. Class IC antiarrhythmic drugs should be avoided in patients with ventricular dysfunction (given their negative inotropic effects) or evidence of ischemic heart disease (given the risk of proarrhythmia). (See "Major side effects of class I antiarrhythmic drugs".) SPECIFIC ARRHYTHMIAS Atrial fibrillation and flutter The preceding discussion has emphasized the symptoms (eg, palpitations, dyspnea, chest pain and syncope) and life-threatening potential of an arrhythmia itself. Atrial fibrillation (AF) and flutter are associated with additional therapeutic issues, each of which must be addressed. Reversion to sinus rhythm Maintenance of sinus rhythm Slowing the ventricular rate in persistent or permanent atrial fibrillation Prevention of systemic embolization and stroke, both at the time of reversion and in patients chronically These issues are discussed in detail separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) Premature atrial complex A PAC is the early activation of the atria arising from a site other than the sinus node. PACs are observed on the surface ECG as a P wave that occurs relatively early in the cardiac cycle (ie, prematurely before the next sinus P wave should occur) and has a different morphology from the sinus P wave. Often the PR interval is different from that during https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 11/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate sinus rhythm; it may be longer or shorter, depending upon the site of origin of the PAC. (See "ECG tutorial: Atrial and atrioventricular nodal (supraventricular) arrhythmias".) PACs may be asymptomatic or cause symptoms such as a sensation of "skipping" or palpitations. PACs are often single and isolated, but may be frequent and may occur in a bigeminal (every other beat) or other repeated pattern. A trigger/stimulant is often identified and its removal may eliminate or significantly reduce symptoms. Antiarrhythmic drug therapy, aside from beta blockers, is rarely recommended. (See "Supraventricular premature beats".) PACs may be blocked in the AV conducting system. This is not necessarily pathologic, and it needs to be differentiated from AV block. Ventricular premature beats Ventricular premature beats (VPBs) are common in the general population and often cause patients to seek medical attention. This includes patients without structural heart disease and those with any form of cardiac disease, independent of severity. The evaluation and management of VPBs is discussed elsewhere. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation".) ARRHYTHMIA IN ATHLETES Arrhythmias are not infrequently documented in athletes and can be a source of morbidity and mortality, particularly ventricular tachyarrhythmia and sudden cardiac arrest. They can be a reason to consider restriction from athletics. (See "Overview of sudden cardiac arrest and sudden cardiac death".) The evaluation and management of arrhythmia in athletes is discussed separately. (See "Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation" and "Athletes with arrhythmias: Treatment and returning to athletic participation".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 12/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Ventricular premature beats (The Basics)") SUMMARY AND RECOMMENDATIONS An arrhythmia is any rhythm that is not normal sinus rhythm with normal atrioventricular (AV) conduction. During sinus rhythm, the heart rate is in the normal range, the P waves are normal on the electrocardiogram (ECG), the AV conduction is normal, and the rate is stable. (See 'Definition' above.) When the primary care clinician (PCC) first encounters a patient with an arrhythmia, the following questions should be addressed (see 'Approach to the patient' above): Is the arrhythmia causing symptoms or could it? Does the arrhythmia pose a risk to the patient? Does the arrhythmia require emergent cardioversion? Which arrhythmia is present? Does the patient require urgent hospitalization? Is specialist consultation required, and if so, how urgently? Should anticoagulation and/or other medical therapy be started? For patients who are symptomatic in the office, the management strategy will depend both on the characteristics of the symptoms and the type of arrhythmia present. In the following clinical scenarios, we recommend urgent transfer to a facility with emergency care capabilities (see 'Patients identified with an arrhythmia' above): Syncope or near syncope in patients with high degree AV block (ie, Mobitz type II second degree or third degree [complete] AV block) or bradycardia. Wide complex rhythms (other than sinus with bundle branch block) including ventricular tachycardia. https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 13/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Patients in whom the diagnosis is uncertain after examination and ECG, but for whom there is a concern about a life-threatening arrhythmia. Patients with a history of heart disease (including coronary artery disease, cardiomyopathy, or heart failure) who present with syncope, near syncope, and/or documented ventricular arrhythmia. Sustained supraventricular tachycardia (SVT). Atrial fibrillation or flutter with rapid or slow rates. All antiarrhythmic drugs have the potential to increase ectopy or induce or aggravate monomorphic VT, torsades de pointes, ventricular fibrillation (VF), conduction disturbances, or bradycardia; this known as proarrhythmia ( table 3). We suggest the involvement of a specialist (cardiologist or electrophysiologist) when initiation of an antiarrhythmic drug is considered. (See 'Initiation of therapy' above.) The role of the PCC in the long-term care of patients with arrhythmias depends upon the particular arrhythmia diagnosis and treatment. All patients should be queried at each routine visit about changes in symptoms relevant to the arrhythmia and its treatment. ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 2. Zimetbaum PJ, Josephson ME. The evolving role of ambulatory arrhythmia monitoring in general clinical practice. Ann Intern Med 1999; 130:848. Topic 961 Version 26.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 14/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate GRAPHICS Classification of cardiac arrhythmias Supraventricular Atrial origin Atrial fibrillation Atrial flutter Atrial tachycardia Ectopic focus (enhanced automaticity) Intraatrial or sinoatrial reentry Atrial extrasystoles (atrial premature beats) AV junction Atrioventricular nodal reentrant tachycardia Atrioventricular reentrant tachycardia AV junctional rhythms (enhanced automaticity) AV junctional extrasystoles Ventricular Ventricular tachycardia Sustained Nonsustained Ventricular fibrillation Ventricular extrasystoles (ventricular premature beats) Graphic 72601 Version 1.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 15/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate ECG of polymorphic ventricular premature beats The ambulatory monitoring tracing demonstrates ventricular premature beats with 3 different morphologies, known as polymorphic ventricular premature beats; 1 ventricular couplet (2 successive premature beats) is also seen (arrow). The blocked P waves after the first and second premature beats (*) are due to concealed retrograde AV nodal conduction from the premature beat. ECG: electrocardiogram; VPBs: ventricular premature beats; AV: atrioventricular. Reproduced with permission by Samuel Levy, MD. Graphic 74977 Version 4.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 16/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate ECG of sinus node dysfunction The continuous lead V2 rhythm strip shows evidence of sinus node dysfunction. Following the third sinus beat (*) there is a pause followed by the occurrence of an escape junctional rhythm at a slower rate. P waves reappear (arrows), which are initially dissociated from the QRS complex, but ultimately they become associated with the QRS, resulting in 1:1 conduction. Reproduced with permission by Samuel Levy, MD. Graphic 78649 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 17/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Causes of bradycardia Intrinsic Extrinsic Idiopathic degenerative disorder Drugs Ischemic heart disease Antiarrhythmic agents Chronic ischemia Class IA - quinidine, procainamide Acute myocardial infarction Class IC - propafenone, flecainide Hypertensive heart disease Class II - -blockers Cardiomyopathy Class III - sotalol, amiodarone, dronedarone Trauma Class IV - diltiazem, verapamil Surgery for congenital heart disease Cardiac glycosides Heart transplant Antihypertensive agents Inflammation Clonidine, reserpine, methyldopa Collagen vascular disease Antipsychotic agents Rheumatic fever Lithium, phenothiazines, amitriptyline Pericarditis Autonomically mediated Infection Vasovagal syncope (cardioinhibitory) Viral myocarditis Carotid sinus hypersensitivity Lyme disease (Borrelia burgdorfer I) Hypothyroidism Neuromuscular disorder Intracranial hypertension Friedreich ataxia Hypothermia X-linked muscular dystrophy Hyperkalemia Familial disorder Hypoxia Anorexia nervosa Reproduced with permission from: Fuster V, Walsh R, Harrington R. Hurst's the Heart, 13th ed, McGraw-Hill Professional, New York 2010. Copyright 2010 The McGraw-Hill Companies, Inc. Graphic 65521 Version 11.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 18/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate ECG of sustained monomorphic ventricular tachycardia Shown are the six precordial electrocardiogram (ECG) leads (V1-V6). The QRS complex is wide and bizarre and the rhythm is ventricular tachycardia (VT). The sixth (+) and seventh (*) QRS complexes show a change in morphology, resembling a normal QRS complex; these represent fusion beats, with partial (+) or complete (*) normalization of the QRS complex. The seventh QRS complex (*) is preceded by a distinct P wave, which is probably conducted, capturing the ventricle for one beat, but not terminating the VT; this is also known as a Dressler beat. Reproduced with permission by Samuel Levy, MD. Graphic 69201 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 19/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Sustained ventricular tachycardia on ambulatory monitoring The ambulatory monitor in a patient being evaluated for syncope, which persisted after pacemaker insertion, shows sustained monomorphic ventricular tachycardia

following questions should be addressed (see 'Approach to the patient' above): Is the arrhythmia causing symptoms or could it? Does the arrhythmia pose a risk to the patient? Does the arrhythmia require emergent cardioversion? Which arrhythmia is present? Does the patient require urgent hospitalization? Is specialist consultation required, and if so, how urgently? Should anticoagulation and/or other medical therapy be started? For patients who are symptomatic in the office, the management strategy will depend both on the characteristics of the symptoms and the type of arrhythmia present. In the following clinical scenarios, we recommend urgent transfer to a facility with emergency care capabilities (see 'Patients identified with an arrhythmia' above): Syncope or near syncope in patients with high degree AV block (ie, Mobitz type II second degree or third degree [complete] AV block) or bradycardia. Wide complex rhythms (other than sinus with bundle branch block) including ventricular tachycardia. https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 13/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Patients in whom the diagnosis is uncertain after examination and ECG, but for whom there is a concern about a life-threatening arrhythmia. Patients with a history of heart disease (including coronary artery disease, cardiomyopathy, or heart failure) who present with syncope, near syncope, and/or documented ventricular arrhythmia. Sustained supraventricular tachycardia (SVT). Atrial fibrillation or flutter with rapid or slow rates. All antiarrhythmic drugs have the potential to increase ectopy or induce or aggravate monomorphic VT, torsades de pointes, ventricular fibrillation (VF), conduction disturbances, or bradycardia; this known as proarrhythmia ( table 3). We suggest the involvement of a specialist (cardiologist or electrophysiologist) when initiation of an antiarrhythmic drug is considered. (See 'Initiation of therapy' above.) The role of the PCC in the long-term care of patients with arrhythmias depends upon the particular arrhythmia diagnosis and treatment. All patients should be queried at each routine visit about changes in symptoms relevant to the arrhythmia and its treatment. ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 2. Zimetbaum PJ, Josephson ME. The evolving role of ambulatory arrhythmia monitoring in general clinical practice. Ann Intern Med 1999; 130:848. Topic 961 Version 26.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 14/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate GRAPHICS Classification of cardiac arrhythmias Supraventricular Atrial origin Atrial fibrillation Atrial flutter Atrial tachycardia Ectopic focus (enhanced automaticity) Intraatrial or sinoatrial reentry Atrial extrasystoles (atrial premature beats) AV junction Atrioventricular nodal reentrant tachycardia Atrioventricular reentrant tachycardia AV junctional rhythms (enhanced automaticity) AV junctional extrasystoles Ventricular Ventricular tachycardia Sustained Nonsustained Ventricular fibrillation Ventricular extrasystoles (ventricular premature beats) Graphic 72601 Version 1.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 15/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate ECG of polymorphic ventricular premature beats The ambulatory monitoring tracing demonstrates ventricular premature beats with 3 different morphologies, known as polymorphic ventricular premature beats; 1 ventricular couplet (2 successive premature beats) is also seen (arrow). The blocked P waves after the first and second premature beats (*) are due to concealed retrograde AV nodal conduction from the premature beat. ECG: electrocardiogram; VPBs: ventricular premature beats; AV: atrioventricular. Reproduced with permission by Samuel Levy, MD. Graphic 74977 Version 4.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 16/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate ECG of sinus node dysfunction The continuous lead V2 rhythm strip shows evidence of sinus node dysfunction. Following the third sinus beat (*) there is a pause followed by the occurrence of an escape junctional rhythm at a slower rate. P waves reappear (arrows), which are initially dissociated from the QRS complex, but ultimately they become associated with the QRS, resulting in 1:1 conduction. Reproduced with permission by Samuel Levy, MD. Graphic 78649 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 17/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Causes of bradycardia Intrinsic Extrinsic Idiopathic degenerative disorder Drugs Ischemic heart disease Antiarrhythmic agents Chronic ischemia Class IA - quinidine, procainamide Acute myocardial infarction Class IC - propafenone, flecainide Hypertensive heart disease Class II - -blockers Cardiomyopathy Class III - sotalol, amiodarone, dronedarone Trauma Class IV - diltiazem, verapamil Surgery for congenital heart disease Cardiac glycosides Heart transplant Antihypertensive agents Inflammation Clonidine, reserpine, methyldopa Collagen vascular disease Antipsychotic agents Rheumatic fever Lithium, phenothiazines, amitriptyline Pericarditis Autonomically mediated Infection Vasovagal syncope (cardioinhibitory) Viral myocarditis Carotid sinus hypersensitivity Lyme disease (Borrelia burgdorfer I) Hypothyroidism Neuromuscular disorder Intracranial hypertension Friedreich ataxia Hypothermia X-linked muscular dystrophy Hyperkalemia Familial disorder Hypoxia Anorexia nervosa Reproduced with permission from: Fuster V, Walsh R, Harrington R. Hurst's the Heart, 13th ed, McGraw-Hill Professional, New York 2010. Copyright 2010 The McGraw-Hill Companies, Inc. Graphic 65521 Version 11.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 18/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate ECG of sustained monomorphic ventricular tachycardia Shown are the six precordial electrocardiogram (ECG) leads (V1-V6). The QRS complex is wide and bizarre and the rhythm is ventricular tachycardia (VT). The sixth (+) and seventh (*) QRS complexes show a change in morphology, resembling a normal QRS complex; these represent fusion beats, with partial (+) or complete (*) normalization of the QRS complex. The seventh QRS complex (*) is preceded by a distinct P wave, which is probably conducted, capturing the ventricle for one beat, but not terminating the VT; this is also known as a Dressler beat. Reproduced with permission by Samuel Levy, MD. Graphic 69201 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 19/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Sustained ventricular tachycardia on ambulatory monitoring The ambulatory monitor in a patient being evaluated for syncope, which persisted after pacemaker insertion, shows sustained monomorphic ventricular tachycardia (SMVT) which terminates spontaneously. A brief period of ventricular pacing follows ventricular tachycardia termination. Reproduced with permission by Samuel Levy, MD. Graphic 54513 Version 2.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 20/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate 12 lead ECG of atrial fibrillation The 12 lead ECG shows atrial fibrillation. The QRS complex is narrow, P waves are absent, and the baseline between successive QRS complexes shows irregular coarse "fibrillatory waves." The QRS complexes occur at irregularly irregular intervals. Reproduced with permission by Samuel Levy, MD. Graphic 64217 Version 2.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 21/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate 12 lead ECG of atrial flutter The 12 lead electrocardiogram (ECG) of atrial flutter shows a regular rhythm with a narrow QRS complex. Flutter waves are present, best seen in leads II, III, and aVF (*). In this ECG, the flutter waves are negative in leads II, III, and aVF, and positive in lead V1. One flutter wave is obvious between the QRS complexes, while the second one is superimposed on the terminal portion of the QRS complex; hence there is 2:1 atrioventricular nodal block, which is the most common presentation for atrial flutter. Reproduced with permission by Samuel Levy, MD. Graphic 75931 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 22/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate ECG of atrial tachycardia with resultant paroxysmal complete AV block The continous lead II electrocardiogram (ECG) tracing initially shows a regular tachycardia at a rate of 160; the QRS complex is wide with a terminal S wave compatible with a right bundle branch block. There is gradual slowing of the rate with the development of atrioventricular (AV) nodal block; ultimately a series of nonconducted P waves (arrows) are seen and there is one escape ventricular premature beat (*). After a second ventricular premature beat (+), sinus rhythm is restored. Reproduced with permission by Samuel Levy, MD. Graphic 56931 Version 4.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 23/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Typical atrioventricular nodal reentrant tachycardia The first two complexes are normal sinus beats with a normal P wave followed by a QRS complex. The third complex, an atrial premature beat (APB), has a prolonged PR interval; it initiates a common or typical atrioventricular nodal reentrant tachycardia (AVNRT) in which antegrade conduction to the ventricle is via the slow pathway and retrograde atrial activation is by the fast pathway. Although no distinct P wave is seen, the QRS complex has a small terminal deflection, known as a pseudo r', which is the P wave superimposed upon the terminal portion of the QRS complex. Graphic 54290 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 24/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate II ECG of mobitz II second degree heart block The lead II rhythm strip shows four sinus beats with P wave followed by a QRS complex; the fifth P wave is not followed by a QRS complex and represents second degree heart block. There is no change in the PR interval prior to or after the blocked P wave and thus this is Mobitz II second degree heart block. A second episode of second degree heart block can be seen after the seventh QRS complex. Reproduced with permission by Samuel Levy, MD. Graphic 51492 Version 2.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 25/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Nonsustained ventricular tachycardia Nonsustained ventricular tachycardia in a patient with underlying atrial fibrillation. The ventricular arrhythmia consists of nine beats at an approximate rate of 170 beats/minute. Courtesy of Ary Goldberger, MD. Graphic 73299 Version 4.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 26/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Types of proarrhythmia during treatment with antiarrhythmic drugs (AADs) for atrial fibrillation or atrial flutter according to the Vaughan Williams Classification Ventricular proarrhythmia Torsade de pointes (Vaughan Williams class IA and type III drugs) Sustained monomorphic ventricular tachycardia (usually class IC drugs) Sustained polymorphic ventricular tachycardia/ventricular fibrillation without long QT interval (class IA, IC, and III drugs) Atrial proarrhythmia Provocation of recurrence (probably class IA, IC, and III drugs) Conversion of atrial fibrillation (AF) to atrial flutter (usually class IC drugs) with 1:1 conduction Increase of defibrillation threshold (a potential problem with class IC drugs) Abnormalities of conduction or impulse formation Accelerate ventricular rate during AF (class IA and type IC drugs) Accelerate conduction over accessory pathway (digoxin, type IV drugs) Sinus node dysfunction, atrioventricular block (almost all drugs) Vaughan Williams classification of AADs used for the treatment of atrial fibrillation or flutter Class IA - Disopyramide, procainamide, quinidine Class IC - Flecainide, propafenone Class III - Amiodarone, dofetilide, ibutilide, sotalol Class IV - Nondihydropyridine calcium channel blockers (diltiazem and verapamil) Data from Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial brillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to revise the 2001 guidelines for the management of patients with atrial brillation). J Am Coll Cardiol 2006; 48:e149. Graphic 66133 Version 4.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 27/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 28/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 29/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 30/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 31/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Example of torsades de pointes and ventricular flutter Shown are three ECG leads (I, II, III); bradycardia and prolongation of the QT interval are present. Several runs of polymorphic ventricular tachycardia, called torsades de pointes (TdP) when associated with QT prolongation are seen (panel A); after several minutes, a rapid sustained ventricular tachycardia, sometimes called ventricular flutter, occurs (panel B). This is closely related to ventricular fibrillation. Reproduced with permission by Samuel Levy, MD. Graphic 60231 Version 3.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 32/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Nonantiarrhythmic agents which may induce torsade de pointes Psychiatric drugs Antihistamines Phenothiazines - thioridazine, chlorpromazine Terfenadine Tricyclic antidepressants - amitriptyline Astemizole Haloperidol Calcium channel blockers Antibiotics Bepridil Azithromycin Lidoflazine Chloroquine Antihyperlipidemics Erythromycin Probucol Pentamidine Other Trimethoprim-sulfamethoxazole Amantadine Toxins Cisapride Arsenic Organophosphate insecticides Diuretics Graphic 72631 Version 2.0 https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 33/34 7/6/23, 2:50 PM Arrhythmia management for the primary care clinician - UpToDate Contributor Disclosures Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/arrhythmia-management-for-the-primary-care-clinician/print 34/34

7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Atrioventricular node ablation : Bradley P Knight, MD, FACC : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 09, 2023. INTRODUCTION In patients with atrial fibrillation (AF), the ventricular rate is determined in large part by the conduction properties of the atrioventricular (AV) node. In the typical patient with untreated AF, the ventricular rate can reach 150 beats per minute or higher. There are three important reasons to prevent a rapid ventricular response in patients with AF: Avoidance of hemodynamic instability. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Avoidance of bothersome symptoms. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'History and physical examination'.) Avoidance of a tachycardia-mediated cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".) A rapid ventricular response can be prevented either by restoring sinus rhythm (ie, rhythm control) or by using therapies that reduce the ventricular response (ie, rate control) to AF. When rate control is chosen, it can usually be accomplished with pharmacologic therapy. However, some AF patients will respond poorly to or be intolerant of rate control medications. Options for such patients include reconsideration of a rhythm control strategy or nonpharmacologic methods to control the ventricular rate. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Management of atrial fibrillation: Rhythm control versus rate control".) https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 1/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate The use of AV node ablation to achieve rate control in AF will be reviewed here. Pharmacologic therapies for rate control in AF are discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) GENERAL PRINCIPLES Choosing the appropriate rate control therapy for a patient with AF is guided by an understanding of the determinants of the ventricular rate and an assessment of the adequacy of rate control. The discussions of rate control and the determinants of ventricular rate in patients with AF are found elsewhere. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) There are several strategies for assessing the adequacy of rate control efforts. With any strategy, rate control should be assessed both at rest and with exertion. Rate control goals are discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) INDICATIONS AV node ablation is an option for rate control in AF patients who have failed medical therapy for rhythm control, have failed or are not candidates for catheter ablation for rhythm control, and have failed aggressive attempts at pharmacological rate control. Many of these patients are labeled as having permanent AF, which is the term used to identify individuals with persistent AF where a joint decision by the patient and clinician has been made to no longer pursue a rhythm control strategy. Patients who are candidates for AV node ablation should be highly symptomatic, hemodynamically intolerant of AF, or have cardiomyopathy that is thought to be at least some part tachycardia induced. In general, the procedure is most commonly performed in elderly patients, many of whom have a preexisting pacemaker or implantable cardioverter-defibrillator (ICD) ( table 1). Other patients include those who are not candidates for rhythm control with catheter ablation or drug therapy, those with refractory AF with tachycardia-induced cardiomyopathy, or those with a preexisting pacemaker. Careful thought needs to be given to other treatment options, including curative attempts with catheter ablation before proceeding to AV node ablation in patients in whom medical therapy has failed to control the ventricular rate. The specific clinical scenario will dictate the appropriateness of AV node ablation vis-a-vis other treatment options. In younger patients, all https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 2/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate treatment options should be considered/exhausted before proceeding to AV node ablation. AV node ablation may be more appropriate in older patients, particularly those with preexisting pacing devices, and in those in whom curative attempts at AF ablation are unlikely to be successful (eg, very longstanding/permanent AF, marked left atrial dilatation, etc). Prior to performing AV node ablation, the patient needs to be informed about the invasive nature of the procedure, the requirement for lifelong permanent pacemaker therapy, and the long-term risk of a pacing-induced cardiomyopathy when RV apical pacing is used. PROCEDURE AV node ablation usually produces complete AV block and often leaves the patient with a slow junctional or idioventricular escape rhythm. Consequently, patients require implantation of a permanent pacing device to adequately control the ventricular rate ( waveform 1A-B). If a preexisting pacemaker or ICD is not already in place, a permanent pacemaker or ICD is implanted prior to AV node ablation. This is usually carried out immediately prior to the AV node ablation, but in some cases the device may be implanted in advance of the ablation procedure. Traditional leaded devices are implanted in the subclavicular region; a leadless pacemaker may be implanted directly in the right ventricle. (See 'Device selection' below and "Permanent cardiac pacing: Overview of devices and indications", section on 'General considerations'.) If a functional pacemaker or ICD is in place and no system revision is planned, the femoral vein is generally used for access for ablation of the AV node. An ablation catheter is advanced to the AV junction where a bundle of His potential can be recorded. Radiofrequency ablation of the AV node/bundle of His is performed. Ablation lesions should be delivered at a site proximal in the AV conduction system where a large atrial electrogram is also recorded to increase the likelihood of a junctional escape rhythm after creation of AV bock to avoid pacemaker dependency. With a successful lesion, there is usually an accelerated junctional rhythm and then heart block. If initial ablation is ineffective, or if conduction recurs, a larger lesion can be created with either a larger tip or saline-irrigated catheter.(See "Overview of catheter ablation of cardiac arrhythmias".) On rare occasions, AV node ablation cannot be accomplished via the right heart. In these cases, establishing femoral arterial access allows passage of an ablation catheter retrograde across the AV node. A bundle of His potential can be recorded just below the aortic valve, in the septal aspect of the left ventricular (LV) outflow tract. Alternatively, ablation by way of the left heart can be accomplished using a patent foramen ovale or transseptal puncture. If left heart access is necessary, systemic anticoagulation with intravenous heparin is generally administered while the left heart is instrumented. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 3/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate If a leadless pacemaker is placed, the same femoral venous sheath can then be used to advance the ablation catheter (see "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'). Care must be taken to make sure that newly placed leads or a leadless pacemaker are not dislodged by the ablation catheter. In rare cases, when right heart ablation of the AV node is ineffective and a new leaded pacing system has just been placed, it may be reasonable to defer the left heart AV node ablation for days/weeks to obviate the need for intravenous heparin with the attendant risks of bleeding. Device selection Following AV node ablation (see 'Procedure' above), most patients are pacemaker dependent. Therefore a device with pacemaker capability must be in place prior to the ablation procedure. The choice of which type of pacing device is implanted depends on the patient's clinical profile. Single-chamber ventricular pacemaker In patients with persistent AF, a single-chamber (right) ventricular pacemaker is often adequate. After AV node ablation, the patient's ventricular rate will not naturally respond to increased demand; therefore, a device with rate-adaptive capabilities is used (ie, VVIR pacing). All contemporary pacemakers have rate-adaptive capabilities. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Rate responsiveness'.) Leadless RV pacing (see "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems') has also been used in association with AV node ablation [1]. Dual-chamber pacemaker In patients with paroxysmal AF, dual-chamber pacemakers are preferred to single-chamber devices because they maintain AV synchrony during periods of sinus rhythm (eg, DDDR pacing). (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Physiologic pacing'.) In order to prevent rapid ventricular pacing during episodes of AF, patients with dual-chamber pacemakers following AV node ablation should have devices with automatic mode-switching capabilities. All contemporary pacemakers have this ability. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Mode switching'.) In patients with paroxysmal AF, two randomized trials demonstrated that dual-chamber pacemakers with mode-switching capabilities improve symptoms and quality of life compared with single- or dual-chamber pacemakers without mode-switching capabilities [2,3]. Many patients who undergo AV node ablation with pacemaker implantation for paroxysmal AF eventually progress to persistent AF [4]. Although dual-chamber pacing has not been shown to prevent this progression [5], we favor dual-chamber pacing in patients with paroxysmal AF https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 4/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate because of the clinical benefits of physiologic pacing. (See "The role of pacemakers in the prevention of atrial fibrillation".) A leadless RV pacemaker capable of sensing atrial mechanical systole and providing AV synchrony has been approved by the U S Food and Drug administration. At this point, leadless RV pacing is not able to pace the atrium, so it would not be an optimal choice in a patient with sinus node dysfunction and paroxysmal AF who is to undergo AV node ablation. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) Cardiac resynchronization therapy The majority of well-selected patients improve hemodynamically following AV junction ablation and standard right ventricle (RV) pacing. However, RV pacing causes the RV to contract before the LV (interventricular dyssynchrony), which may impair LV systolic function, reduce functional status, and increase mortality. In patients with significant dyssynchrony due to intrinsic conduction disease or pacing, cardiac resynchronization therapy (CRT) can improve ventricular synchrony. Use of CRT in patients with AF with or without AV node ablation is presented separately. (See "Cardiac resynchronization therapy in atrial fibrillation", section on 'Atrioventricular node ablation'.) There is a trend toward using CRT in many patients who undergo AV node ablation. If the implant and ablation are to be done concurrently, we use CRT with an atrial lead if the AF is paroxysmal and no atrial lead if persistent/permanent. In addition to providing CRT, two ventricular leads mitigate the unlikely but potentially disastrous effects of RV lead dislodgment and loss of RV capture. If transient pacing inhibition due to RV lead malfunction is noted, the sensing vector can sometimes be reprogrammed to an LV vector, which may mitigate the need for urgent lead revision. If, however, in the unlikely event that RV lead dislodgement or fracture results in continuous oversensing and inhibition of pacing, the additional LV pacing lead will not prevent asystole. If the patient has a preexisting non-CRT device and is undergoing AV node ablation, we will usually see how the patient responds to unopposed RV pacing, particularly if LV function is preserved. If LV function is significantly depressed and/or systolic heart failure has already been an issue, we may upgrade the patient to a CRT pacing or defibrillator system (as appropriate) at the time of AV node ablation. The main "downsides" to concurrent device upgrade are the associated procedural risks, most notably the risk of infection in a patient who will be pacemaker dependent. Adding a device upgrade procedure to an AV ablation increases procedure time considerably, so in patients who are very tenuous hemodynamically due to rapid ventricular rates and/or rate controlling, it may be reasonable to initially perform AV node ablation alone, and then upgrade the device if the patient does not improve. The relative efficacy of CRT with AV node ablation for rate control and pulmonary vein isolation for rhythm control in patients with HF is discussed separately. (See "The management of atrial https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 5/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate fibrillation in patients with heart failure", section on 'Atrioventricular node ablation with pacing' and "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'.) Implantable cardioverter-defibrillators All of the aforementioned pacing modalities (eg, single chamber, dual chamber, and CRT) and functions (eg, rate adaptive pacing and mode switching) are available on contemporary ICDs. Thus, patients with an ICD who require an AV node ablation procedure can sometimes be managed without changing the device. As most of these patients have significant LV dysfunction and systolic heart failure (given the indications for prophylactic ICD implantation), consideration should be given to upgrading to a CRT-D system with an atrial lead, if appropriate, at the time of AV node ablation. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) Physiological pacing CRT (or biventricular pacing) is a strategy to avoid the dyssynchrony associated with standard RV apical pacing in patients who become pacemaker dependent after AV node ablation (see 'Cardiac resynchronization therapy' above). A potential alternative to CRT is the positioning of a pacing lead near the His bundle ( image 1) or deep in the ventricular septum near the area of the left bundle branch. A pacing lead near the His bundle will activate the native conduction system, resulting in less dyssynchrony and a more normal QRS complex. It is technically difficult to place a conventional pacing lead in a position that results in capture of the His bundle at a reasonable pacing output because the His bundle is insulated from the endocardium. Newer, small caliber, screw-in pacing leads that are delivered using a guiding sheath rather than a stylet may improve the ability to accomplish permanent His bundle capture [6]. The value of this approach was evaluated in a prospective single-center trial of 52 patients with heart failure and refractory AF who underwent attempted AV node ablation and permanent His bundle pacing; backup RV or LV leads were placed as well [7]. During His bundle pacing, the average QRS duration was 105 msec, compared with 107 msec at baseline. The mean New York Heart Association functional class improved from baseline 2.9 in patients with heart failure with reduced ejection fraction to 1.4 with His bundle pacing, and from baseline 2.7 in patients with heart failure with preserved ejection fraction to 1.4. LV end-diastolic dimension, LV ejection fraction (LVEF), and mitral regurgitation all improved with His bundle pacing compared with baseline. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 6/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate Successful His bundle pacing is technically difficult to accomplish. In addition, lead dislodgement may be more likely compared with conventional pacing sites. Pacing thresholds may also be higher with His bundle pacing, leading to shorter generator longevity. Lead dislodgement would have serious complications in this setting due to complete heart block after ablation of the AV node. Another alternative to CRT is left bundle branch area pacing. Pacing the left bundle branch has been shown to avoid some of the limitations of His-bundle pacing such as high pacing thresholds and atrial oversensing, and has been used in patients undergoing AV node ablation. This is accomplished by placing an active fixation, sheath-delivered, pacing lead deep into the RV septum to capture the left bundle branch, giving rise to a relatively narrow QRS complex to minimize pacing-induced ventricular dyssynchrony. An image shows the position of the tip of a left bundle branch pacing lead in the RV septum during administration of contrast through the delivery sheath at the time of implant. (See "Permanent cardiac pacing: Overview of devices and indications".) Further studies in larger populations are necessary to clarify both the clinical benefits and safety of these physiological pacing approaches in patients undergoing AV node ablation. In addition, given the risks of lead dislodgement, the safety and efficacy of His bundle pacing should be compared against biventricular pacing. At this point, a backup RV lead is generally placed when His bundle pacing is employed, particularly in pacemaker-dependent patients. Ventricular rate regularization Ventricular rate regularization (or ventricular rate stabilization) is a pacemaker mode that can attenuate the rate and irregularity of the ventricular response during AF [8]. The ventricle is paced at a variable rate at or near the mean native rate. This causes concealed retrograde conduction into the AV node, which makes it refractory to subsequent anterograde impulses from the atria. This tends to reduce the number of short RR intervals, which may improve symptoms by making the ventricular rate more regular during AF and sometimes slower. A potential advantage of this approach is that no catheter ablation of the AV junction is performed. However, this technique may be less effective at controlling AF during physical activity than at rest. EFFICACY AV node ablation is highly effective, as demonstrated by the following reports: AV node ablation was acutely successful in 97.4 percent of 646 patients, although 3.5 percent had recurrence of AV conduction during follow-up [9]. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 7/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate In a report from the prospective Ablate and Pace trial, the procedure was successful in all but 1 of 156 patients who underwent radiofrequency ablation of the AV node [10]. Persistent complete heart block was present in 96 percent; 33 percent of patients had no escape rhythm, while 35 percent had an escape rhythm with an escape rate <40 beats per minute. OUTCOMES Symptoms and quality of life are significantly improved in patients with poorly controlled AF who undergo AV node ablation and permanent pacemaker implantation [11-15]. In a series of 107 such patients, ablative treatment was associated with significant reductions in [11]: Physician visits (5 versus 10 prior to ablation) Hospital admissions (0.17 versus 2.8 prior to ablation) Episodes of heart failure (8 versus 18 prior to ablation) Antiarrhythmic drug trials Further support for the benefits of this approach come from a meta-analysis of 21 studies, involving 1181 patients [12]. This report noted significant improvement in all 19 outcome measures evaluated, including quality of life, ventricular function, exercise duration, and health care use [12]. While such benefits are often due to improved LV systolic function, improvement in some patients occurs independent of changes in LVEF and probably results from the slower and more regular heart rate [13,14]. To date, there is no convincing evidence of a mortality benefit with AV node ablation [12,15,16]: AV node ablation has also been compared with other nonpharmacologic therapies. In the 2008 PABA-CHF study, in which 81 patients were randomly assigned to AV node ablation with cardiac resynchronization therapy pacing or pulmonary vein isolation, the composite primary endpoint (Minnesota Living with Heart Failure score, 6MW distance, EF) favored the pulmonary vein isolation group [17]. COMPLICATIONS AV node ablation incurs risks similar to other catheter ablation procedures that require right heart access, though typically only a single venous sheath is required. If a pacemaker or ICD is implanted immediately prior to AV node ablation, the risks of device implantation are also https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 8/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate incurred. If simple RV pacing is used, there will be a risk of developing LV dysfunction and/or heart failure. (See "Cardiac implantable electronic devices: Periprocedural complications".) Specific to patients who undergo AV node ablation and pacing is a very rare but catastrophic risk of ventricular fibrillation (VF) and sudden cardiac death (SCD). In a review of 334 patients who underwent AV node ablation, nine (2.7 percent) experienced SCD [18]. Four events occurred within four days of the procedure, an additional three events occurred within three months, and two occurred late and were thought to be unrelated to the procedure. Possible causes of post-ablation VF include [18-20]: Underlying heart disease Activation of the sympathetic nervous system Prolongation in action potential duration Repolarization abnormalities induced by bradycardia Increased dispersion of ventricular refractoriness The potential for reducing the frequency of early VF with post-ablation pacing at a higher rate was evaluated in a report of 235 patients [21]. The incidence of VF was 6 percent in the first 100 patients in whom the post-ablation chronic pacing rate was 70 beats per minute. In the next 135 patients, however, a pacing rate of 90 beats per minute was used for the first three months after the ablation, and there were no episodes of VF. Pacing at a rate of 90 beats per minute decreases sympathetic activity, which may contribute to the reduction in VF or SCD [19]. Other procedural risks are those related to catheter ablation and pacemaker/ICD implant/upgrade procedures. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) NEED FOR ANTICOAGULATION While AV node ablation results in adequate heart rate control, it does not stop the atria from fibrillating. Thus, the risk of thromboembolic events is not affected [22]. As a result, there is a need for long-term anticoagulation similar to that in patients with chronic AF whose heart rate control is achieved pharmacologically. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) RECOMMENDATIONS OF OTHERS https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 9/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate Our recommendations for patients with AF in whom a rate control strategy has been chosen are in general agreement with those made in major societal guidelines [23-25]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS Background Atrioventricular (AV) node ablation is an option for rate control in atrial fibrillation (AF) patients who have failed medical therapy for rhythm control, have failed or are not candidates for catheter ablation for rhythm control, and have failed aggressive attempts at pharmacological rate control. Indications For AF patients with a rapid ventricular response who do not respond to or are intolerant of aggressive attempts at pharmacologic therapy to slow the ventricular rate, and in whom nonpharmacologic approaches, including curative attempts at AF ablation, are not successful or appropriate, we recommend AV node ablation in association with implantation of a permanent pacing device to improve symptoms and quality of life (Grade 1B). (See 'Indications' above.) Pacing procedure For AF patients who undergo AV node ablation, a pacing device is needed to prevent symptomatic bradycardia. A single-chamber ventricular pacemaker with rate-adaptive capability may be appropriate for patients with persistent AF, and a dual- chamber pacemaker with both mode switching and rate-adaptive capabilities may be appropriate for patients with paroxysmal AF. The roles of cardiac resynchronization therapy, physiological pacing, and implantable cardioverter-defibrillator depend on left ventricular function, heart failure symptoms, and history. (See 'Device selection' above.) No need for anticoagulation AV node ablation has no impact on thromboembolic risk and most individuals require long-term oral anticoagulation. (See 'Need for anticoagulation' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 10/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Yarlagadda B, Turagam MK, Dar T, et al. Safety and feasibility of leadless pacemaker in patients undergoing atrioventricular node ablation for atrial fibrillation. Heart Rhythm 2018; 15:994. 2. Marshall HJ, Harris ZI, Griffith MJ, et al. Prospective randomized study of ablation and pacing versus medical therapy for paroxysmal atrial fibrillation: effects of pacing mode and mode- switch algorithm. Circulation 1999; 99:1587. 3. Kamalvand K, Tan K, Kotsakis A, et al. Is mode switching beneficial? A randomized study in patients with paroxysmal atrial tachyarrhythmias. J Am Coll Cardiol 1997; 30:496. 4. Gribbin GM, Bourke JP, McComb JM. Predictors of atrial rhythm after atrioventricular node ablation for the treatment of paroxysmal atrial arrhythmias. Heart 1998; 79:548. 5. Gillis AM, Connolly SJ, Lacombe P, et al. Randomized crossover comparison of DDDR versus VDD pacing after atrioventricular junction ablation for prevention of atrial fibrillation. The atrial pacing peri-ablation for paroxysmal atrial fibrillation (PA (3)) study investigators. Circulation 2000; 102:736. 6. Dandamudi G, Vijayaraman P. How to perform permanent His bundle pacing in routine clinical practice. Heart Rhythm 2016; 13:1362. 7. Huang W, Su L, Wu S, et al. Benefits of Permanent His Bundle Pacing Combined With Atrioventricular Node Ablation in Atrial Fibrillation Patients With Heart Failure With Both Preserved and Reduced Left Ventricular Ejection Fraction. J Am Heart Assoc 2017; 6. 8. Wood MA. Trials of pacing to control ventricular rate during atrial fibrillation. J Interv Card Electrophysiol 2004; 10 Suppl 1:63. 9. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 2000; 23:1020. 10. Curtis AB, Kutalek SP, Prior M, Newhouse TT. Prevalence and characteristics of escape rhythms after radiofrequency ablation of the atrioventricular junction: results from the registry for AV junction ablation and pacing in atrial fibrillation. Ablate and Pace Trial Investigators. Am Heart J 2000; 139:122. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 11/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate 11. Fitzpatrick AP, Kourouyan HD, Siu A, et al. Quality of life and outcomes after radiofrequency His-bundle catheter ablation and permanent pacemaker implantation: impact of treatment in paroxysmal and established atrial fibrillation. Am Heart J 1996; 131:499. 12. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after ablation and pacing therapy for atrial fibrillation : a meta-analysis. Circulation 2000; 101:1138. 13. Brown CS, Mills RM Jr, Conti JB, Curtis AB. Clinical improvement after atrioventricular nodal ablation for atrial fibrillation does not correlate with improved ejection fraction. Am J Cardiol 1997; 80:1090. 14. Weerasooriya R, Davis M, Powell A, et al. The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT). J Am Coll Cardiol 2003; 41:1697. 15. Ozcan C, Jahangir A, Friedman PA, et al. Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation. N Engl J Med 2001; 344:1043. 16. Garcia B, Clementy N, Benhenda N, et al. Mortality After Atrioventricular Nodal Radiofrequency Catheter Ablation With Permanent Ventricular Pacing in Atrial Fibrillation: Outcomes From a Controlled Nonrandomized Study. Circ Arrhythm Electrophysiol 2016; 9. 17. Khan MN, Ja s P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359:1778. 18. Ozcan C, Jahangir A, Friedman PA, et al. Sudden death after radiofrequency ablation of the atrioventricular node in patients with atrial fibrillation. J Am Coll Cardiol 2002; 40:105. 19. Hamdan MH, Page RL, Sheehan CJ, et al. Increased sympathetic activity after atrioventricular junction ablation in patients with chronic atrial fibrillation. J Am Coll Cardiol 2000; 36:151. 20. Evans GT Jr, Scheinman MM, Bardy G, et al. Predictors of in-hospital mortality after DC catheter ablation of atrioventricular junction. Results of a prospective, international, multicenter study. Circulation 1991; 84:1924. 21. Geelen P, Brugada J, Andries E, Brugada P. Ventricular fibrillation and sudden death after radiofrequency catheter ablation of the atrioventricular junction. Pacing Clin Electrophysiol 1997; 20:343. 22. Gasparini M, Mantica M, Brignole M, et al. Thromboembolism after atrioventricular node ablation and pacing: long term follow up. Heart 1999; 82:494. 23. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 12/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 24. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 25. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1012 Version 28.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 13/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate GRAPHICS Clinical factors favoring atrioventricular node ablation in patients with refractory atrial fibrillation Favors atrial fibrillation ablation Favors atrioventricular node ablation/pacing Clinical characteristics Age Younger Older, particularly very elderly Atrial fibrillation pattern Paroxysmal Persistent, particularly very longstanding ("permanent") Left atrial size Normal/near normal Markedly dilated Comorbidities Minimal Extensive Overall health Robust Frail Miscellaneous High infection risk Previous failed atrial fibrillation ablation Courtesy of Leonard Ganz, MD. Graphic 129004 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 14/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate Intracardiac and surface ECG recordings during electrophysiologic study in a person with atrial fibrillation Three surface ECG leads (I, aVF, V1) and intracardiac recordings from the atrioventricular unction region (HBE1-2, HBE3-4), and the right ventricular apex (RVA3-4) in a patient with atrial fibrillation. The patient has extremely symptomatic, medically refractory atrial fibrillation with rapid ventricular rates and recurrent heart failure. The mapping catheter (HBE) has been maneuvered from the area of maximal His bundle activity to a more proximal position, where a larger atrial (A) and smaller His electrogram (H) are recorded. ECG: electrocardiograph; V: ventricular electrogram. Graphic 74286 Version 5.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 15/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate Intracardiac and surface ECG recordings during electrophysiologic study and radiofrequency catheter ablation of the AV junction in atrial fibrillation Three surface ECG leads (I, aVF, V1) and intracardiac recordings from the region of the atrioventricular junction (HBE1-2, HBE3-4), and the right ventricular apex (RVA3- 4) in a patient with atrial fibrillation. Application of radiofrequency (RF) energy from the tip of the mapping catheter (HBE1-2) causes complete AV nodal block; pacing (P) is initiated from the right ventricular apex. A permanent VVIR pacemaker was implanted, and the patient has noted a marked improvement in symptoms. ECG: electrocardiograph; AV: atrioventricular. Graphic 67363 Version 5.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 16/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate Para Hisian pacing lead Patient #6. Right anterior oblique (RAO) and left anterior oblique (LAO) fluoroscopic projections showing leads position during the "ablate and pace" procedure and Hisian pacing; 1 = quadripolar Hisian mapping catheter; 2 = screw-in bipolar lead positioned in close proximity to the His-bundle; 3 = bipolar passive fixation positioned in right ventricular apex. Reproduced with permission from: Occhetta E, Bortnik M, Magnani A, et al. Prevention of ventricular desynchronization by permanent para-Hisian pacing after atrioventricular node ablation in chronic atrial brillation: a crossover, blinded, randomized study versus apical right ventricular pacing. J Am Coll Cardiol 2006; 47:1938. Copyright 2006 American College of Cardiology Foundation. Graphic 56944 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 17/18 7/6/23, 2:50 PM Atrial fibrillation: Atrioventricular node ablation - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 18/18

7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Cardioversion : Gerald V Naccarelli, MD, Warren J Manning, MD : Bradley P Knight, MD, FACC, Brian Olshansky, MD, James Hoekstra, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 26, 2022. INTRODUCTION The restoration (cardioversion) to sinus rhythm (SR) from atrial fibrillation (AF) is performed primarily to improve symptoms, but it may also prevent tachycardia-induced cardiomyopathy, facilitate management of congestive heart failure, and reduce the risk of inappropriate shocks in those with implanted defibrillators. This topic will focus on our approach to cardioversion and the efficacy and safety of the two most widely used approaches: electrical (direct current) and pharmacologic cardioversion. Other related topics include: (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Restoration of sinus rhythm in atrial flutter".) INDICATIONS In this topic, we are generally referring to cardioversion in stable patients with recently diagnosed symptomatic AF that does not terminate spontaneously. Cardioversion is indicated to improve symptoms, hemodynamic status from AF and in some cases, need for chronic anticoagulation. Among patients with early AF and who are at high risk https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 1/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate for cardiovascular complications, cardioversion with accompanying rhythm control strategy of AF management can reduce cardiovascular death or stroke. Patients who may benefit from rhythm versus rate control are discussed separately. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Indications for initial rhythm control'.) Cardioversion is most commonly performed in patients who are expected to have long-term maintenance of sinus rhythm, who are expected to convert to normal sinus rhythm, and are at low risk for cardioversion. These may be patients with persistent AF (ie, lasting >7 days) or even paroxysmal AF, if AF is highly symptomatic and cannot be otherwise controlled. It is also preferred in other patient groups. Long-term rhythm control Patients who will be placed on long-term antiarrhythmic drugs or who will undergo catheter ablation will have SR restored as the initial part of that process. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Atrial fibrillation: Catheter ablation".) Long-standing persistent AF It may be reasonable to attempt to restore SR in patients with long-standing, persistent AF who are symptomatic (or occasionally in patients with presumed permanent AF). An example of the latter is a patient with long-duration AF who now has developed increasing heart failure or worsening cardiomyopathy felt to be related to poorly controlled ventricular rate. However, maintenance of sinus rhythm even for a short time period is not assured. (See "Arrhythmia-induced cardiomyopathy" and "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control' and "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control'.) Frequently, the only way to determine if subtle, nonspecific symptoms are attributable to AF is to restore SR to observe for symptom improvement. Symptom improvement may be delayed for several weeks due to markedly delayed recovery of atrial mechanical function. Cardioversion may be used in patients who have very infrequent, persistent episodes who do not respond to a pill-in-the-pocket approach. These individuals may cardioverted as needed from time to time. (See 'Pill-in-the-pocket' below.) Unstable patients In some hemodynamically unstable patients who manifest with signs or symptoms such as hypotension, altered mental status, or heart failure, if there is time to attempt ventricular rate slowing or to wait for possible spontaneous reversion to SR, https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 2/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate cardioversion may be deferred. Emergency cardioversion should be performed if the patient is hemodynamically compromised due to an uncontrolled rapid ventricular rate or the lack of atrial contraction is thought to impair their cardiac output. If angina is felt to be related to the hemodynamic compromise or lack of atrial contraction with AF, we perform emergency cardioversion; however, the risk for a thromboembolic event needs to be considered. This includes patients with severe acute heart failure, ongoing myocardial ischemia, or hypotension. However, if hypotension occurs with a slow or moderate ventricular response (<110 beats/min), other causes of hypotension should be sought, such as myocardial infarction, pulmonary embolism, sepsis, pericardial effusion/tamponade, or hypovolemia. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Adverse hemodynamics in AF'.) REASONS NOT TO PERFORM CARDIOVERSION Patients in whom it is reasonable to avoid early cardioversion include: Those who are asymptomatic or minimally symptomatic, particularly those with multiple comorbidities, advanced age, or poor overall prognosis, where the risks of undergoing cardioversion and/or pharmacologic rhythm control may outweigh the benefits of restoring SR. Not performing cardioversion may also be appropriate in those with a low likelihood of long-term maintenance of SR, such as those with marked left atrial enlargement/dilatation, significant mitral regurgitation, or those with florid hyperthyroidism. Those who cannot receive anticoagulation, if indicated, are generally not candidates for cardioversion unless the duration of AF is less than 48 hours. (See 'Anticoagulation' below and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration uncertain or 48 or more hours'.) Those with left atrial thrombus identified during a transesophageal echocardiogram or who have presented with a thrombotic event (eg, stroke or transient ischemia). (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'Transesophageal echocardiography-based approach'.) Some experts would not pursue cardioversion in a person who has previously failed the procedure (ie, had only a brief period of sustained sinus rhythm following a prior cardioversion). Other reasons to consider not cardioverting include: https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 3/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Those where AF has been continuously present for more than one year [1-6]. Those with a left atrium that is markedly enlarged (atrial dimension >6.0 cm, 2 transthoracic echocardiographic biplane atrial volume index >48 mL/m ) [6-11]. Those with AF recurrence while taking adequate doses of appropriate antiarrhythmic drug therapy and who have recently undergone cardioversion. Drug refractory patients may have successful conversion to SR but are less likely to maintain SR long term. Cather ablation for AF may be a solution to maintaining SR for some patients in this situation. Those who do not or no longer respond to more than one antiarrhythmic drug are less likely to maintain SR with other drugs. Those for whom cardioversion with long-term maintenance of SR is likely to be unsuccessful if the underlying precipitant (eg, thyrotoxicosis, pericarditis, pneumonia, or mitral valve disease) has not been corrected prior to cardioversion. PRECARDIOVERSION ISSUES Prior to cardioversion with either electrical energy or antiarrhythmic drug therapy in stable patients, decisions regarding rate control, timing, and anticoagulation need to be made. Ventricular rate control Patients with a rapid ventricular response (>100 beats per minute) usually need control of their ventricular rate to improve symptoms. This can be achieved by oral (and occasionally intravenous) administration of short-acting beta blockers or nondihydropyridine calcium channel antagonists, such as diltiazem or verapamil [1]. In the acute setting, the target resting ventricular rate should usually be 80 to 100 beats per minute. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Anticoagulation Most patients who will undergo cardioversion should be anticoagulated as soon as the decision is made to cardiovert or after assessment of their clinical thromboembolic risk based on their CHA DS -VASc score. Issues related to anticoagulation around the time of 2 2 cardioversion are discussed in detail separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours'.) Timing Occasionally, hemodynamically unstable patients may need to be cardioverted urgently, without time to institute optimal oral anticoagulation (see 'Anticoagulation' above). For https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 4/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate these patients who are not chronically anticoagulated but are candidates, intravenous heparin or low molecular weight heparin should be started as soon as possible, possibly with a loading dose of heparin prior to cardioversion due to further transient impairment of atrial appendage mechanical function after cardioversion. For stable patients, the timing of elective cardioversion is determined in large part by the anticoagulant strategy chosen. If possible, patients with valvular and nonvalvular AF duration longer than 48 hours or of unknown duration should be therapeutically anticoagulated for at least four weeks or receive short-term anticoagulation followed by screening transesophageal echocardiography to exclude an atrial thrombus prior to cardioversion [12]. Some of our authors use this approach if the duration is longer than 24 hours. Patients with a history of neurologic event, diabetes, and heart failure also appear to be at high risk for thromboembolism post- cardioversion, and four weeks of anticoagulation or short-term anticoagulation with transesophageal echocardiography should be considered [13]. Evaluation for underlying cause It is useful to consider the potential for an underlying or precipitating cause, such as hyperthyroidism, but also acute pulmonary embolism, myopericarditis, pneumonia, pericarditis, or sepsis, though atrial fibrillation is rarely the sole manifestation of any of these other than hyperthyroidism. (See 'Reasons not to perform cardioversion' above and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Triggers'.) ELECTRICAL VERSUS PHARMACOLOGIC CARDIOVERSION This section compares an electrical with a pharmacologic approach for cardioversion. However, patients who fail pharmacologic cardioversion are generally referred for electrical cardioversion. Thus, the comparison is really an electrical compared with a pharmacologic/electrical approach. For a first episode, electrical cardioversion is preferred in most cases. This is particularly true for younger patients (<65 years of age) even if they have no symptoms. For other patients (not the first episode) who need to be cardioverted from AF to SR, either electrical or pharmacologic cardioversion (potentially followed by electrical cardioversion) is a reasonable approach. The choice between the two should take into account the strengths and weaknesses of each approach as well as patient preference. For most patients, we proceed directly to electrical cardioversion to avoid the potential of drug side effect and prolonged monitoring. Reasons to prefer electrical rather than pharmacologic cardioversion include: https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 5/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Avoiding drug side effects, including but not limited to transient hypotension or prolongation of the QTc interval. Avoiding need for prolonged telemetric monitoring to screen for a proarrhythmic response. This can result in longer observation periods in the emergency department or procedural area. Some antiarrhythmic agents have the potential to convert AF to atrial flutter. Superior efficacy as compared with pharmacologic cardioversion. In contrast, potential benefits from a pharmacologic (rather than an electrical) approach include: Avoiding the risk(s) of sedation (required at the time of electrical cardioversion) (see "Cardioversion for specific arrhythmias", section on 'Preparation and personnel') Testing for drug tolerance, in the occasional patient (eg, someone with long-standing AF) in whom it has been decided to continue oral antiarrhythmic drug therapy (see 'Preprocedural antiarrhythmic drugs' below) Studies comparing the two approaches are somewhat limited. Mortality outcomes following electrical and pharmacologic cardioversion were similar in an observational cohort of 7175 patients from a large anticoagulation registry [14]. There were 2427 (34 percent) patients who received pharmacological cardioversion and 4748 (66 percent) who received electrical cardioversion. During one-year follow-up, event rates (per 100 patient years) for mortality in patients who received electrical and pharmacological cardioversion were 1.36 (1.13 to 1.64) and 1.70 (1.35 to 2.14), respectively. In the RAFF2 trial, 396 patients with acute AF were randomly assigned to pharmacologic cardioversion with intravenous procainamide or placebo followed by electrical cardioversion, if necessary [15]. The primary outcome of conversion to normal SR for at least 30 minutes at any time after randomization and up to a point immediately after three shocks occurred with equal frequency in the two groups (96 versus 92 percent, respectively; p = 0.07). After procainamide infusion, 52 percent of patients converted (median time of 23 minutes), therefore not requiring subsequent electrical cardioversion. RAFF2 demonstrates that it is feasible for patients to be rapidly cardioverted with medical therapy in the emergency department, resolving their acute symptoms and enabling discharge home. However, we do not anticipate adoption of intravenous procainamide in this setting due to the additional time required for chemical cardioversion compared with electrical cardioversion and https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 6/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate the general lack of familiarity and experience with procainamide and its potential side effects by emergency department clinicians and general cardiologists. Further, the drug has a substantial half-life, making the risk of torsades de pointes due to early discharge problematic. Ibutilide is an antiarrhythmic drug that is more familiar to most clinicians caring for these patients and more likely to be chosen in this setting if an initial pharmacologic approach is attempted. (See 'Specific antiarrhythmic drugs' below.) ELECTRICAL CARDIOVERSION Electrical cardioversion of AF is a commonly performed medical procedure with a high success rate and a low complication rate when performed in the setting of anticoagulation. (See 'Arrhythmic complications' below and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'Rationale for anticoagulation'.) The overall immediate success rate of electrical cardioversion is greater than 90 percent [4,5,7- 10,16,17]. However, the overall success rate falls as the AF duration increases and early recurrences are possible. Preprocedural antiarrhythmic drugs Many patients who undergo direct current cardioversion do not receive pretreatment with antiarrhythmic drugs. This is particularly true for unstable and other patients who need immediate restoration of SR. Pretreatment with antiarrhythmic drugs may also be omitted in patients for whom long-term therapy is not anticipated, such as those with new onset AF or those in whom the potential for drug-induced arrhythmias are a concern. The following are reasons to consider initiation of antiarrhythmic drug therapy prior to electrical cardioversion: To increase the likelihood of successful cardioversion [1]. Sotalol, ibutilide, and dofetilide seem to decrease the cardioversion energy requirement and may be helpful in refractory patients. (See 'Electrical versus pharmacologic cardioversion' above.) To prevent recurrent episodes of AF soon after cardioversion. Ibutilide or verapamil may be useful in preventing early recurrences of AF after cardioversion, particularly if it is of recent onset [18,19]. To allow for an evaluation of tolerability of one or more drugs. For those patients in whom a decision has been made to attempt the long-term maintenance of SR with antiarrhythmic drug therapy, we believe it is reasonable to preferentially select an agent for cardioversion https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 7/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate that can also be used for long-term maintenance of SR (such as amiodarone, flecainide, or propafenone). To potentially avoid the need for intravenous sedation and subsequent electrical cardioversion. Procedure A detailed discussion of electrical cardioversion is found elsewhere. (See "Cardioversion for specific arrhythmias" and "Basic principles and technique of external electrical cardioversion and defibrillation".) The following are a few important points: If possible, the patient should be fasting for at least six hours. Oxygen saturation and electrolytes (particularly serum potassium) should be close to normal and anticoagulation status should be reviewed (anticoagulation status is crucial to prevent thromboembolism in the week after conversion; the need for and the type of anticoagulation depends on the patient s clinical presentation as discussed elsewhere), and drug levels, when measured, should be within the therapeutic range. Digoxin need not be withheld unless digitalis toxicity is suspected [20]. (See "Digitalis (cardiac glycoside) poisoning".) Electrical cardioversion, synchronized to the QRS complex, should be performed while the patient is under the influence of procedural sedation and is having blood pressure, heart rate, oxygen saturation, and carbon dioxide capnography monitored. Generally, cardioversion should be done in a situation where airway equipment and airway expertise are present. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications".) Electrical cardioversion is very rarely associated with complications such as thromboembolism, respiratory distress due to acute heart failure, myocardial necrosis, skin burns, transient ventricular dysfunction, and transient arrhythmias including bradycardia. These are discussed in detail separately. (See "Cardioversion for specific arrhythmias", section on 'Complications'.) Postprocedural considerations Most cardioversions take place without any significant adverse events. However, the following should be kept in mind. Hemodynamic changes after reversion Left ventricular systolic function often improves and may normalize after achievement of SR, although it may take months for this to happen. In one study, left ventricular function improved soon after the restoration of SR, a change that was attributed to the reduction in heart rate and return of atrial mechanical contraction [21]. Atrial contractility improves more slowly (atrial "stunning ) when the duration of AF prior to https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 8/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate cardioversion is prolonged [22]. In uncommon instances, there can be ventricular "stunning." In these rare cases, there can be acute pulmonary edema after cardioversion. (See "Mechanisms of thrombogenesis in atrial fibrillation", section on 'Atrial stunning after cardioversion'.) Recurrence of AF after cardioversion The recurrence rate of AF after electrical cardioversion can be high, especially in patients with prior recurrences, a large left atrium, underlying structural disease, and a history of heart failure. There are times when it is appropriate to start an antiarrhythmic drug before cardioversion to lower the risk of recurrence soon after cardioversion. For the first attempt, however, especially if the heart is normal and there is no heart failure, a cardioversion without an antiarrhythmic is reasonable, particularly without maintenance antiarrhythmic therapy [23]. The timing of AF recurrence was evaluated in a review of 61 patients who had daily electrocardiographic recordings using transtelephonic monitoring: 57 percent had recurrent AF during the first month after cardioversion, with a peak incidence during the first five days [24]. This is one of the reasons that post-cardioversion anticoagulation should be used independently of CHADS or CHA DS -VASc score, as this may obviate the need for a transesophageal 2 2 2 echocardiogram or an additional month of anticoagulation prior to another cardioversion. Electrical cardioversion may be repeated if AF recurs acutely in patients who have not been pretreated with antiarrhythmic therapy. In such patients or those in whom cardioversion fails, the combination of an atrioventricular (AV) nodal blocker plus intravenous loading with amiodarone, ibutilide, or procainamide, or oral dosing with flecainide, sotalol, or propafenone may restore SR pharmacologically. If the AF persists, electrical cardioversion may be performed and if successful, the patient may be placed on long-term antiarrhythmic therapy. (See 'Pharmacologic cardioversion' below.) A separate issue is whether to perform repeat cardioversion for later recurrence. One study has shown that two repeat cardioversions increase the likelihood of maintaining SR long-term [25]. However, an important consideration is the time interval between AF episodes. In both of the above reports, a third cardioversion for recurrent AF was performed within seven days of the second cardioversion. Repeated cardioversion may be a reasonable approach for patients with AF that recurs after a longer duration of SR (eg, years). It is most likely to be successful in younger patients with fair exercise tolerance and AF duration of less than three years [26]. Repeat cardioversion or nonpharmacologic therapy (catheter ablation of AF or AV nodal ablation) may be necessary in patients who remain symptomatic when in recurrent AF. Arrhythmic complications Bradyarrhythmias are occasionally seen after electrical cardioversion, especially when patients are being treated with drugs to control the rate in AF, in https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 9/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate older patients with tachycardia-bradycardia syndrome, and those with known preexisting bradycardia; ventricular tachyarrhythmias are rare but torsades de pointes can occur in patients treated with class III antiarrhythmics, especially in the first 24 hours after cardioversion and especially if there is bradycardia after cardioversion. In a retrospective study of 6906 cardioversions of acute AF in 2868 patients, 63 patients had bradyarrhythmias (51 episodes of asystole >5 seconds and 12 episodes of bradycardia with heart rate <40 bpm) [27]. No episodes of ventricular arrhythmia requiring intervention were reported. Patients with sinus or AV node dysfunction, as in the tachycardia-bradycardia syndrome, are at higher risk for prolonged sinus pauses and bradycardia if AF is converted without a backup pacemaker. Nevertheless, the hemodynamic benefit from cardioversion may be sufficient to warrant restoration of SR with control of the atrial rate and/or AV conduction with a pacemaker. Physiologic pacing in patients with sinus node dysfunction and SR appears to decrease the likelihood of recurrent AF, especially if the initiation of AF episodes is bradycardia dependent [28]. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history" and "Sinus node dysfunction: Treatment".) PHARMACOLOGIC CARDIOVERSION As discussed above, we generally prefer electrical cardioversion to pharmacologic cardioversion in most patients.(See 'Electrical versus pharmacologic cardioversion' above.) Flecainide, propafenone, ibutilide, dofetilide, procainamide, and, to a lesser degree, amiodarone have efficacy for pharmacologic conversion of AF. Of these, we prefer flecainide or propafenone unless there is evidence for coronary artery disease, left ventricular systolic dysfunction, or the duration of AF is greater than seven days, in which case dofetilide, or to a lesser degree, amiodarone or ibutilide have some role for medical conversion. None of these drugs is as efficacious as electrical cardioversion. In order to avoid side effects and proarrhythmia, we do not use two or more antiarrhythmic drugs at the same time. Structural heart disease is a contraindication to the use of some of the antiarrhythmic drugs. For the purpose of this topic, we define it as any condition in which there is a deviation in the size, shape, function, or structure of the atria or ventricles (such as left ventricular hypertrophy or dilated cardiomyopathy). This also includes coronary artery disease. The definition does not include processes that alter the electrical properties of the heart, such as electrical activation, conduction, automaticity, or refractoriness. Specific antiarrhythmic drugs The following antiarrhythmic drugs have been used to cardiovert patients in AF: https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 10/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Flecainide is a very effective antiarrhythmic drug for the pharmacologic conversion of a patient with AF of short (<24 hours) duration. Flecainide should not be used in patients with structural heart disease, particularly those with left ventricular systolic dysfunction or with coronary artery disease. (See "Major side effects of class I antiarrhythmic drugs".) Intravenous flecainide (2 mg/kg over 10 minutes) acutely reverts recent onset AF in 67 to 92 percent of patients within six hours and is more effective than procainamide, sotalol, propafenone, and amiodarone. The intravenous preparation is not available in the United States. An oral dose of 200 to 300 mg has also been used. A single, large oral dose of flecainide (100 to 400 mg) is effective for AF reversion [29,30]. One study randomly assigned 79 patients to intravenous or large oral dose of flecainide. The rate of reversion to SR was similar at two hours (64 versus 68 percent for oral drug) and eight hours after treatment (72 versus 75 percent); however, the mean time to reversion was shorter with intravenous flecainide (52 versus 110 minutes) [31]. Propafenone is significantly more effective in paroxysmal as opposed to persistent AF, with rates likely approaching those seen with flecainide. As with flecainide, we do not recommend propafenone in patients with structural heart disease, particularly those with left ventricular systolic dysfunction or coronary artery disease. (See "Major side effects of class I antiarrhythmic drugs".) Intravenous propafenone (2 mg/kg over 10 to 20 minutes) is used in Europe for the acute termination of AF. Conversion rates of 23 to 54 percent in patients with AF of variable duration have been reported [32,33]. Oral propafenone can be given as a large dose of 450 to 600 mg. A single oral loading dose reverted AF in 56 to 83 percent of patients, depending upon the duration of AF, in one study [34,35]. The administration of propafenone prior to electrical cardioversion does not alter the energy requirements for, or the success rate of, cardioversion [36]. Dofetilide has primarily been studied for the medical conversion of persistent AF. Dofetilide has not been directly compared with amiodarone or vernakalant. Its principal use is to help maintain SR, rather than to be used for cardioversion. It has been used successfully in patients with structural heart disease. As an oral agent, it is rarely used solely for the purpose of cardioversion. It can be started prior to anticipated electrical cardioversion to help maintain SR shortly after either electrical or spontaneous cardioversion, or in those patients in whom it is chosen for the long-term maintenance of sinus rhythm. (See "Clinical use of dofetilide".) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 11/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Dofetilide is more effective than placebo for the conversion of persistent AF to SR, particularly at a dose of 500 mcg twice daily [37-39]. As an example, the SAFIRE-D study randomized 325 patients (including 60 percent with structural heart disease) with AF (n = 277) or atrial flutter (n = 48) to oral therapy with 125, 250, and 500 mcg twice daily [37]. Overall conversion rates were 6, 9.8, and 30 percent, respectively. Among patients who convert with dofetilide, successful conversion occurred in 70 percent within 24 hours, while 91 percent converted within 36 hours. Postmarket uncontrolled trials have suggested that oral dofetilide is useful in the medical conversion of persistent AF in up to 60 percent of patients [39]. Dofetilide also appears safe and efficacious in the setting of heart failure (including patients with AF); this is discussed separately. (See "Clinical use of dofetilide", section on 'Heart failure'.) Dofetilide has the disadvantage of requiring the patient to be hospitalized, as it can cause nonsustained ventricular tachycardia (VT), torsades de pointes, or sudden death [40,41]. In the SAFIRE-D trial, the incidence of torsades de pointes was 1.2 percent [37]. This risk is minimized by dosing based on the creatinine clearance and avoidance of other drugs that may cause torsades de pointes. Initiation of dofetilide is required to be in-hospital, under telemetry conditions by a doctor certified in its use, with a total of at least six dosages given before discharge. (See "Clinical use of dofetilide", section on 'Protocol for administration'.) Amiodarone (either oral or intravenous) is not particularly effective for cardioversion. If reversion to SR occurs it does so several hours later than with flecainide, propafenone, ibutilide, and vernakalant [42-52]. Intravenous amiodarone may be more effective in converting AF after it has been given for hours and days. Oral amiodarone requires long- term loading and is effective in converting about 25 percent of patients with persistent AF to SR after six weeks of loading. Thus, we do not recommend it solely for the purpose of cardioversion. It is not approved by the US Food and Drug Administration for the treatment of AF. (See "Amiodarone: Clinical uses" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) However, amiodarone may occasionally have value before cardioversion in patients who will receive the drug long term for maintenance and may be considered as adjunctive therapy to increase the likelihood of successful cardioversion in patients who are known to be refractory to electrical cardioversion or in those in whom there is a concern about early relapse. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 12/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Intravenous amiodarone is given at a dose of 150 mg over 10 minutes, with a subsequent infusion of 1 mg/minute for six hours, then 0.5 mg/minute for 18 hours or change to oral maintenance dosing (eg, 100 to 200 mg once daily) [53]. It should be kept in mind that the drug will likely have a significant rate-slowing effect, which may be beneficial in some patients [54]. A table on monitoring for adverse effects is available ( table 1). Vernakalant is available in Europe and Canada in intravenous forms for the rapid conversion (50 percent conversion within 10 minutes) of recent onset AF (less than eight days duration for patients not undergoing surgery, and less than four days duration for post-cardiac surgery patients) to SR. This drug is not available in the United States. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Vernakalant'.) In a 2019 systematic review and meta-analysis of nine trials (n = 1358) comparing vernakalant with placebo, amiodarone, or ibutilide [55], significant methodological bias was found in four trials. The following was also found: Vernakalant was superior to placebo for conversion within 90 minutes (50 percent conversion; risk ratio 5.15, 95% CI 2.24-11.84). No significant difference in the rate of conversion was found comparing vernakalant with active drug (56 versus 24 percent; risk ratio 2.40, 95% CI 0.76-7.58). Ibutilide, due to its propensity to prolong repolarization and the QT interval, has the potential to provoke torsades de pointes. Ibutilide is available only as an intravenous preparation (1 mg over 10 minutes and potentially repeated once after 20 minutes) and is useful for the acute reversion of AF [56-58]. It has been used in patients with structural heart disease (but without heart failure). We use ibutilide very rarely in this setting. (See "Therapeutic use of ibutilide".) In trials, the acute AF conversion rate is 28 to 51 percent. Ibutilide is more effective at converting atrial flutter to SR, with conversion rates of 50 to 75 percent. Ibutilide can work in acute situations of persistent AF and can be used (with caution) in patients with structural heart disease. However, while these rates seem low compared with flecainide or propafenone, ibutilide has never been directly compared with these other drugs. In addition, the average conversion times with ibutilide seem shorter than with flecainide and propafenone. Arrhythmia conversion occurred within a mean of 27 to 33 minutes after the start of the infusion [57,58]. In comparative studies, ibutilide has been more effective for AF reversion https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 13/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate than procainamide (51 versus 21 percent and 32 versus 5 percent) [59,60] or intravenous sotalol (44 versus 11 percent) [61]. In four large series, the rate of torsades de pointes with ibutilide ranged between 3.6 and 8.3 percent [56-58,60]. Sustained episodes of torsades de pointes, requiring cardioversion, were seen in 1.7 to 2.4 percent. In addition to polymorphic VT, nonsustained monomorphic VT occurred in an additional 3.2 to 3.6 percent of patients [57,58]. Because of the risk of ventricular proarrhythmia, patients treated with ibutilide should be observed with continuous rhythm monitoring for at least four hours after the infusion or until the QTc interval has returned to baseline. Pretreatment with intravenous magnesium appears to minimize the risk of ibutilide-induced torsades de pointes without affecting the efficacy of conversion [62]. Risk factors for the development of torsades de pointes with ibutilide are heart failure, baseline increase in QTc interval, and low potassium or magnesium. Electrolytes should be checked and normalized before cardioversion with ibutilide. We occasionally use ibutilide in patients resistant to electrical cardioversion and in patients for whom anesthesia, in conjunction with direct current cardioversion, is not readily available. The recommended dose varies with patient size. For patients weighing less than 60 kg, the recommended dose is 0.01 mg/kg infused over 10 minutes. If the arrhythmia does not terminate 10 minutes after the end of the infusion, a second bolus (same dose over 10 minutes) can be given. For patients weighing more than 60 kg, the recommended starting intravenous dose is 1 mg over 10 minutes. If AF does not terminate 10 minutes after the end of the infusion, a second bolus of 1 mg over 10 minutes can be given. Most patients studied have had arrhythmia for less than 90 days. Efficacy has not been proven with an AF duration exceeding 90 days. We do not use ibutilide in combination with other antiarrhythmic medications. Less effective or ineffective drugs Several medications such as quinidine and procainamide are no longer used for cardioversion as most of the agents presented above have greater efficacy or fewer side effects or both. The following antiarrhythmic drugs are not particularly effective for the restoration of SR: Sotalol Oral sotalol is less effective than quinidine [63] and equally effective to amiodarone for chemical cardioversion of AF (27 percent at 28 days) [64]. Intravenous sotalol is less effective than intravenous flecainide or ibutilide for reversion of AF [61,65]. Thus, we do not recommend either form for chemical cardioversion of AF. (See "Clinical uses of sotalol".) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 14/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Dronedarone We do not recommend dronedarone for the restoration of SR in patients with AF since conversion rates are very low [66]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Rate-control drugs such as digoxin, nondihydropyridine calcium channel blockers (eg, diltiazem or verapamil), and beta blockers have not been effective in restoring SR in placebo-controlled studies. Many clinicians overestimate the effectiveness (for cardioversion) of these agents [1,67-72]. Pill-in-the-pocket A "pill-in-the-pocket" approach with either flecainide (<70 kg: 200 mg; may not repeat in 24 hours; 70 kg: 300 mg; may not repeat in 24 hours) or propafenone can be used to terminate out-of-hospital paroxysmal AF of short duration after these drugs have been shown to be efficacious and safe in a monitored setting. In this approach, we have the patient take a diltiazem or a beta blocker 30 minutes or more (if they are not on chronic AV nodal

ibutilide, and vernakalant [42-52]. Intravenous amiodarone may be more effective in converting AF after it has been given for hours and days. Oral amiodarone requires long- term loading and is effective in converting about 25 percent of patients with persistent AF to SR after six weeks of loading. Thus, we do not recommend it solely for the purpose of cardioversion. It is not approved by the US Food and Drug Administration for the treatment of AF. (See "Amiodarone: Clinical uses" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) However, amiodarone may occasionally have value before cardioversion in patients who will receive the drug long term for maintenance and may be considered as adjunctive therapy to increase the likelihood of successful cardioversion in patients who are known to be refractory to electrical cardioversion or in those in whom there is a concern about early relapse. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 12/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Intravenous amiodarone is given at a dose of 150 mg over 10 minutes, with a subsequent infusion of 1 mg/minute for six hours, then 0.5 mg/minute for 18 hours or change to oral maintenance dosing (eg, 100 to 200 mg once daily) [53]. It should be kept in mind that the drug will likely have a significant rate-slowing effect, which may be beneficial in some patients [54]. A table on monitoring for adverse effects is available ( table 1). Vernakalant is available in Europe and Canada in intravenous forms for the rapid conversion (50 percent conversion within 10 minutes) of recent onset AF (less than eight days duration for patients not undergoing surgery, and less than four days duration for post-cardiac surgery patients) to SR. This drug is not available in the United States. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Vernakalant'.) In a 2019 systematic review and meta-analysis of nine trials (n = 1358) comparing vernakalant with placebo, amiodarone, or ibutilide [55], significant methodological bias was found in four trials. The following was also found: Vernakalant was superior to placebo for conversion within 90 minutes (50 percent conversion; risk ratio 5.15, 95% CI 2.24-11.84). No significant difference in the rate of conversion was found comparing vernakalant with active drug (56 versus 24 percent; risk ratio 2.40, 95% CI 0.76-7.58). Ibutilide, due to its propensity to prolong repolarization and the QT interval, has the potential to provoke torsades de pointes. Ibutilide is available only as an intravenous preparation (1 mg over 10 minutes and potentially repeated once after 20 minutes) and is useful for the acute reversion of AF [56-58]. It has been used in patients with structural heart disease (but without heart failure). We use ibutilide very rarely in this setting. (See "Therapeutic use of ibutilide".) In trials, the acute AF conversion rate is 28 to 51 percent. Ibutilide is more effective at converting atrial flutter to SR, with conversion rates of 50 to 75 percent. Ibutilide can work in acute situations of persistent AF and can be used (with caution) in patients with structural heart disease. However, while these rates seem low compared with flecainide or propafenone, ibutilide has never been directly compared with these other drugs. In addition, the average conversion times with ibutilide seem shorter than with flecainide and propafenone. Arrhythmia conversion occurred within a mean of 27 to 33 minutes after the start of the infusion [57,58]. In comparative studies, ibutilide has been more effective for AF reversion https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 13/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate than procainamide (51 versus 21 percent and 32 versus 5 percent) [59,60] or intravenous sotalol (44 versus 11 percent) [61]. In four large series, the rate of torsades de pointes with ibutilide ranged between 3.6 and 8.3 percent [56-58,60]. Sustained episodes of torsades de pointes, requiring cardioversion, were seen in 1.7 to 2.4 percent. In addition to polymorphic VT, nonsustained monomorphic VT occurred in an additional 3.2 to 3.6 percent of patients [57,58]. Because of the risk of ventricular proarrhythmia, patients treated with ibutilide should be observed with continuous rhythm monitoring for at least four hours after the infusion or until the QTc interval has returned to baseline. Pretreatment with intravenous magnesium appears to minimize the risk of ibutilide-induced torsades de pointes without affecting the efficacy of conversion [62]. Risk factors for the development of torsades de pointes with ibutilide are heart failure, baseline increase in QTc interval, and low potassium or magnesium. Electrolytes should be checked and normalized before cardioversion with ibutilide. We occasionally use ibutilide in patients resistant to electrical cardioversion and in patients for whom anesthesia, in conjunction with direct current cardioversion, is not readily available. The recommended dose varies with patient size. For patients weighing less than 60 kg, the recommended dose is 0.01 mg/kg infused over 10 minutes. If the arrhythmia does not terminate 10 minutes after the end of the infusion, a second bolus (same dose over 10 minutes) can be given. For patients weighing more than 60 kg, the recommended starting intravenous dose is 1 mg over 10 minutes. If AF does not terminate 10 minutes after the end of the infusion, a second bolus of 1 mg over 10 minutes can be given. Most patients studied have had arrhythmia for less than 90 days. Efficacy has not been proven with an AF duration exceeding 90 days. We do not use ibutilide in combination with other antiarrhythmic medications. Less effective or ineffective drugs Several medications such as quinidine and procainamide are no longer used for cardioversion as most of the agents presented above have greater efficacy or fewer side effects or both. The following antiarrhythmic drugs are not particularly effective for the restoration of SR: Sotalol Oral sotalol is less effective than quinidine [63] and equally effective to amiodarone for chemical cardioversion of AF (27 percent at 28 days) [64]. Intravenous sotalol is less effective than intravenous flecainide or ibutilide for reversion of AF [61,65]. Thus, we do not recommend either form for chemical cardioversion of AF. (See "Clinical uses of sotalol".) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 14/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Dronedarone We do not recommend dronedarone for the restoration of SR in patients with AF since conversion rates are very low [66]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Rate-control drugs such as digoxin, nondihydropyridine calcium channel blockers (eg, diltiazem or verapamil), and beta blockers have not been effective in restoring SR in placebo-controlled studies. Many clinicians overestimate the effectiveness (for cardioversion) of these agents [1,67-72]. Pill-in-the-pocket A "pill-in-the-pocket" approach with either flecainide (<70 kg: 200 mg; may not repeat in 24 hours; 70 kg: 300 mg; may not repeat in 24 hours) or propafenone can be used to terminate out-of-hospital paroxysmal AF of short duration after these drugs have been shown to be efficacious and safe in a monitored setting. In this approach, we have the patient take a diltiazem or a beta blocker 30 minutes or more (if they are not on chronic AV nodal blocker) before the oral antiarrhythmic drug to prevent a rapid ventricular rate should conversion to atrial flutter occur. Some of our contributors prefer the patient to be observed in the emergency department (or potentially during inpatient hospitalization) the first time the "pill-in-the-pocket" approach is taken so that monitoring of safety and efficacy occurs. Some authors also instruct their patients to begin a direct-acting oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) at the time of the beta blocker/diltiazem so as to decrease the risk of thrombus formation should the patient not convert to SR in the subsequent 48 hours and to prophylaxis for thrombus formation during the transient periconversion period of atrial appendage mechanical dysfunction. MAINTENANCE ANTIARRHYTHMIC DRUG THERAPY After successful electrical cardioversion, antiarrhythmic drugs increase the likelihood of long- term maintenance of SR [1]. The use of antiarrhythmic drugs to maintain SR is discussed elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) We do not generally recommend maintenance antiarrhythmic drugs after electrical cardioversion in patients with their first episode of non-valvular AF, particularly those at low risk for recurrence (eg, short-duration AF, normal or only mildly increased left atrial size, normal left ventricular systolic function, absence of valvular dysfunction) or those with a transient cause (eg, pericarditis, pulmonary embolism, and corrected or treated hyperthyroidism) [73]. (See 'Recurrence of AF after cardioversion' above.) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 15/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate RECOMMENDATIONS OF OTHERS Societal guidelines are available [53,74-76]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS Unstable patients For the uncommon patient who is hemodynamically unstable or has angina due to AF and is at low risk for thromboembolism, we recommend urgent electrical cardioversion rather than no cardioversion (Grade 1C). (See 'Indications' above.) Stable patients Most patients with AF do not need emergency or even urgent cardioversion, as rate slowing will often improve symptoms. We also attempt to defer cardioversion to allow for initiation of heparin anticoagulation. For select, stable patients with nonvalvular AF, the restoration of sinus rhythm (SR) with either electrical or pharmacologic cardioversion is necessary or reasonable (see 'Ventricular rate control' above and 'Indications' above): Symptomatic, first episode of AF For most symptomatic patients with new onset/first episode of AF, we suggest an attempt at cardioversion, as opposed to no attempt (Grade 2C). In patients who do have factors that predict a high likelihood of success of electrical cardioversion, and in whom long-term maintenance antiarrhythmic drug therapy is not planned, we suggest electrical instead of pharmacologic cardioversion (Grade 2B). (See 'Reasons not to perform cardioversion' above and 'Electrical versus pharmacologic cardioversion' above.) In such patients who are older or have multiple medical comorbidities, it is reasonable to avoid cardioversion if the symptoms can be minimized and pharmacologic ventricular rate control is achieved; the approach needs to be individualized. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 16/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Patients who fail long-term rate control For patients in whom a long-term rate control strategy has failed due to persistent symptoms, a rhythm control strategy involving cardioversion is reasonable. Infrequent episodes of AF Periodic electrical cardioversion is an option for patients with infrequent episodes of AF that do not spontaneously convert, including those being managed with a rhythm control strategy. Roles of rate control and anticoagulation Most patients in whom cardioversion is chosen will need the ventricular rate controlled and the need for anticoagulation assessed prior to cardioversion. (See 'Ventricular rate control' above and 'Anticoagulation' above.) Antiarrhythmic drugs These may be initiated prior to electrical cardioversion to increase the likelihood of a successful electrical cardioversion, to increase the likelihood of maintaining SR in the hours after cardioversion, or as the first step in a plan for long-term antiarrhythmic therapy. (See 'Preprocedural antiarrhythmic drugs' above.) For patients with AF and no structural heart disease (including no evidence of coronary artery disease) for whom pharmacologic cardioversion is chosen, we suggest either flecainide or propafenone rather than other antiarrhythmic drugs (Grade 2B). The choice between these two drugs should be influenced by the practitioner s experience and the clinical situation. (See 'Pharmacologic cardioversion' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Naccarelli GV, Dell'Orfano JT, Wolbrette DL, et al. Cost-effective management of acute atrial fibrillation: role of rate control, spontaneous conversion, medical and direct current cardioversion, transesophageal echocardiography, and antiembolic therapy. Am J Cardiol 2000; 85:36D. 2. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 17/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate 3. Resnekov L, McDonald L. Appraisal of electroconversion in treatment of cardiac dysrhythmias. Br Heart J 1968; 30:786. 4. Elhendy A, Gentile F, Khandheria BK, et al. Predictors of unsuccessful electrical cardioversion in atrial fibrillation. Am J Cardiol 2002; 89:83. 5. Gallagher MM, Guo XH, Poloniecki JD, et al. Initial energy setting, outcome and efficiency in direct current cardioversion of atrial fibrillation and flutter. J Am Coll Cardiol 2001; 38:1498. 6. Frick M, Frykman V, Jensen-Urstad M, et al. Factors predicting success rate and recurrence of atrial fibrillation after first electrical cardioversion in patients with persistent atrial fibrillation. Clin Cardiol 2001; 24:238. 7. Dittrich HC, Erickson JS, Schneiderman T, et al. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:193. 8. Henry WL, Morganroth J, Pearlman AS, et al. Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation 1976; 53:273. 9. Lundstr m T, Ryd n L. Chronic atrial fibrillation. Long-term results of direct current conversion. Acta Med Scand 1988; 223:53. 10. Dalzell GW, Anderson J, Adgey AA. Factors determining success and energy requirements for cardioversion of atrial fibrillation. Q J Med 1990; 76:903. 11. Pritchett EL. Management of atrial fibrillation. N Engl J Med 1992; 326:1264. 12. Garg A, Khunger M, Seicean S, et al. Incidence of Thromboembolic Complications Within 30 Days of Electrical Cardioversion Performed Within 48 Hours of Atrial Fibrillation Onset. JACC Clin Electrophysiol 2016; 2:487. 13. Airaksinen KE, Gr nberg T, Nuotio I, et al. Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study. J Am Coll Cardiol 2013; 62:1187. 14. Pope MK, Hall TS, Schirripa V, et al. Cardioversion in patients with newly diagnosed non- valvular atrial fibrillation: observational study using prospectively collected registry data. BMJ 2021; 375:e066450. 15. Stiell IG, Sivilotti MLA, Taljaard M, et al. Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomised trial. Lancet 2020; 395:339. 16. Schwartzman D, Musley SK, Swerdlow C, et al. Early recurrence of atrial fibrillation after ambulatory shock conversion. J Am Coll Cardiol 2002; 40:93. 17. Gurevitz OT, Ammash NM, Malouf JF, et al. Comparative efficacy of monophasic and biphasic waveforms for transthoracic cardioversion of atrial fibrillation and atrial flutter. Am Heart J https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 18/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate 2005; 149:316. 18. Tieleman RG, De Langen C, Van Gelder IC, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997; 95:1945. 19. De Simone A, Stabile G, Vitale DF, et al. Pretreatment with verapamil in patients with persistent or chronic atrial fibrillation who underwent electrical cardioversion. J Am Coll Cardiol 1999; 34:810. 20. Mann DL, Maisel AS, Atwood JE, et al. Absence of cardioversion-induced ventricular arrhythmias in patients with therapeutic digoxin levels. J Am Coll Cardiol 1985; 5:882. 21. Alam M, Thorstrand C. Left ventricular function in patients with atrial fibrillation before and after cardioversion. Am J Cardiol 1992; 69:694. 22. Fatkin D, Kuchar DL, Thorburn CW, Feneley MP. Transesophageal echocardiography before and during direct current cardioversion of atrial fibrillation: evidence for "atrial stunning" as a mechanism of thromboembolic complications. J Am Coll Cardiol 1994; 23:307. 23. Schilling RJ. Cardioversion of atrial fibrillation: the use of antiarrhythmic drugs. Heart 2010; 96:333. 24. Tieleman RG, Van Gelder IC, Crijns HJ, et al. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillation-induced electrical remodeling of the atria? J Am Coll Cardiol 1998; 31:167. 25. Bertaglia E, D'Este D, Zerbo F, et al. Success of serial external electrical cardioversion of persistent atrial fibrillation in maintaining sinus rhythm; a randomized study. Eur Heart J 2002; 23:1522. 26. Van Gelder IC, Crijns HJ, Tieleman RG, et al. Chronic atrial fibrillation. Success of serial cardioversion therapy and safety of oral anticoagulation. Arch Intern Med 1996; 156:2585. 27. Gr nberg T, Nuotio I, Nikkinen M, et al. Arrhythmic complications after electrical cardioversion of acute atrial fibrillation: the FinCV study. Europace 2013; 15:1432. 28. Saksena S, Prakash A, Hill M, et al. Prevention of recurrent atrial fibrillation with chronic dual-site right atrial pacing. J Am Coll Cardiol 1996; 28:687. 29. Capucci A, Lenzi T, Boriani G, et al. Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension. Am J Cardiol 1992; 70:69. 30. Alboni P, Botto GL, Baldi N, et al. Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach. N Engl J Med 2004; 351:2384. 31. Alp NJ, Bell JA, Shahi M. Randomised double blind trial of oral versus intravenous flecainide for the cardioversion of acute atrial fibrillation. Heart 2000; 84:37. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 19/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate 32. Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Propafenone Atrial Fibrillation Trial Investigators. Am J Cardiol 1997; 79:418. 33. Conti A, Del Taglia B, Mariannini Y, et al. Management of patients with acute atrial fibrillation in the ED. Am J Emerg Med 2010; 28:903. 34. Khan IA. Single oral loading dose of propafenone for pharmacological cardioversion of recent-onset atrial fibrillation. J Am Coll Cardiol 2001; 37:542. 35. Botto GL, Bonini W, Broffoni T, et al. Conversion of recent onset atrial fibrillation with single loading oral dose of propafenone: is in-hospital admission absolutely necessary? Pacing Clin Electrophysiol 1996; 19:1939. 36. Bianconi L, Mennuni M, Lukic V, et al. Effects of oral propafenone administration before electrical cardioversion of chronic atrial fibrillation: a placebo-controlled study. J Am Coll Cardiol 1996; 28:700. 37. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000; 102:2385. 38. Greenbaum RA, Campbell TJ, Channer KS, et al. Conversion of atrial fibrillation and mainten ance of sinus rhythm by dofetilide. The EMERALD (European and Australian Multicenter Eval uative Research on Atrial Fibrillation Dofetilide) study (Abstr). Circulation 1998; 98(17 Suppl): 1633. 39. Banchs JE, Wolbrette DL, Samii SM, et al. Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter. J Interv Card Electrophysiol 2008; 23:111. 40. Mounsey JP, DiMarco JP. Cardiovascular drugs. Dofetilide. Circulation 2000; 102:2665. 41. Abraham JM, Saliba WI, Vekstein C, et al. Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter. Circ Arrhythm Electrophysiol 2015; 8:772. 42. Vietti-Ramus G, Veglio F, Marchisio U, et al. Efficacy and safety of short intravenous amiodarone in supraventricular tachyarrhythmias. Int J Cardiol 1992; 35:77. 43. Noc M, Stajer D, Horvat M. Intravenous amiodarone versus verapamil for acute conversion of paroxysmal atrial fibrillation to sinus rhythm. Am J Cardiol 1990; 65:679. 44. Galve E, Rius T, Ballester R, et al. Intravenous amiodarone in treatment of recent-onset atrial fibrillation: results of a randomized, controlled study. J Am Coll Cardiol 1996; 27:1079. 45. Camm AJ, Capucci A, Hohnloser SH, et al. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol 2011; 57:313. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 20/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate 46. Mart nez-Marcos FJ, Garc a-Garmendia JL, Ortega-Carpio A, et al. Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm. Am J Cardiol 2000; 86:950. 47. Peuhkurinen K, Niemel M, Ylitalo A, et al. Effectiveness of amiodarone as a single oral dose for recent-onset atrial fibrillation. Am J Cardiol 2000; 85:462. 48. Blanc JJ, Voinov C, Maarek M. Comparison of oral loading dose of propafenone and amiodarone for converting recent-onset atrial fibrillation. PARSIFAL Study Group. Am J Cardiol 1999; 84:1029. 49. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 50. Tieleman RG, Gosselink AT, Crijns HJ, et al. Efficacy, safety, and determinants of conversion of atrial fibrillation and flutter with oral amiodarone. Am J Cardiol 1997; 79:53. 51. Kowey PR, Dorian P, Mitchell LB, et al. Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery: a randomized, double-blind, placebo-controlled trial. Circ Arrhythm Electrophysiol 2009; 2:652. 52. Vardas PE, Kochiadakis GE, Igoumenidis NE, et al. Amiodarone as a first-choice drug for restoring sinus rhythm in patients with atrial fibrillation: a randomized, controlled study. Chest 2000; 117:1538. 53. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 54. Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Intravenous amiodarone for acute heart rate control in the critically ill patient with atrial tachyarrhythmias. Am J Cardiol 1998; 81:594. 55. McIntyre WF, Healey JS, Bhatnagar AK, et al. Vernakalant for cardioversion of recent-onset atrial fibrillation: a systematic review and meta-analysis. Europace 2019; 21:1159. 56. Ellenbogen KA, Stambler BS, Wood MA, et al. Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study. J Am Coll Cardiol 1996; 28:130. 57. Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation 1996; 94:1613. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 21/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate 58. Abi-Mansour P, Carberry PA, McCowan RJ, et al. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Study Investigators. Am Heart J 1998; 136:632. 59. Volgman AS, Carberry PA, Stambler B, et al. Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation. J Am Coll Cardiol 1998; 31:1414. 60. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intravenous ibutilide compared with procainamide during human atrial flutter and fibrillation: electrophysiological determinants of enhanced conversion efficacy. Circulation 1997; 96:4298. 61. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL- sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568. 62. Patsilinakos S, Christou A, Kafkas N, et al. Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. Am J Cardiol 2010; 106:673. 63. Ferreira E, Sunderji R, Gin K. Is oral sotalol effective in converting atrial fibrillation to sinus rhythm? Pharmacotherapy 1997; 17:1233. 64. Chevalier P, Durand-Dubief A, Burri H, et al. Amiodarone versus placebo and class Ic drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis. J Am Coll Cardiol 2003; 41:255. 65. Reisinger J, Gatterer E, Heinze G, et al. Prospective comparison of flecainide versus sotalol for immediate cardioversion of atrial fibrillation. Am J Cardiol 1998; 81:1450. 66. Iannone P, Haupt E, Flego G, et al. Dronedarone for atrial fibrillation: the limited reliability of clinical practice guidelines. JAMA Intern Med 2014; 174:625. 67. Intravenous digoxin in acute atrial fibrillation. Results of a randomized, placebo-controlled multicentre trial in 239 patients. The Digitalis in Acute Atrial Fibrillation (DAAF) Trial Group. Eur Heart J 1997; 18:649. 68. Roberts SA, Diaz C, Nolan PE, et al. Effectiveness and costs of digoxin treatment for atrial fibrillation and flutter. Am J Cardiol 1993; 72:567. 69. Anderson S, Blanski L, Byrd RC, et al. Comparison of the efficacy and safety of esmolol, a short-acting beta blocker, with placebo in the treatment of supraventricular tachyarrhythmias. The Esmolol vs Placebo Multicenter Study Group. Am Heart J 1986; 111:42. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 22/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate 70. Waxman HL, Myerburg RJ, Appel R, Sung RJ. Verapamil for control of ventricular rate in paroxysmal supraventricular tachycardia and atrial fibrillation or flutter: a double-blind randomized cross-over study. Ann Intern Med 1981; 94:1. 71. Salerno DM, Dias VC, Kleiger RE, et al. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atrial flutter. The Diltiazem-Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1989; 63:1046. 72. Farshi R, Kistner D, Sarma JS, et al. Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug regimens. J Am Coll Cardiol 1999; 33:304. 73. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33:2719. 74. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 75. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 76. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 1025 Version 66.0 https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 23/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate GRAPHICS Amiodarone baseline testing and monitoring for side effects Monitoring Area of interest for monitoring Possible adverse effect Baseline testing Follow-up testing Cardiac ECG (at baseline and Yearly QT prolongation; during loading dose) torsades de pointes After adding medications that interact with Symptomatic sinoatrial or conduction system amiodarone or prolong impairment the QT interval Implantable cardioverter- Defibrillation threshold testing (if clinically As needed for signs/symptoms Increased defibrillation threshold defibrillators indicated) Dermatologic Physical examination As needed for Photosensitivity to UV signs/symptoms light Blue-gray skin discoloration Endocrine TSH (with reflex testing 3 to 4 months after Hyperthyroidism, if abnormal) starting drug, then yearly hypothyroidism As needed for signs/symptoms Hepatic AST and ALT 6 months after starting drug, then yearly AST or ALT elevation 2 upper limit of reference range Ophthalmologic Eye examination Yearly Corneal microdeposits Optic neuropathy Pulmonary Chest radiograph, PFTs* Yearly for surveillance Pulmonary toxicity (cough, fever, dyspnea) Along with PFTs (including DLCO) and chest computed tomography for signs/symptoms Refer to UpToDate topics on pulmonary toxicity, thyroid toxicity, and clinical uses of amiodarone for additional information. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 24/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate ECG: electrocardiogram; UV: ultraviolet; TSH: thyroid-stimulating hormone; AST: aspartate aminotransferase; ALT: alanine transaminase; PFTs: pulmonary function tests; DLCO: diffusing capacity of the lungs for carbon monoxide. There are differing opinions, and no concensus, of obtaining formal PFTs with assessment of diffusion capacity (ie, DLCO) as baseline testing in all patients. Some experts obtain baseline PFTs with DLCO prior to starting amiodarone, particularly among patients with underlying lung disease, while other experts rarely or never obtain baseline PFTs. Graphic 126072 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 25/26 7/6/23, 2:49 PM Atrial fibrillation: Cardioversion - UpToDate Contributor Disclosures Gerald V Naccarelli, MD Consultant/Advisory Boards: Acesion [Antiarrhythmic drug development]; InCarda Therapeutics [Antiarrhythmic drug development]; Milestone [Antiarrhythmic drug development]; Sanofi [Antiarrhythmic agent]. All of the relevant financial relationships listed have been mitigated. Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. James Hoekstra, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 26/26

7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Catheter ablation : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 27, 2022. INTRODUCTION The three principal goals of therapy in patients with atrial fibrillation (AF) are the alleviation of symptoms, the prevention of tachycardia-mediated cardiomyopathy, and the reduction in the risk of stroke. The first two goals can be achieved with either a rate or rhythm control strategy (see "Management of atrial fibrillation: Rhythm control versus rate control"). For patients in whom a rhythm control strategy is chosen, catheter ablation (CA) and antiarrhythmic drug therapy are the two principle therapeutic strategies to reduce the frequency or eliminate episodes of AF. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) This topic will discuss the use of CA in patients with AF and provide the clinician with much of the information needed to discuss the procedure with the patient. The discussion of surgery to prevent recurrent AF is found elsewhere. (See "Atrial fibrillation: Surgical ablation".) Stroke prevention is usually achieved with anticoagulation. This topic is discussed in detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) WHAT TO TELL YOUR PATIENT When discussing CA to reduce symptoms in an AF patient, the following information should be provided: https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 1/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate CA is a reasonable treatment option for AF patients when medications are unable to adequately control symptoms or are not tolerated. All patients who undergo CA must take oral anticoagulation for at least two to three months after the procedure. Anticoagulation should be continued long term in many patients with risk factors for stroke even if AF is not present after the ablation. This is because patients may continue to have some AF episodes that may be asymptomatic; in addition, the reduction in AF burden seen post-ablation has not yet been shown to reduce stroke risk. It is a common misconception that patients who undergo successful ablation can stop oral anticoagulation. About 70 to 75 percent of patients are symptom free at one year [1]. A lower percentage is likely for persistent AF (about 60 percent). About 50 percent of patients have detectable AF at one year (this includes symptomatic and asymptomatic patients) [2,3]. The success rate for ablation in patients with long-standing persistent AF (over one year) is poor. The risk of a major complication is about 4 percent, with vascular access complications being the most common. Other important, less common complications include stroke, cardiac perforation, or damage that includes injury to the pulmonary veins, esophagus, or phrenic nerve. The risk of dying within 30 days after an AF ablation procedure is about 1 in 1000 patients. The risk of a major complication is significantly higher at low-volume ablation centers. [4]. TECHNICAL CONSIDERATIONS Technical considerations for CA are presented separately. (See "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) COMPARISON WITH ANTIARRHYTHMIC THERAPY For patients with symptomatic paroxysmal AF in a rhythm- rather than a rate-control strategy, either a trial of an antiarrhythmic drug or CA is a reasonable approach. We are more inclined to https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 2/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate perform CA in patients for whom the odds of success are high and if they prefer to avoid the use of long-term antiarrhythmic drug therapy. Studies comparing these strategies are discussed separately. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients without prior antiarrhythmic drug treatment'.) EFFICACY CA leads to significant symptom improvement in most patients. Over 70 to 75 percent are symptom free at one year. Some symptoms may be due to atrial or ventricular premature complexes rather than AF. The absence of symptomatic AF recurrence is the primary efficacy outcome in most studies. However, with continuous invasive monitoring, approximately 50 percent of patients have had one or more documented episodes lasting 30 seconds or longer at one year. This becomes part of the rationale to continue long-term oral anticoagulation in many patients. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Our approach to anticoagulation'.) How is recurrence defined and measured? Recurrence of AF after CA is categorized as early or late. Each have distinct mechanisms and management implications [5]. From a clinical perspective, recurrences after the initial two-to-three-month post-ablation healing phase are more clinically relevant. Early recurrences of AF are defined as those that occur within the first two to three months after CA. This period is often referred to as the "blanking period," and recurrences during this time are not included in studies examining the long-term success of AF ablation. Early recurrences occur as often as 40 percent of the time with radiofrequency ablation (RFA) [6] and about 17 percent of the time for those treated with second-generation cryoballoon [7]. It is postulated to be related to several potential mechanisms including sterile pericarditis, recovered pulmonary vein (PV) conduction, or proarrhythmic effects of the ablation procedure [8]. Some studies suggest that early recurrence appears to be a predictor of late recurrence, especially when the episodes occur late in the blanking period. However, most clinicians will treat early recurrences with antiarrhythmic drug therapy before consideration of repeat ablation in these patients. Episodes of AF occurring after three months are considered to be recurrent AF and are referred to as "late recurrent AF." The possible mechanisms for late recurrent AF following CA are discussed separately. (See "Mechanisms of atrial fibrillation", section on 'Specific clinical situations'.) https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 3/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate The frequency of late recurrent AF varies significantly across studies in part due to factors such as the method and intensity of surveillance, whether other atrial arrhythmias such as atrial flutter are counted, whether patients remained on antiarrhythmic drug therapy, and patient characteristics (eg, paroxysmal or persistent AF). In some studies, success has been defined as the absence of recurrent AF or other atrial arrhythmias with or without antiarrhythmic drug therapy; a more rigorous definition requires the absence of AF >30 seconds in patients not taking antiarrhythmic drugs. The following studies illustrate the rates of late recurrence [9]: The DISCERN AF study evaluated episodes of symptomatic and asymptomatic AF (as well as atrial flutter and atrial tachycardia) before and after the procedure in 50 patients (80 percent with paroxysmal AF), using an implantable cardiac monitor capable of recording all AF episodes [10]. The total atrial arrhythmia burden was significantly reduced by 86 percent from a mean of two hours per day per patient before to 0.3 hours per day after. The ratio of asymptomatic to symptomatic episodes increased significantly after ablation from 1.1 to 3.7. After 18 months and a mean of 1.4 ablations, 58 percent of patients were symptom free. A 2013 meta-analysis of 19 observational studies (n = 6167) with outcomes at 3 years found that freedom from atrial arrhythmia at long-term follow-up (mean 24 months) after a single procedure was about 53 percent [11]. With multiple procedures, the long-term success rate was nearly 80 percent. However, there are several limitations of this analysis, including significant heterogeneity among the studies, disparities in post-ablation AF surveillance, and the inclusion of patients ablated with early-generation technologies no longer in current use. In the MANTRA and RAAFT-2 randomized trials, which allowed for antiarrhythmic drug use after CA, freedom from AF at two years was 85 and 72 percent, respectively [12,13]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients without prior antiarrhythmic drug treatment'.) In a meta-analysis of seven studies of first-generation cryoballoon ablation, one-year freedom from AF was 73 percent, but the analysis evaluated studies that allowed inclusion of patients taking antiarrhythmic drug therapy in the CA group [14]. Two real-world population studies found significantly lower rates of freedom from AF when only patients not taking antiarrhythmic drug therapy were counted (40 and 41 percent at one year) [3,15]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 4/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate The 2019 CIRCA-DOSE study randomly assigned 346 patients with drug-refractory, paroxysmal AF to contact-force-guided RFA or two differing duration protocols for cryoballoon ablation [1] (see 'Technical considerations' above). All patients received an implantable loop recorder, and they also received noninvasive surveillance. Follow-up was for 12 months. The primary endpoint of one-year freedom from atrial tachyarrhythmia (symptomatic or asymptomatic) as detected by continuous rhythm monitoring was about 53 percent in the three groups. One-year freedom from symptomatic atrial tachyarrhythmia, defined by continuous monitoring, ranged between 73 and 79 percent (p = 0.87). AF burden was reduced by about 99 percent in the three groups (p = 0.36). Predictors of recurrence Recurrence is more likely in patients with underlying cardiovascular disease such as hypertension, complicated heart disease (including valvular heart disease), older age, persistent as opposed to paroxysmal AF, procedure performed at a low-volume center, untreated obstructive sleep apnea, obesity, increasing plasma B-type natriuretic peptide level, or left atrial (LA) dilation [8,16-22]. LA dilation We rarely perform CA in patients with long-standing persistent AF and severe LA dilation (>5.5 cm). LA dilation should be assessed by volume determination rather than linear measurements if possible [23]. One study has shown that an LA volume 130 cc, assessed by computed tomography, predicts a recurrence rate of >90 percent at one year [24]. Other LA remodeling parameters Greater atrial wall thickness, lipid composition, and epicardial fat volume on cardiac computed tomography also predict AF recurrence in observational studies, but low measurement reproducibility may limit their clinical use [25]. Among 732 patients undergoing CA, 270 had AF recurrence after seven months. Patients with AF recurrence had higher LA wall thickness (anterior wall 1.9 versus 1.7 mm), 3 epicardial adipose volume (145 versus 129 mm ) and lower LA wall attenuation reflective of higher lipid composition (-69.1 versus -67.5 Hounsfield Units). Comparison of radiofrequency and cryothermal ablation The commonly used approved energy sources for CA are RF and cryothermal ablation. The efficacy and safety associated with these two energy sources have been found to be similar in multiple studies [1,14,26-30]. The three major randomized trials comparing the two energy sources are as follows: In the FIRE AND ICE trial, 762 patients with symptomatic, drug-refractory, paroxysmal AF were randomly assigned to cryoballoon ablation or RFA [31]. The primary efficacy endpoint https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 5/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate was the first documented clinical failure (eg, recurrence of AF, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) following a 90-day blanking period after the index ablation. Arrhythmia surveillance was noninvasive. The mean duration of follow-up was 1.5 years. The primary efficacy endpoint was similar in both groups (34.6 versus 35.9 percent, respectively; hazard ratio 0.96, 95% CI 0.76-1.22). In the FreezeAF trial, 315 patients with paroxysmal AF were randomly assigned to RFA or cryoballoon ablation [26]. The primary endpoint of freedom from atrial arrhythmia with absence of persistent complications was similar in the two groups at 12 months (70.7 versus 73.6 percent). Arrhythmia surveillance was noninvasive. In the 2019 CIRCA-DOSE study, which is discussed above, the two energy sources led to similar efficacy outcomes. (See 'How is recurrence defined and measured?' above.) Complications of cryoballoon ablation may differ somewhat from standard RFA. Pericardial effusions, tamponade, and atrioesophageal fistula have been reported less frequently in cryoballoon ablation. Non-AF atrial tachyarrhythmias have also been less frequently reported in long-term follow-up of cryoballoon ablation. However, phrenic nerve paralysis has been reported in up to 6.3 percent of 1349 procedures, significantly higher than seen with standard RFA. Resolution occurs acutely in most patients and in >90 percent within one year [14]. The use of larger balloons that prevent distal ablation and the assessment of diaphragmatic compound motor action potentials have lowered the rate of this complication. Recordings of diaphragmatic electromyograms during cryoballoon ablation for AF accurately predict phrenic nerve injury [32]. Patients with persistent atrial fibrillation The majority of patients in the studies of CA presented above had paroxysmal AF. The efficacy of CA in patients with persistent AF is lower than in patients with paroxysmal AF [33]. Our threshold for recommending CA is higher for patients with persistent AF given the lower success rates. Also, we avoid the use of CA as first- line therapy in patients with persistent AF. We believe CA is a reasonable choice for individuals with symptomatic persistent AF who either fail or cannot tolerate antiarrhythmic drug therapy or, in certain circumstances (ie, tachycardia- mediated cardiomyopathy), where there may be a benefit to maintaining sinus rhythm even in the absence of symptoms. To improve outcomes, standard pulmonary vein isolation (PVI) with or without additional ablative lesions can be performed. However, the utility of these additional lesion sets has not been consistently demonstrated, and we recommend standard PVI without the creation of additional lesions for the first ablation attempt in the majority of patients. We consider https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 6/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate additional lesions in patients with long-standing persistent AF or a markedly enlarged LA (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'). In patients with persistent AF, one small randomized trial (VENUS) found that the addition of vein-of-Marshall ethanol (see "Mechanisms of atrial fibrillation", section on 'Role of premature atrial complex and other arrhythmia triggers') infusion to catheter ablation, compared with catheter ablation alone, increased the likelihood of remaining free of AF at 6 and 12 months [34]. Further study of this procedure is needed. A 2014 systematic review and meta-analysis identified 46 randomized trials and observational studies of 3819 patients who underwent CA for persistent AF [35]. Compared with medical therapy, CA reduced the risk of recurrent AF (odds ratio 0.32, 95% CI 0.20-0.53). Various ablation strategies were employed in the studies, and the most efficacious combined isolation of the PVs with limited linear ablation (eg, roof ablation, mitral isthmus ablation) within the LA. The success rate after two procedures was about 60 percent in all groups. (See 'Comparison with antiarrhythmic therapy' above.) The STAR AF II trial was published subsequently to the meta-analysis [2]. In this trial, 589 patients with persistent AF were randomly assigned in a 1:4:4 ratio to ablation with PVI alone, PVI plus ablation of electrograms showing complex fractionated activity, or PVI plus additional linear ablation across the LA roof and mitral valve isthmus. There was no significant difference in the rates of the primary endpoint of freedom from any documented recurrence of AF lasting longer than 30 seconds after a single ablation procedure at 18 months (59 versus 49 versus 46 percent, respectively). Although serious adverse events appeared to be lower in the PVI-alone group, there were too few events for this endpoint to achieve statistical significance. Patients with concomitant atrial flutter Atrial fibrillation and flutter often coexist in part due to their common risk factors. In many atrial flutter patients, AF is thought to be the inciting arrhythmia, and as much as 55 percent of patients who undergo ablation for typical atrial flutter are also found to have AF on long-term follow-up [36]. Some studies have shown that PV triggers play an important role in the development of flutter [37]. While ablation of the tricuspid annulus-inferior vena cava (TA-IVC) isthmus is a highly successful treatment option for atrial flutter, the ablation approach to the patient with concomitant AF and atrial flutter requires a more extensive approach and has been evaluated: In a study of 108 patients with both AF and typical atrial flutter, patients were randomly assigned to either a dual-ablative procedure (PVI and TA-IVC isthmus ablation, 49 patients) or PVI alone (59 patients) [38]. After ablation, the following observations were made: https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 7/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate During the first eight weeks post-procedure, none of the dual-procedure patients and 32 patients treated with PVI alone developed atrial flutter and required cardioversion and/or antiarrhythmic drugs. After eight weeks, all antiarrhythmic drugs were discontinued. Only three patients treated with PVI alone had further recurrences of atrial flutter, which was successfully treated with TA-IVC ablation. Seven of the dual-procedure patients and six of those treated with PVI alone developed recurrent AF. Of these 13 patients (12 percent of the total group), 10 underwent successful repeat PVI, and three remained in sinus rhythm on antiarrhythmic drugs. These findings suggest that AF initiated by PV triggers may be the precursor rather than the consequence of atrial flutter. This conclusion is consistent with the observation that atrial flutter often starts after a transitional rhythm of variable duration, usually AF [39,40]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Attempts to control all atrial arrhythmias in patients with atrial flutter by performing PVI alone or at the time of an atrial flutter ablation have been studied: In the Triple A trial, 60 patients with atrial flutter but no documented AF were randomized to receive antiarrhythmic drugs alone, ablation of the cavotricuspid isthmus (CTI), or PVI. The primary endpoint, defined as any recurrent atrial tachyarrhythmia, occurred in 82.4 percent of the drug-treated group, 60.9 percent in the CTI group, and 10 percent in the PVI group during a mean follow-up time of 1.42 years [37]. In the PReVENT AF study [41], 50 patients with atrial flutter and no documented AF were randomized to CTI ablation alone or with concomitant PVI. More patients in the isthmus- ablation-only group experienced new-onset AF during follow-up (52 versus 12 percent), and the one-year burden also favored the combined ablation group compared with the isthmus-ablation-only group (8.3 versus 4 percent). These findings suggest that PVI either alone or in conjunction with atrial flutter ablation may have a beneficial effect on long-term suppression of all atrial arrhythmias. However, we do not recommend performing this procedure in lieu of or at the time of TA-IVC ablation in patients whose only documented arrhythmia is atrial flutter given the potential risks associated with additional ablation. (See "Atrial flutter: Maintenance of sinus rhythm".) Patients with structural heart disease The presence of structural heart disease may influence both the safety and efficacy of ablation procedures. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 8/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Heart failure CA appears to be safe and effective for the prevention of AF recurrence in patients with heart failure or impaired left ventricular function. The experience with ablation in this setting is discussed elsewhere. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control'.) Cardiac resynchronization therapy CA as an alternative to cardiac resynchronization therapy with atrioventricular node ablation in patients with heart failure is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Preference for rhythm over rate control'.) Mitral valve prosthesis A potential concern with CA in patients with a mitral valve prosthesis is injury to the valve. Furthermore, entrapment of the ablation catheter in a mechanical mitral valve, necessitating open-heart surgery, has been reported in patients undergoing left-sided ablation procedures. This issue was addressed in a report of 26 patients with mitral valve prostheses who were compared with a matched group of 52 patients without a mitral valve prosthesis [42]. The rate of maintenance of sinus rhythm was the same in the two groups, but the patients with a mitral valve prosthesis had longer fluoroscopy times with greater radiation exposure and a higher rate of post-ablation atrial tachycardia (23 versus 2 percent). Rheumatic heart disease The role of CA for chronic AF in patients with rheumatic heart disease is not well defined. One study performed electrophysiologic mapping in 17 patients with mitral stenosis who had chronic AF and were converted to sinus rhythm after balloon valvulotomy [43]. An organized atrial arrhythmia, which degenerated into AF, was induced in all patients; the focus was most often near the coronary sinus ostium. RFA was successful in 13 patients and, after a mean follow-up of 32 weeks, 10 were still in sinus rhythm. Cardiac surgery Either the Maze procedure or off-pump CA using an epicardial approach should be considered in patients with AF and an indication for open-heart surgery. These approaches are not generally recommended for patients without an indication for cardiac surgery, except in special circumstances, because of the mortality and morbidity associated with surgery. (See "Atrial fibrillation: Surgical ablation", section on 'Maze procedure'.) Patients with hypertension Renal sympathetic nerve denervation has been proposed as an adjunctive treatment to CA in hypertensive AF patients. We do not feel the available evidence supports its use in this setting. The rationale for the adding renal nerve denervation to CA is that hypertension is a major risk factor for the development of AF and that many hypertensive AF patients have increased https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 9/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate sympathetic tone. Renal nerve denervation has been evaluated as a treatment for hypertension, but its efficacy has not yet been established. (See "Treatment of resistant hypertension".) The issue of whether renal nerve denervation, when added to CA, can further lower the rate of AF recurrence was evaluated in the ERADICATE-AF trial [44]. In this study, 302 hypertensive (paroxysmal) AF patients were randomly assigned to CA or CA plus renal nerve denervation. The primary endpoint of freedom from AF, atrial flutter, or tachycardia at 12 months occurred in 56.5 and 72.1 percent of the two groups, respectively (hazard ratio 0.57, 95% CI 0.38-0.85). There was no significant difference in the rate of procedural complications between the two groups. Although the use of renal denervation as adjunctive therapy to CA improved the primary outcome, the lack of a sham-control group, that is CA plus sham renal denervation, is a major limitation of this study. COMPLICATIONS The types and rates of complications that occur in patients undergoing CA vary from series to series ( table 1 and table 2). The overall rate of major complications is about 4 percent, with vascular access complications being the most frequent [45]. There may be an increased rate of adverse effects with more extensive circumferential ablation [46-50]. (See "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) Two large studies published in 2013 came to somewhat differing conclusions as to whether the complication rate was falling with time: An analysis of 93,801 CA procedures performed in community hospitals in the United States between 2000 and 2010 did not identify a trend toward lower mortality [51]. The majority (81 percent) of procedures were performed in low-volume hospitals by low-volume operators. The overall frequency of complications was 6.29 percent, and there was a small but nonsignificant rise with time. In a meta-analysis of 192 published studies, including 83,236 patients, there was a significant decrease in the acute complication rate from 2007 to 2012 compared with 2000 to 2006 (2.6 versus 4 percent; p = 0.003) [52]. In these studies, cardiac complications accounted for at least 50 percent of all complications. Most [51,53], but not all [54], studies have suggested that advanced age and female sex are risk factors for complications. In addition, annual operator (<25 procedures) and hospital volume (<50 procedures) have been associated with adverse outcomes [51]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 10/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Complications reported in series of patients undergoing CA to prevent recurrent AF will be reviewed here. Other complications that might occur with any electrophysiology study, such as radiation exposure and valve, vascular, or myocardial injury, are discussed separately. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) Mortality Early case series found a death rate of about 1 to 1.5 in every 1000 patients [55,56]. More recent studies suggest a mortality closer to 5 per 1000. In the two large series (2000 to 2010 and 2007 to 2012) discussed directly above, the in-hospital mortality rates varied between 4.6 and 0.6 per 1000 patients [51,52]. The leading causes of death were cardiac tamponade (n = 8, 25 percent), stroke (n = 5, 16 percent), and atrioesophageal fistula (n = 5, 16 percent). Other causes included pneumonia, pulmonary vein (PV) perforation, and sepsis [55]. Cardiac tamponade Cardiac tamponade resulting from perforation is the most frequent serious complication of CA for AF, occurring in slightly more than 1 percent of procedures using radiofrequency (RF) [53,55,57], and it is the leading cause of death [55]. Tamponade results from either catheter perforation of an atrial or ventricular free wall, especially with overheating during energy delivery, or less frequently with transseptal puncture. Some cases of tamponade may be delayed in onset. In one study of delayed tamponade, the median duration was 10 days, with a range of several hours up to 30 days [55]. Pericardial effusion associated with PV isolation (PVI) was significantly less common in patients who underwent cryoballoon ablation (0.8 versus 2.1 percent) in one meta-analysis [30]. The treatment of tamponade caused by CA is similar to that in other settings. (See "Cardiac tamponade", section on 'Treatment'.) Catheter entrapment Entrapment of the circular mapping (LASSO) catheter in the mitral valve apparatus is a rare complication that can require cardiac surgery to resolve. The estimated incidence of this complication ranges between 0.01 and 0.9 percent, and specific sites of transeptal puncture or catheter manipulation may predispose to this adverse event [58-60]. Pulmonary vein stenosis PV stenosis is a potential complication of ablation near or within the PVs. The lesion is characterized by fibrosis and scarring of the PV; specific pathologic changes include intimal thickening, thrombus formation, endocardial contraction, and proliferation of elastic laminae [61]. The diagnosis may be delayed or missed entirely, as symptomatic patients may come to attention months after their initial ablation. In one series, symptoms developed 4 3 months after the most recent ablation, and the average delay between the onset of symptoms and diagnosis was 4.4 5.4 months. Symptoms of PV stenosis include dyspnea with exertion (or less often at rest), cough, chest pain, hemoptysis, and recurrent lung infections [62,63]. The mean onset of symptoms is two to five months after the https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 11/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate procedure [62-64]. The intensity of symptoms may be directly related to the degree of obstruction and inversely related to the duration of time to develop the stenosis [65]. Incorrect diagnoses including pneumonia, bronchitis, or suspected malignancy are often considered and result in unnecessary testing, treatment, and delayed intervention. Delays in diagnosis and treatment may allow for progression of stenosis and irreversible intraparenchymal lung damage. The reported rate of PV stenosis depends not only on the factors described above, but also on the definition of stenosis severity and the intensity of screening. Early reports cited rates as high as 38 percent, but more studies cite rates for severe stenosis as low as 1 to 3 percent [53,58,63,66]. A minority of diagnosed patients appear to develop symptoms [67,68]. The incidence of severe PV stenosis is between 0.32 and 3.4 percent, but the risk may be lower with cryoballoon compared with radiofrequency energy [69]. The rate of PV stenosis requiring intervention may be as low as 0.1 to 0.3 percent [57]. Diagnostic evaluation for PV stenosis should be performed in patients who develop respiratory symptoms after RF ablation (RFA). The joint Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society expert consensus statement of catheter and surgical ablation of AF suggests computed tomography or magnetic resonance imaging (MRI) as the preferred tests in suspected cases [65]. A ventilation/perfusion lung scan can also be used to diagnose PV stenosis. Stent placement is a more effective therapy for PV stenosis compared with balloon angioplasty [69]. It is associated with a significant and almost immediate improvement in symptoms and pulmonary blood flow [62-64]. In series of patients who underwent balloon angioplasty with or without stenting, in-segment or in-stent stenosis requiring repeat intervention developed in approximately 50 percent of patients [63,64]. The roles of either elective stenting or surgery are not well defined [65]. However, the incidence of PV stenosis has significantly decreased due to improvement in ablative techniques, especially with moving the ablation lesions toward the atrial side of the PV-atrial junction. Periprocedural embolic events Patients undergoing CA to prevent recurrent AF are at risk for embolic events before, during, and after the procedure. The incidence of clinical stroke or transient ischemic attack is between 0 and 2 percent [9]. The role of anticoagulant therapy in this setting is discussed in detail separately. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) MRI-detected brain lesions and cognitive impairment Stroke and transient ischemic attack are not the only neurologic sequelae of CA. Multiple MRI studies performed within 24 hours https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 12/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate after RFA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [70-72]. However, in a study of 60 AF patients at relatively low risk for stroke who underwent CA, only one patient developed new asymptomatic lesions on MRI soon after the procedure [73]. These lesions were presumed secondary to microemboli [74]. Studies of the impact of these lesions on neurocognitive function have come to differing conclusions as to the significance of these lesions, as illustrated by the following studies: The prevalence of cognitive impairment after RFA was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal AF, 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [75]. All RFA patients received periprocedural enoxaparin, and most patients with AF had a CHADS 2 score of 0 or 1 ( table 3). All patients underwent eight neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively. In a study of 37 patients with paroxysmal AF who underwent 41 ablation procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [72]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing. Vascular complications Vascular complications are among the most common adverse events related to AF ablation, likely due to the number and size of intravascular sheaths and the need for anticoagulation both during and immediately following the procedure. These complications include hematoma at the sites of catheter insertion, pseudoaneurysm, arteriovenous fistula, or retroperitoneal bleeding. Pseudoaneurysm and arteriovenous fistulae rates of 0.53 and 0.43 percent, respectively, have been reported [57,58]. This risk can be significantly reduced by the use of vascular ultrasound, which was demonstrated, in one study of 689 patients, to reduce the risk of vascular access complications from 5.3 to 1.1 percent [76]. Conservative management alone is usually sufficient for large hematomas and retroperitoneal bleeding, though anticoagulation may need to be held, and transfusion may be necessary in those patients where the risks of such interventions are warranted. Echo-guided manual compression and percutaneous intervention are usually effective treatments of femoral pseudoaneurysms or arteriovenous fistula, but direct surgical intervention is sometimes required [77]. Atrial esophageal fistula This is a potentially life-threatening medical emergency for which the exact mechanism is unknown. The overall incidence is 0.3 to 0.54 percent, and mortality is between 50 and 83 percent [78]. Early recognition can be missed due to the low awareness of https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 13/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate this rare complication. It is important for patients to be educated as to warning signs and to contact their AF ablation center should any suggestive symptoms develop. Clinical manifestations usually present one to four weeks post-ablation (range of 2 to 60 days), and the most common symptoms are fever, chest pain, and recurrent neurologic events from septic emboli. Chest computed tomography is the preferred diagnostic modality. Endoscopy with air insufflation should not be performed. Arrhythmic complications New reentrant circuits created by the ablation lesions can lead to atypical left atrial (LA) flutter. These circuits tend to develop around regions of LA scar and often involve the perimitral region. Due to anatomic variability and technical challenges, successful ablation is more difficult than that for typical right atrial flutter involving the isthmus of the inferior vena cava and tricuspid annulus. A significant percentage of LA flutter following PVI may also involve the musculature of the coronary sinus or the roof of the left atrium [79]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Typical atrial flutter may also occur after LA ablation due to alterations in activation patterns of the LA and may have an unusual electrocardiographic morphology. LA flutter appears to be more common following circumferential (as opposed to segmental) PVI [49,79-82]. In a randomized comparison of circumferential and segmental PVI, LA flutter developed in 9 of the 50 patients undergoing circumferential PVI, and in 1 of the 50 patients in the segmental PVI group [49]. In addition, many of the recurrent LA arrhythmias following segmental PVI are focal atrial tachycardias, as opposed to macroreentrant flutter circuits, and are often successfully treated with repeat isolation of the PVs. Other Other complications with their respective incidences are summarized: Phrenic nerve injury (<1 percent) [57,58] in patients receiving RFA (and up to 6.3 percent in those receiving cryoablation). (See 'Comparison of radiofrequency and cryothermal ablation' above.) Periesophageal vagal injury (gastric hypomotility) [48,83]. Acute coronary artery occlusion/injury (<1 percent) [65,84]. Iatrogenic atrial septal defect after cryoballoon ablation without clinical consequence (20 percent) [85]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 14/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate PREVENTION OF RECURRENCE The following therapies have been evaluated for their ability to prevent late recurrent AF; only treatment of obstructive sleep apnea (OSA) seems to be beneficial: Glucocorticoid therapy We do not believe there is sufficient evidence to recommend the use of prophylactic glucocorticoid therapy. Two observations raise the possibility that corticosteroid therapy might be useful for the prevention of early recurrence. Firstly, inflammation is associated with the development of AF, and systemic and local inflammatory responses may result from radiofrequency ablation (RFA) [86] (see "Epidemiology, risk factors, and prevention of atrial fibrillation",

the preferred tests in suspected cases [65]. A ventilation/perfusion lung scan can also be used to diagnose PV stenosis. Stent placement is a more effective therapy for PV stenosis compared with balloon angioplasty [69]. It is associated with a significant and almost immediate improvement in symptoms and pulmonary blood flow [62-64]. In series of patients who underwent balloon angioplasty with or without stenting, in-segment or in-stent stenosis requiring repeat intervention developed in approximately 50 percent of patients [63,64]. The roles of either elective stenting or surgery are not well defined [65]. However, the incidence of PV stenosis has significantly decreased due to improvement in ablative techniques, especially with moving the ablation lesions toward the atrial side of the PV-atrial junction. Periprocedural embolic events Patients undergoing CA to prevent recurrent AF are at risk for embolic events before, during, and after the procedure. The incidence of clinical stroke or transient ischemic attack is between 0 and 2 percent [9]. The role of anticoagulant therapy in this setting is discussed in detail separately. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) MRI-detected brain lesions and cognitive impairment Stroke and transient ischemic attack are not the only neurologic sequelae of CA. Multiple MRI studies performed within 24 hours https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 12/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate after RFA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [70-72]. However, in a study of 60 AF patients at relatively low risk for stroke who underwent CA, only one patient developed new asymptomatic lesions on MRI soon after the procedure [73]. These lesions were presumed secondary to microemboli [74]. Studies of the impact of these lesions on neurocognitive function have come to differing conclusions as to the significance of these lesions, as illustrated by the following studies: The prevalence of cognitive impairment after RFA was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal AF, 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [75]. All RFA patients received periprocedural enoxaparin, and most patients with AF had a CHADS 2 score of 0 or 1 ( table 3). All patients underwent eight neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively. In a study of 37 patients with paroxysmal AF who underwent 41 ablation procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [72]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing. Vascular complications Vascular complications are among the most common adverse events related to AF ablation, likely due to the number and size of intravascular sheaths and the need for anticoagulation both during and immediately following the procedure. These complications include hematoma at the sites of catheter insertion, pseudoaneurysm, arteriovenous fistula, or retroperitoneal bleeding. Pseudoaneurysm and arteriovenous fistulae rates of 0.53 and 0.43 percent, respectively, have been reported [57,58]. This risk can be significantly reduced by the use of vascular ultrasound, which was demonstrated, in one study of 689 patients, to reduce the risk of vascular access complications from 5.3 to 1.1 percent [76]. Conservative management alone is usually sufficient for large hematomas and retroperitoneal bleeding, though anticoagulation may need to be held, and transfusion may be necessary in those patients where the risks of such interventions are warranted. Echo-guided manual compression and percutaneous intervention are usually effective treatments of femoral pseudoaneurysms or arteriovenous fistula, but direct surgical intervention is sometimes required [77]. Atrial esophageal fistula This is a potentially life-threatening medical emergency for which the exact mechanism is unknown. The overall incidence is 0.3 to 0.54 percent, and mortality is between 50 and 83 percent [78]. Early recognition can be missed due to the low awareness of https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 13/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate this rare complication. It is important for patients to be educated as to warning signs and to contact their AF ablation center should any suggestive symptoms develop. Clinical manifestations usually present one to four weeks post-ablation (range of 2 to 60 days), and the most common symptoms are fever, chest pain, and recurrent neurologic events from septic emboli. Chest computed tomography is the preferred diagnostic modality. Endoscopy with air insufflation should not be performed. Arrhythmic complications New reentrant circuits created by the ablation lesions can lead to atypical left atrial (LA) flutter. These circuits tend to develop around regions of LA scar and often involve the perimitral region. Due to anatomic variability and technical challenges, successful ablation is more difficult than that for typical right atrial flutter involving the isthmus of the inferior vena cava and tricuspid annulus. A significant percentage of LA flutter following PVI may also involve the musculature of the coronary sinus or the roof of the left atrium [79]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Typical atrial flutter may also occur after LA ablation due to alterations in activation patterns of the LA and may have an unusual electrocardiographic morphology. LA flutter appears to be more common following circumferential (as opposed to segmental) PVI [49,79-82]. In a randomized comparison of circumferential and segmental PVI, LA flutter developed in 9 of the 50 patients undergoing circumferential PVI, and in 1 of the 50 patients in the segmental PVI group [49]. In addition, many of the recurrent LA arrhythmias following segmental PVI are focal atrial tachycardias, as opposed to macroreentrant flutter circuits, and are often successfully treated with repeat isolation of the PVs. Other Other complications with their respective incidences are summarized: Phrenic nerve injury (<1 percent) [57,58] in patients receiving RFA (and up to 6.3 percent in those receiving cryoablation). (See 'Comparison of radiofrequency and cryothermal ablation' above.) Periesophageal vagal injury (gastric hypomotility) [48,83]. Acute coronary artery occlusion/injury (<1 percent) [65,84]. Iatrogenic atrial septal defect after cryoballoon ablation without clinical consequence (20 percent) [85]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 14/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate PREVENTION OF RECURRENCE The following therapies have been evaluated for their ability to prevent late recurrent AF; only treatment of obstructive sleep apnea (OSA) seems to be beneficial: Glucocorticoid therapy We do not believe there is sufficient evidence to recommend the use of prophylactic glucocorticoid therapy. Two observations raise the possibility that corticosteroid therapy might be useful for the prevention of early recurrence. Firstly, inflammation is associated with the development of AF, and systemic and local inflammatory responses may result from radiofrequency ablation (RFA) [86] (see "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Inflammation and infection'). Secondly, glucocorticoid prophylaxis reduces the risk of the development of perioperative AF in patients undergoing coronary artery bypass graft surgery. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.) The possible benefit from prophylactic glucocorticoid therapy was evaluated in a study of 125 patients with paroxysmal AF who were randomly assigned to either three days of glucocorticoid therapy or placebo starting immediately after the procedure [87]. The rate of AF recurrence (primary endpoint) was significantly lower in the glucocorticoid group at one month (27 versus 49 percent), with most of the benefit occurring during the first three days (7 versus 31 percent). Treatment of OSA OSA is a predictor of recurrent AF after RFA. Patients with OSA who undergo CA should be encouraged to be evaluated for treatment with continuous positive airway pressure [88,89]. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".) Colchicine Colchicine, another drug with antiinflammatory properties, has been shown to decrease the risk of postoperative AF after cardiac surgery, particularly in patients with post-pericardiotomy syndrome. However, pending additional studies showing benefit, we do not use prophylactic colchicine. (See "Post-cardiac injury syndromes", section on 'Prevention'.) The potential ability of colchicine to reduce the incidence of early recurrent AF after pulmonary vein isolation was evaluated in a study of 206 individuals with paroxysmal AF who were randomly assigned to colchicine 0.5 mg twice daily or placebo beginning on the day of CA and continuing for three months [90]. After follow-up of about 15 months, there https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 15/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate was a lower recurrence rate of AF in patients taking colchicine (31.1 versus 49.5 percent; odds ratio [OR] 0.46, 95% CI 0.26-0.81). Angiotensin inhibition The data are mixed as to whether angiotensin converting enzyme inhibitors/angiotensin II receptor blockers reduce AF after CA procedures. This issue is discussed elsewhere. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation", section on 'Catheter ablation of atrial fibrillation'.) Periprocedural weight reduction Some studies suggest that periprocedural weight reduction may be a helpful adjunct to CA. Pre-procedure weight reduction In a retrospective study of 600 patients, weight reduction before CA was associated with reduced AF occurrence [91]. Freedom from AF was observed in 420 patients (70 percent) at 15 months. Percent weight loss during the year before CA independently predicted freedom from AF through the next 15 months (OR 1.17, 95% CI 1.11-1.23). Post-procedure weight reduction The SORT-AF Study compared one-year AF burden in patients with obesity participating in a weight loss program versus usual care after CA [92]. The intervention group had a small reduction in weight loss (5 versus 1 kg in controls). AF burden (measured with implantable loop recorder) after ablation did not differ between the two groups (OR 1.14, 95% CI 0.37-3.6). However, a reduction in body mass index was associated with a decrease in AF recurrence in persistent compared with paroxysmal AF patients. FOLLOW-UP Surveillance for recurrence of atrial arrhythmias is important in patients who have undergone CA. We agree with the joint Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society expert consensus statement of catheter and surgical ablation of AF [65], which recommends the following: First visit with electrophysiologist at a minimum of three months, and then every six months for at least two years. Electrocardiograms (ECGs) at all visits; symptomatic (eg, palpitations) patients should be evaluated with some form of event monitoring. The optimal method for screening for episodes of AF after ablation is not known. In the above studies, late recurrent AF was detected by patient symptoms, serial ECGs, 24- to 48-hour Holter https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 16/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate monitoring, and implantable cardiac monitor [10,16,93,94]. Rhythm transmitters were also used in the first few months [94]. With the exceptions of implantable cardiac monitor, preexisting dual-chamber pacemaker, or implantable cardioverter-defibrillator with AF detection capabilities, these methods may underestimate the incidence of recurrence due to sampling error [95]. In addition, as has been well demonstrated, patients with AF have a high rate of asymptomatic episodes. (See "Paroxysmal atrial fibrillation", section on 'Natural history' and 'Efficacy' above.) MANAGEMENT OF RECURRENCE Some patients with symptomatic AF after CA are candidates for a repeat procedure. The decision to do so is usually based on a patient's assessment of the potential benefit and risks. Other patients may choose a trial of antiarrhythmic drug therapy to reduce symptoms. The most common reason for recurrence of paroxysmal AF is reconnection of previously ablated electrically active tissue. Based upon the recurrence rates of AF after ablation, many patients are candidates for repeat ablation. We tell our patients that the success rate is in the range of 50 to 85 percent for a single procedure based primarily on AF type and anatomy, and that about 20 percent of patients have at least a second procedure. Success rates after a second procedure can be as high as 90 percent. Some experts and patients have agreed to repeat the procedure a third time. Patients with a history of persistent AF have a lower success rate and are less often felt to be good candidates for repeat procedures. The issue of whether patients with AF recurrence should undergo a repeat procedure or be placed on antiarrhythmic drug therapy was addressed in a study that randomly assigned 154 patients with symptomatic, paroxysmal AF recurrence to either repeat ablation or antiarrhythmic drugs [96]. During three-year follow-up, fewer patients in the repeat ablation group demonstrated AF progression, defined as an increase in AF burden >30 percent relative to baseline based on insertable cardiac monitor (also sometimes referred to as implantable cardiac monitor or implantable loop recorder) data or development of persistent AF (25 versus 79 percent; p<0.01). Despite limitations of this study, it supports our approach of offering a second ablation procedure to most patients. CONTRAINDICATIONS While there are few absolute contraindications, the risks and benefits of AF ablation should be carefully considered in each patient. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 17/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Contraindications to AF ablation include preexisting left atrial or left atrial appendage thrombus, inability to safely administer anticoagulation during or after the procedure, inability to tolerate sedation, patients with atrial septal defect closure devices in whom transseptal access cannot be performed, and those with interruption of the inferior vena cava. While not contraindicated, ablations performed on those with very long-standing persistent AF (ie, >2 years), severe mitral stenosis or regurgitation, or large left atria are expected to have lower success rates. (See 'Predictors of recurrence' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Role of catheter ablation (CA) CA for atrial fibrillation (AF) leads to symptom improvement in many patients. However, it has not convincingly been shown to decrease the risks of embolization (eg, stroke) or death. (See 'Efficacy' above.) https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 18/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Efficacy Current techniques for CA should lead to one-year freedom from symptomatic AF while off antiarrhythmic drug therapy in about 75 to 90 percent of patients with drug- resistant paroxysmal AF and no significant structural heart disease. (See 'Efficacy' above.) Complications Important complications of CA include death, cardiac tamponade, stroke, vascular trauma, and phrenic nerve palsy ( table 1). Specific signs and symptoms can help identify complications ( table 2). (See 'Complications' above.) Recurrence For patients who have recurrent AF after a first ablation, there are two reasonable management strategies: a clinical trial of an antiarrhythmic agent or proceeding directly to a second ablation. Patients may have a preference for one or the other. (See 'Management of recurrence' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or Radiofrequency Ablation for Atrial Fibrillation Assessed by Continuous Monitoring: A Randomized Clinical Trial. Circulation 2019; 140:1779. 2. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015; 372:1812. 3. Arbelo E, Brugada J, Hindricks G, et al. The atrial fibrillation ablation pilot study: a European Survey on Methodology and results of catheter ablation for atrial fibrillation conducted by the European Heart Rhythm Association. Eur Heart J 2014; 35:1466. 4. Cheng EP, Liu CF, Yeo I, et al. Risk of Mortality Following Catheter Ablation of Atrial Fibrillation. J Am Coll Cardiol 2019; 74:2254. 5. Ouyang F, Antz M, Ernst S, et al. Recovered pulmonary vein conduction as a dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: lessons from double Lasso technique. Circulation 2005; 111:127. 6. Oral H, Knight BP, Ozaydin M, et al. Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation. J Am Coll Cardiol 2002; 40:100. 7. Mugnai G, de Asmundis C, H n k B, et al. Second-generation cryoballoon ablation for paroxysmal atrial fibrillation: Predictive role of atrial arrhythmias occurring in the blanking period on the incidence of late recurrences. Heart Rhythm 2016; 13:845. 8. Lubitz SA, Fischer A, Fuster V. Catheter ablation for atrial fibrillation. BMJ 2008; 336:819. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 19/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate 9. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:e275. 10. Verma A, Champagne J, Sapp J, et al. Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study. JAMA Intern Med 2013; 173:149. 11. Ganesan AN, Shipp NJ, Brooks AG, et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc 2013; 2:e004549. 12. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012; 367:1587. 13. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. JAMA 2014; 311:692. 14. Andrade JG, Khairy P, Guerra PG, et al. Efficacy and safety of cryoballoon ablation for atrial fibrillation: a systematic review of published studies. Heart Rhythm 2011; 8:1444. 15. Van Brabandt H, Neyt M, Devos C. Effectiveness of catheter ablation of atrial fibrillation in Belgian practice: a cohort analysis on administrative data. Europace 2013; 15:663. 16. Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001; 104:2539. 17. Marine JE. Catheter ablation therapy for supraventricular arrhythmias. JAMA 2007; 298:2768. 18. Berruezo A, Tamborero D, Mont L, et al. Pre-procedural predictors of atrial fibrillation recurrence after circumferential pulmonary vein ablation. Eur Heart J 2007; 28:836. 19. Miyazaki S, Kuwahara T, Kobori A, et al. Catheter ablation of atrial fibrillation in patients with valvular heart disease: long-term follow-up results. J Cardiovasc Electrophysiol 2010; 21:1193. 20. Balk EM, Garlitski AC, Alsheikh-Ali AA, et al. Predictors of atrial fibrillation recurrence after radiofrequency catheter ablation: a systematic review. J Cardiovasc Electrophysiol 2010; 21:1208. 21. Hussein AA, Saliba WI, Martin DO, et al. Plasma B-type natriuretic peptide levels and recurrent arrhythmia after successful ablation of lone atrial fibrillation. Circulation 2011; 123:2077. 22. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004; 110:364. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 20/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate 23. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18:1440. 24. Parikh SS, Jons C, McNitt S, et al. Predictive capability of left atrial size measured by CT, TEE, and TTE for recurrence of atrial fibrillation following radiofrequency catheter ablation. Pacing Clin Electrophysiol 2010; 33:532. 25. Beyer C, Tokarska L, St hlinger M, et al. Structural Cardiac Remodeling in Atrial Fibrillation. JACC Cardiovasc Imaging 2021; 14:2199. 26. Luik A, Radzewitz A, Kieser M, et al. Cryoballoon versus open irrigated radiofrequency ablation in patients with paroxysmal atrial fibrillation: The prospective, randomized, controlled, noninferiority FreezeAF Study. Circulation 2015; 132:1311. 27. Schmidt M, Dorwarth U, Andresen D, et al. Cryoballoon versus RF ablation in paroxysmal atrial fibrillation: results from the German Ablation Registry. J Cardiovasc Electrophysiol 2014; 25:1. 28. Linhart M, Bellmann B, Mittmann-Braun E, et al. Comparison of cryoballoon and radiofrequency ablation of pulmonary veins in 40 patients with paroxysmal atrial fibrillation: a case-control study. J Cardiovasc Electrophysiol 2009; 20:1343. 29. Kojodjojo P, O'Neill MD, Lim PB, et al. Pulmonary venous isolation by antral ablation with a large cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: medium- term outcomes and non-randomised comparison with pulmonary venous isolation by radiofrequency ablation. Heart 2010; 96:1379. 30. Cardoso R, Mendirichaga R, Fernandes G, et al. Cryoballoon versus Radiofrequency Catheter Ablation in Atrial Fibrillation: A Meta-Analysis. J Cardiovasc Electrophysiol 2016; 27:1151. 31. Kuck KH, Brugada J, F rnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016; 374:2235. 32. Lakhani M, Saiful F, Parikh V, et al. Recordings of diaphragmatic electromyograms during cryoballoon ablation for atrial fibrillation accurately predict phrenic nerve injury. Heart Rhythm 2014; 11:369. 33. Brooks AG, Stiles MK, Laborderie J, et al. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010; 7:835. 34. Valderr bano M, Peterson LE, Swarup V, et al. Effect of Catheter Ablation With Vein of Marshall Ethanol Infusion vs Catheter Ablation Alone on Persistent Atrial Fibrillation: The VENUS Randomized Clinical Trial. JAMA 2020; 324:1620. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 21/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate 35. Wynn GJ, Das M, Bonnett LJ, et al. Efficacy of catheter ablation for persistent atrial fibrillation: a systematic review and meta-analysis of evidence from randomized and nonrandomized controlled trials. Circ Arrhythm Electrophysiol 2014; 7:841. 36. Mittal S, Pokushalov E, Romanov A, et al. Long-term ECG monitoring using an implantable loop recorder for the detection of atrial fibrillation after cavotricuspid isthmus ablation in patients with atrial flutter. Heart Rhythm 2013; 10:1598. 37. Schneider R, Lauschke J, Tischer T, et al. Pulmonary vein triggers play an important role in the initiation of atrial flutter: Initial results from the prospective randomized Atrial Fibrillation Ablation in Atrial Flutter (Triple A) trial. Heart Rhythm 2015; 12:865. 38. Wazni O, Marrouche NF, Martin DO, et al. Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein-left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation. Circulation 2003; 108:2479. 39. Waldo AL, Cooper TB. Spontaneous onset of type I atrial flutter in patients. J Am Coll Cardiol 1996; 28:707. 40. Waldo AL. Mechanisms of atrial flutter and atrial fibrillation: distinct entities or two sides of a coin? Cardiovasc Res 2002; 54:217. 41. Steinberg JS, Romanov A, Musat D, et al. Prophylactic pulmonary vein isolation during isthmus ablation for atrial flutter: the PReVENT AF Study I. Heart Rhythm 2014; 11:1567. 42. Lang CC, Santinelli V, Augello G, et al. Transcatheter radiofrequency ablation of atrial fibrillation in patients with mitral valve prostheses and enlarged atria: safety, feasibility, and efficacy. J Am Coll Cardiol 2005; 45:868. 43. Nair M, Shah P, Batra R, et al. Chronic atrial fibrillation in patients with rheumatic heart disease: mapping and radiofrequency ablation of flutter circuits seen at initiation after cardioversion. Circulation 2001; 104:802. 44. Steinberg JS, Shabanov V, Ponomarev D, et al. Effect of Renal Denervation and Catheter Ablation vs Catheter Ablation Alone on Atrial Fibrillation Recurrence Among Patients With Paroxysmal Atrial Fibrillation and Hypertension: The ERADICATE-AF Randomized Clinical Trial. JAMA 2020; 323:248. 45. Bertaglia E, Stabile G, Pappone A, et al. Updated national multicenter registry on procedural safety of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2013; 24:1069. 46. Pappone C, Oral H, Santinelli V, et al. Atrio-esophageal fistula as a complication of percutaneous transcatheter ablation of atrial fibrillation. Circulation 2004; 109:2724. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 22/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate 47. Scanavacca MI, D' vila A, Parga J, Sosa E. Left atrial-esophageal fistula following radiofrequency catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2004; 15:960. 48. Shah D, Dumonceau JM, Burri H, et al. Acute pyloric spasm and gastric hypomotility: an extracardiac adverse effect of percutaneous radiofrequency ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:327. 49. Karch MR, Zrenner B, Deisenhofer I, et al. Freedom from atrial tachyarrhythmias after catheter ablation of atrial fibrillation: a randomized comparison between 2 current ablation strategies. Circulation 2005; 111:2875. 50. Oral H, Scharf C, Chugh A, et al. Catheter ablation for paroxysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation. Circulation 2003; 108:2355. 51. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation 2013; 128:2104. 52. Gupta A, Perera T, Ganesan A, et al. Complications of catheter ablation of atrial fibrillation: a systematic review. Circ Arrhythm Electrophysiol 2013; 6:1082. 53. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 54. Zado E, Callans DJ, Riley M, et al. Long-term clinical efficacy and risk of catheter ablation for atrial fibrillation in the elderly. J Cardiovasc Electrophysiol 2008; 19:621. 55. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798. 56. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3:32. 57. Maan A, Shaikh AY, Mansour M, et al. Complications from catheter ablation of atrial fibrillation: a systematic review. Crit Pathw Cardiol 2011; 10:76. 58. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005; 111:1100. 59. Zeljko HM, Mont L, Sitges M, et al. Entrapment of the circular mapping catheter in the mitral valve in two patients undergoing atrial fibrillation ablation. Europace 2011; 13:132. 60. Kesek M, Englund A, Jensen SM, Jensen-Urstad M. Entrapment of circular mapping catheter in the mitral valve. Heart Rhythm 2007; 4:17. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 23/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate 61. Taylor GW, Kay GN, Zheng X, et al. Pathological effects of extensive radiofrequency energy applications in the pulmonary veins in dogs. Circulation 2000; 101:1736. 62. Saad EB, Marrouche NF, Saad CP, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome. Ann Intern Med 2003; 138:634. 63. Packer DL, Keelan P, Munger TM, et al. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation 2005; 111:546. 64. Qureshi AM, Prieto LR, Latson LA, et al. Transcatheter angioplasty for acquired pulmonary vein stenosis after radiofrequency ablation. Circulation 2003; 108:1336. 65. European Heart Rhythm Association (EHRA), European Cardiac Arrhythmia Scoiety (ECAS), American College of Cardiology (ACC), et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007; 4:816. 66. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation 2003; 108:3102. 67. Arentz T, Weber R, Jander N, et al. Pulmonary haemodynamics at rest and during exercise in patients with significant pulmonary vein stenosis after radiofrequency catheter ablation for drug resistant atrial fibrillation. Eur Heart J 2005; 26:1410. 68. Di Biase L, Fahmy TS, Wazni OM, et al. Pulmonary vein total occlusion following catheter ablation for atrial fibrillation: clinical implications after long-term follow-up. J Am Coll Cardiol 2006; 48:2493. 69. Fender EA, Widmer RJ, Hodge DO, et al. Severe Pulmonary Vein Stenosis Resulting From Ablation for Atrial Fibrillation: Presentation, Management, and Clinical Outcomes. Circulation 2016; 134:1812. 70. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 71. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 72. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 24/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Circ Arrhythm Electrophysiol 2013; 6:843. 73. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 74. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 75. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 76. Sharma PS, Padala SK, Gunda S, et al. Vascular complications during catheter ablation of cardiac arrhythmias: A comparison between vascular ultrasound guided access and conventional vascular access. J Cardiovasc Electrophysiol 2016; 27:1160. 77. Waigand J, Uhlich F, Gross CM, et al. Percutaneous treatment of pseudoaneurysms and arteriovenous fistulas after invasive vascular procedures. Catheter Cardiovasc Interv 1999; 47:157. 78. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 79. Chugh A, Oral H, Good E, et al. Catheter ablation of atypical atrial flutter and atrial tachycardia within the coronary sinus after left atrial ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:83. 80. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: long-term follow-up. Pacing Clin Electrophysiol 2001; 24:1774. 81. Cummings JE, Schweikert R, Saliba W, et al. Left atrial flutter following pulmonary vein antrum isolation with radiofrequency energy: linear lesions or repeat isolation. J Cardiovasc Electrophysiol 2005; 16:293. 82. Gerstenfeld EP, Callans DJ, Dixit S, et al. Mechanisms of organized left atrial tachycardias occurring after pulmonary vein isolation. Circulation 2004; 110:1351. 83. Dumonceau JM, Giostra E, Bech C, et al. Acute delayed gastric emptying after ablation of atrial fibrillation: treatment with botulinum toxin injection. Endoscopy 2006; 38:543. 84. Roberts-Thomson KC, Steven D, Seiler J, et al. Coronary artery injury due to catheter ablation in adults: presentations and outcomes. Circulation 2009; 120:1465. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 25/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate 85. Sieira J, Chierchia GB, Di Giovanni G, et al. One year incidence of iatrogenic atrial septal defect after cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014; 25:11. 86. Koyama T, Sekiguchi Y, Tada H, et al. Comparison of characteristics and significance of immediate versus early versus no recurrence of atrial fibrillation after catheter ablation. Am J Cardiol 2009; 103:1249. 87. Koyama T, Tada H, Sekiguchi Y, et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. J Am Coll Cardiol 2010; 56:1463. 88. Fein AS, Shvilkin A, Shah D, et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013; 62:300. 89. Naruse Y, Tada H, Satoh M, et al. Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm 2013; 10:331. 90. Deftereos S, Giannopoulos G, Efremidis M, et al. Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life. Heart Rhythm 2014; 11:620. 91. Peigh G, Wasserlauf J, Vogel K, et al. Impact of pre-ablation weight loss on the success of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2021; 32:2097. 92. Gessler N, Willems S, Steven D, et al. Supervised Obesity Reduction Trial for AF ablation patients: results from the SORT-AF trial. Europace 2021; 23:1548. 93. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 94. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 95. Senatore G, Stabile G, Bertaglia E, et al. Role of transtelephonic electrocardiographic monitoring in detecting short-term arrhythmia recurrences after radiofrequency ablation in patients with atrial fibrillation. J Am Coll Cardiol 2005; 45:873. 96. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol 2013; 6:754. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 26/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Topic 949 Version 66.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 27/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate GRAPHICS Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation

American College of Cardiology (ACC), et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007; 4:816. 66. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation 2003; 108:3102. 67. Arentz T, Weber R, Jander N, et al. Pulmonary haemodynamics at rest and during exercise in patients with significant pulmonary vein stenosis after radiofrequency catheter ablation for drug resistant atrial fibrillation. Eur Heart J 2005; 26:1410. 68. Di Biase L, Fahmy TS, Wazni OM, et al. Pulmonary vein total occlusion following catheter ablation for atrial fibrillation: clinical implications after long-term follow-up. J Am Coll Cardiol 2006; 48:2493. 69. Fender EA, Widmer RJ, Hodge DO, et al. Severe Pulmonary Vein Stenosis Resulting From Ablation for Atrial Fibrillation: Presentation, Management, and Clinical Outcomes. Circulation 2016; 134:1812. 70. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 71. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 72. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 24/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Circ Arrhythm Electrophysiol 2013; 6:843. 73. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 74. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 75. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 76. Sharma PS, Padala SK, Gunda S, et al. Vascular complications during catheter ablation of cardiac arrhythmias: A comparison between vascular ultrasound guided access and conventional vascular access. J Cardiovasc Electrophysiol 2016; 27:1160. 77. Waigand J, Uhlich F, Gross CM, et al. Percutaneous treatment of pseudoaneurysms and arteriovenous fistulas after invasive vascular procedures. Catheter Cardiovasc Interv 1999; 47:157. 78. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 79. Chugh A, Oral H, Good E, et al. Catheter ablation of atypical atrial flutter and atrial tachycardia within the coronary sinus after left atrial ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:83. 80. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: long-term follow-up. Pacing Clin Electrophysiol 2001; 24:1774. 81. Cummings JE, Schweikert R, Saliba W, et al. Left atrial flutter following pulmonary vein antrum isolation with radiofrequency energy: linear lesions or repeat isolation. J Cardiovasc Electrophysiol 2005; 16:293. 82. Gerstenfeld EP, Callans DJ, Dixit S, et al. Mechanisms of organized left atrial tachycardias occurring after pulmonary vein isolation. Circulation 2004; 110:1351. 83. Dumonceau JM, Giostra E, Bech C, et al. Acute delayed gastric emptying after ablation of atrial fibrillation: treatment with botulinum toxin injection. Endoscopy 2006; 38:543. 84. Roberts-Thomson KC, Steven D, Seiler J, et al. Coronary artery injury due to catheter ablation in adults: presentations and outcomes. Circulation 2009; 120:1465. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 25/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate 85. Sieira J, Chierchia GB, Di Giovanni G, et al. One year incidence of iatrogenic atrial septal defect after cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014; 25:11. 86. Koyama T, Sekiguchi Y, Tada H, et al. Comparison of characteristics and significance of immediate versus early versus no recurrence of atrial fibrillation after catheter ablation. Am J Cardiol 2009; 103:1249. 87. Koyama T, Tada H, Sekiguchi Y, et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. J Am Coll Cardiol 2010; 56:1463. 88. Fein AS, Shvilkin A, Shah D, et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013; 62:300. 89. Naruse Y, Tada H, Satoh M, et al. Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm 2013; 10:331. 90. Deftereos S, Giannopoulos G, Efremidis M, et al. Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life. Heart Rhythm 2014; 11:620. 91. Peigh G, Wasserlauf J, Vogel K, et al. Impact of pre-ablation weight loss on the success of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2021; 32:2097. 92. Gessler N, Willems S, Steven D, et al. Supervised Obesity Reduction Trial for AF ablation patients: results from the SORT-AF trial. Europace 2021; 23:1548. 93. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 94. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 95. Senatore G, Stabile G, Bertaglia E, et al. Role of transtelephonic electrocardiographic monitoring in detecting short-term arrhythmia recurrences after radiofrequency ablation in patients with atrial fibrillation. J Am Coll Cardiol 2005; 45:873. 96. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol 2013; 6:754. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 26/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Topic 949 Version 66.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 27/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate GRAPHICS Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation Back pain Musculoskeletal, retroperitoneal hematoma Physical exam, CT imaging Chest pain Pericarditis, pericardial effusion, Physical exam, chest coronary stenosis (ablation radiograph, ECG, related), pulmonary vein stenosis, musculoskeletal (after echocardiogram, stress test, cardiac catheterization, chest CT cardioversion), worsening reflux Cough Infectious process, bronchial irritation (mechanical, Physical exam, chest radiograph, chest CT cryoballoon), pulmonary vein stenosis Dysphagia Esophageal irritation (related to Physical exam, chest CT, MRI transesophageal echocardiography), atrioesophageal fistula Early satiety, nausea Gastric denervation Physical exam, gastric emptying study Fever Infectious process, pericarditis, atrioesophageal fistula Physical exam, chest radiograph, chest CT, urinalysis, laboratory blood work Fever, dysphagia, neurological symptoms Atrial esophageal fistula Physical exam, laboratory blood work, chest CT or MRI; avoid endoscopy with air insufflation Groin pain Pseudoaneurysm, AV fistula, hematoma Ultrasound of the groin, laboratory blood work; consider CT scan if ultrasound negative Hypotension Pericardial effusion/tamponade, bleeding, sepsis, persistent Echocardiography, laboratory blood work vagal reaction Hemoptysis Pulmonary vein stenosis or Chest radiograph, chest CT or occlusion, pneumonia MR scan, VQ scan Neurological symptoms Cerebral embolic event, atrial Physical exam, brain imaging, esophageal fistula chest CT or MRI https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 28/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Shortness of breath Volume overload, pneumonia, Physical exam, chest pulmonary vein stenosis, radiograph, chest CT, laboratory phrenic nerve injury blood work CT: computed tomography; ECG: electrocardiogram; MRI: magnetic resonance imaging; AV: atrioventricular. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127127 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 29/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Intraprocedural risks of ablation for atrial fibrillation Complication Incidence Diagnostic testing Air embolism <1% Nothing or cardiac catheterization Asymptomatic cerebral emboli 2 to 15% Brain MRI Cardiac tamponade 0.2 to 5% Echocardiography Coronary stenosis/occlusion <0.1% Cardiac catheterization Death <0.1 to 0.4% N/A Mitral valve entrapment <0.1% Echocardiography Permanent phrenic nerve paralysis 0 to 0.4% Chest radiograph, sniff test Radiation injury <0.1% None Stroke or TIA 0 to 2% Head CT/MRI, cerebral angiography Vascular complications 0.2 to 1.5% Vascular ultrasound, CT scan MRI: magnetic resonance imaging; TIA: transient ischemic attack; CT: computed tomography. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127125 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 30/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate CHADS score, thromboembolic risk, and effect of warfarin anticoagulation 2 Clinical parameter Points Congestive heart failure (any history) 1 Hypertension (prior history) 1 Age 75 years 1 Diabetes mellitus 1 Secondary prevention in patients with a prior ischemic stroke or a transient 2 ischemic attack; most experts also include patients with a systemic embolic event Events per 100 person-years* CHADS score 2 NNT Warfarin No warfarin 0 0.25 0.49 417 1 0.72 1.52 125 2 1.27 2.50 81 3 2.20 5.27 33 4 2.35 6.02 27 5 or 6 4.60 6.88 44 NNT: number needed to treat to prevent 1 stroke per year with warfarin. The CHADS score estimates the risk of stroke, which is defined as focal neurologic signs or symptoms that persist for more than 24 hours and that cannot be explained by hemorrhage, trauma, 2 or other factors, or peripheral embolization, which is much less common. Transient ischemic attacks are not included. All differences between warfarin and no warfarin groups are statistically significant, except for a trend with a CHADS score of 0. Patients are considered to be at low risk with a score of 0, at intermediate risk with a score of 1 or 2, and at high risk with a score 3. One exception is that most experts would consider patients with a prior ischemic stroke, transient ischemic attack, or 2 systemic embolic event to be at high risk, even if they had no other risk factors and, therefore, a score of 2. However, the great majority of these patients have some other risk factor and a score of at least 3. Data from: Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial brillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685; and CHADS2 score from Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. Graphic 61615 Version 8.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 31/32 7/6/23, 2:50 PM Atrial fibrillation: Catheter ablation - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 32/32

7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Overview and management of new- onset atrial fibrillation : Kapil Kumar, MD : Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 22, 2023. INTRODUCTION Atrial fibrillation (AF) is the most commonly treated cardiac arrhythmia. AF is generally associated with an irregularly irregular ventricular rhythm and absence of distinct P waves. This topic will provide a broad overview of the classification, clinical presentation, diagnosis, management, and sequelae of AF, including new-onset AF. The initiation and maintenance of AF reflect electrophysiologic alterations in atrial myocardium. The pathophysiology of AF is discussed in detail elsewhere. (See "Mechanisms of atrial fibrillation".) The epidemiology of AF including prevalence, risk factors, and associated chronic conditions is discussed in detail separately. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) The following topics provide detail about specific types of AF and other management issues: (See "Atrial fibrillation in adults: Use of oral anticoagulants".) (See "Management of atrial fibrillation: Rhythm control versus rate control".) (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 1/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate CLASSIFICATION AND TERMINOLOGY AF can be classified according to its duration and length of episodes; these were described in the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines on AF management [1]. Paroxysmal (ie, self-terminating or intermittent) AF Paroxysmal AF is defined as AF that terminates spontaneously or with intervention within seven days of onset. Episodes may recur with variable frequency. (See "Paroxysmal atrial fibrillation".) Persistent AF Persistent AF is defined as AF that fails to self-terminate within seven days. Episodes often require pharmacologic or electrical cardioversion to restore sinus rhythm. While a patient who has had persistent AF can have later episodes of paroxysmal AF, AF is generally considered a progressive disease. Long-standing persistent AF Long-standing persistent AF refers to AF that has lasted for more than 12 months. Permanent AF Permanent AF is a term used to identify persistent AF for which a joint decision by the patient and clinician has been made to no longer pursue a rhythm control strategy. Acceptance of persistent AF may change as symptoms, therapeutic options, and patient and clinician preferences evolve [1]. While AF typically progresses from paroxysmal to persistent states, patients can present with both types throughout their lives. AF can also be classified based by the way it presents or whether specific valvular conditions are present: Subclinical or occult AF This refers to AF that is largely asymptomatic and only becomes apparent in the setting of a thromboembolic event, acute heart failure exacerbation, other medical illness, or upon routine electrocardiogram (ECG) done for other purposes. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Occult atrial fibrillation' and "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation' and 'Common scenarios' below.) Screening for AF is discussed separately. (See 'Screening' below.) Valvular AF This refers to patients with moderate to severe mitral stenosis; these patients have a higher risk of stroke than patients without this condition. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 2/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Lone AF The term "lone AF" is a historical term that is now disfavored, as it may be confusing and does not enhance patient care [1,2]. The term lone AF has been used to describe AF in younger patients (eg, 60 years) with paroxysmal, persistent, or permanent AF who have no structural heart disease or cardiovascular risk factors. These characteristics identify a group of individuals with a CHA DS -VASc score of "0" and who are at lowest risk 2 2 for thromboembolism from AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) SCREENING We do not currently screen asymptomatic patients for AF. In a general population and among persons >65 years of age, screening has not been shown to be better than usual care (eg, pulse palpation on physical examination) for AF detection. Furthermore, screening showed modest to no benefit on reducing cardiovascular outcomes and death in one of two randomized studies. Screening may lead to more anticoagulation, but this has not been shown to be associated with robust protection from stroke or thromboembolic events [3-5]. The United States Preventive Services Task Force (USPSTF) also does not recommend screening for AF. Effects on cardiovascular outcomes and death Two randomized studies of screening for AF (with either single-lead ECGs or implantable loop recorders) showed only a modest or no reduction in clinical events and are also limited in that they included a narrow patient population that may not be widely generalizable. A randomized, unmasked, parallel group study in Sweden (STROKESTOP) of 28,768 individuals aged 75 to 76 years compared outcomes (ie, a composite of ischemic or hemorrhagic stroke, systemic embolism, bleeding leading to hospitalization, and all-cause death) in patients who underwent two-week intermittent ECG screening with subsequent anticoagulation strategy versus those who received usual care [3]. After a median follow-up of 6.9 years, somewhat fewer outcomes occurred in the intervention group than in the control group (5.45 versus 5.68 events per 100 years; hazard ratio [HR] 0.96; 95% CI 0.92- 1.00), but the overall risks and absolute benefit are very low. However, despite this low absolute risk reduction, an analysis using a Markov model based on the STROKESTOP study suggested that screening for AF in this older adult population may still be cost effective and possibly even cost saving [6]. In the LOOP study, 6004 individuals with stroke risk factors were randomly assigned to either implantable loop recorder monitoring (also called implantable cardiac monitor) or usual care [4]. Those in the implantable loop recorder group had three times the rates of https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 3/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate AF detection and anticoagulation initiation but no change in rates of stroke or arterial embolization. AF detection Data are mixed as to whether screening for AF increases the number of new AF cases detected; however, the potential benefit appears to be small at best. The choice of test used to detect AF and population characteristics likely impacts these results. In the VITAL-AF trial, 16 primary clinics were randomly assigned either to AF screening using a handheld single-lead ECG (AliveCor KardiaMobile) during vital sign assessments or to usual care [7]. More than 30,000 patients 65 years of age were followed for one year for the development of new-onset AF. New AF diagnosis in the screening and control groups was similar (1.72 versus 1.59 percent). In a prespecified subgroup analysis of persons aged 85 years, new AF diagnoses were more frequent in the screening versus control group (5.56 versus 3.76 percent). In a meta-analysis of three cluster randomized studies (not including VITAL-AF), screening identified more cases of AF compared with no screening when using one-time approaches (pulse palpation, ECG, and/or Holter monitor [absolute risk difference range 0.06 to 0.60 percentage points; relative risk range 1.04 to 1.58]). However, this difference was small and statistically significant in only one of the studies in the meta-analysis [5]. The Apple Watch in combination with iPhone application was evaluated in over 400,000 individuals without a history of AF [8]. Irregular pulse notifications were sent to 2161 participants (0.52 percent). Of these, 450 participants were sent and returned an ECG patch and were not otherwise excluded per study protocol. AF was present in 34 percent of 450 patients. Among those who were notified of an irregular pulse on the watch while wearing the patch, 84 percent were concordant with AF. The Apple Watch study did not employ the gold standard reference of 12-lead ECG analyzed by two cardiologists, which limits interpretation of device accuracy for AF detection. Accuracy of detection method The accuracies of specific AF detection tests were reviewed by the USPSTF [5]. In most studies, test accuracy was measured against the reference of 12-lead ECG (interpreted by two cardiologists). Sensitivity and specificity were generally high for single-lead ECG and oscillometric blood pressure monitors. Implantable cardiac monitors are more sensitive than ECG and external monitoring [9]. ECGs do not appear more effective than pulse palpation at AF detection. A USPSTF review of randomized trials and observational studies (17 studies and 135,300 patients age 65 years and older) found that systematic screening with ECG identified more cases of AF than no screening (absolute increase from 0.6 to 2.8 percent over 12 months) [10]. However, https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 4/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate systematic screening with ECG did not detect more cases than a systematic approach using pulse palpation. Enrichment of population to be screened Although at this time there is no sufficient evidence to screen for AF in broad populations, focusing screening efforts on patients at significantly higher risk for development of AF may be more fruitful. Using the CHADS2- VASc score can be a starting point, but risk scores such as the CHARGE-AF score derived from clinical variables [11], or a polygenic risk score derived from genetic testing [12] may potentially be more effective. The role of evaluating patients with cryptogenic stroke for AF is discussed separately. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Occult atrial fibrillation'.) CLINICAL PRESENTATION Symptoms AF may or may not have associated symptoms, and the spectrum of symptoms is broad and nonspecific. Typical symptoms include the following: Palpitations Tachycardia Fatigue Weakness Dizziness Lightheadedness Reduced exercise capacity Increased urination Mild dyspnea. Some patients have more severe symptoms. These include the following: Dyspnea at rest Angina Presyncope or rarely syncope Symptoms of stroke or other systemic embolic event Symptoms of heart failure (eg, dyspnea on exertion, peripheral edema, weight gain, and abdominal swelling from ascites) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 5/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate The severity and extent of symptoms are affected by the patient's underlying cardiac condition, age, presence of diabetes [13,14], and rapidity and regularity of the ventricular response. For example, one study of 2400 AF patients showed that the 420 patients with diabetes felt fewer AF- related symptoms (eg, palpitations, dizziness, exercise intolerance [odds ratio 0.74; 95% CI 0.59- 0.92]), but had a worse quality of life (beta = -4.54; 95% CI -6.40 to -2.68) than those without diabetes [13]. Quality of life was measured on the 100-point European Quality of Life-5 Dimensions Questionnaire (EQ-5D). The hemodynamic consequences of AF are discussed in detail separately. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Common scenarios A new diagnosis of AF may result from several clinical scenarios that are described below: At the time of a routine examination, during which the patient complains of symptoms possibly due to AF or is being evaluated for another reason and is found to have an irregularly irregular pulse. On an ECG obtained for other reasons such as a preoperative evaluation. (See "The electrocardiogram in atrial fibrillation".) A patient with a stroke or other arterial thromboembolism can be found to have AF that had not been previously diagnosed [15]. In some cases, AF is detected during extended monitoring in an attempt to diagnose the cause for the stroke. (See "Stroke in patients with atrial fibrillation" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Occult atrial fibrillation'.) Subclinical AF can be also detected by intracardiac, implantable, or wearable monitors [16]. Subclinical AF usually occurs in individuals without characteristic symptoms of AF and without a prior diagnosis. Most of these individuals will have paroxysmal AF. A scientific statement from the American Heart Association on subclinical and cardiac implantable electronic device-detected AF was published in 2019 [16]. (See "Ambulatory ECG monitoring" and "Paroxysmal atrial fibrillation", section on 'Evaluation' and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'ECG monitoring and storage'.) The ASSERT study of 2580 patients (65 years or older) with either a dual-chamber pacemaker or implantable cardioverter-defibrillator, hypertension, and no history of AF found that at three months, subclinical AF was detected in about 10 percent of patients [17]. Clinical AF developed in about 16 percent of patients with subclinical AF. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 6/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate In a study of 590 individuals with stroke risk factors but without AF who underwent screening with an implantable loop recorder for an average of 40 months, 35 percent of participants were found to have AF [9]. During ECG monitoring with a 24-hour ambulatory monitor obtained for some other reason or during interrogation of an implanted cardiac rhythm device. (See "Ambulatory ECG monitoring" and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'ECG monitoring and storage'.) During hospitalization for another reason such as infection, recent myocardial infarction, thyrotoxicosis, pulmonary embolism, chronic obstructive pulmonary disease, myocarditis, and pericarditis, among others [18-21]. (See "Arrhythmias in COPD" and "Cardiovascular effects of hyperthyroidism" and "Pneumococcal pneumonia in patients requiring hospitalization", section on 'Cardiac events and other noninfectious complications'.) During or after cardiac or noncardiac surgery. (See "Atrial fibrillation in patients undergoing noncardiac surgery" and "Atrial fibrillation and flutter after cardiac surgery" and "Arrhythmias during anesthesia", section on 'Atrial fibrillation'.) During recording from a patient-acquired recording device (eg, Apple watch, AliveCor KardiaMobile, etc). (See "The electrocardiogram in atrial fibrillation", section on 'Wearable consumer devices' and 'Screening' above.) EVALUATION History and physical examination Descriptions of any associated symptoms should include: Onset or date of discovery Possible precipitating factors Frequency and duration Severity of episodes and symptoms Qualitative characteristics Previous medical records of any prior supraventricular arrhythmias A semi-quantitative method to classify symptoms has been developed, but the clinical utility of such a system has not been demonstrated [22]. Associated conditions The presence and status of associated conditions such as other cardiovascular disease, cerebrovascular disease, diabetes, hypertension, chronic obstructive pulmonary disease, obstructive sleep apnea should be ascertained. (See https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 7/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Arrhythmias in COPD", section on 'Atrial fibrillation' and "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Atrial fibrillation'.) The presence of potentially reversible causes should be assessed (eg, hyperthyroidism, unhealthy alcohol use). (See "Overview of the clinical manifestations of hyperthyroidism in adults" and "Diagnosis of hyperthyroidism" and "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".) Physical examination The physical examination should focus on the cardiovascular system and any associated conditions. Abnormal findings may inform healthcare providers about associated conditions that might be contributing to the onset of AF and/or impacting the severity. Examples include heart murmurs or arterial pulse abnormalities indicative of mitral or aortic stenosis or regurgitation, hypertrophic cardiomyopathy, and signs and symptoms of heart failure. (See "Examination of the precordial pulsation" and "Auscultation of cardiac murmurs in adults" and "Examination of the jugular venous pulse" and "Examination of the arterial pulse".) During AF with an irregularly irregular pulse, there is commonly a slight variation in the intensity of the first heart sound. S4 sounds are not heard, and jugular venous "a" waves are absent since atrial contraction is lost. (See "Auscultation of heart sounds", section on 'Clinical significance of S4'.) An apical-radial pulse deficit is commonly observed in patients in AF. When one assesses the rates of the left ventricular apex and the radial pulse simultaneously, the radial pulse rate may be less than the apical heart rate. Since the heart rate is irregular, some ventricular contractions will occur, preceded by shorter periods of diastole in which there is a reduction in left ventricular filling. This results in ventricular beats with insufficient stroke volume to transmit the pressure wave to the arm. Variation in cuff blood pressure readings is also common during AF due to changes in the beat-to-beat cadence and changes in left ventricular filling and stroke volume. It is often necessary to measure the blood pressure multiple times and average these values to obtain a more accurate blood pressure readings. In addition, automated blood pressure machines may have difficulty in accurately measuring blood pressure during AF, so a manual blood pressure check is recommended. Electrocardiogram For all patients with suspected new-onset AF, we obtain a 12-lead ECG. On an ECG with AF, there are no discrete P waves but rapid, low-amplitude, continuously varying fibrillatory (f) waves are seen. The ventricular rhythm is generally irregularly irregular (lacking a repetitive pattern), although AF is uncommonly associated with a regular ventricular rate. The https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 8/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate ECG in patients with AF is described in detail separately ( waveform 1). (See "The electrocardiogram in atrial fibrillation".) There are a number of potential pitfalls in the ECG diagnosis of AF. Errors in the diagnosis of AF are especially common with computerized ECG interpretation and in patients who are continuously or intermittently paced. Hence, it is important that the automated ECG interpretation provided by the machine is confirmed by a skilled reader. A baseline ECG, preferably in sinus rhythm, should also be evaluated for the following information: Markers of nonelectrical cardiac disease, such as left ventricular hypertrophy (possible hypertension) or Q waves (possible coronary artery disease). Markers of electrical heart disease, including the presence of ventricular pre-excitation or infranodal conduction disease (bundle branch block). The QT interval (to identify the potential risk of antiarrhythmic therapy) Evidence of severe bradycardia or sinus node dysfunction Echocardiogram We obtain a transthoracic echocardiogram (TTE) even if the physical examination is otherwise normal. We obtain a TTE in order to evaluate the size of the right and left atria and the size and systolic function of the right and left ventricles; to detect possible valvular heart disease, left ventricular hypertrophy, diastolic dysfunction, and pericardial disease; and to assess peak right ventricular and right atrial pressures. The TTE may also identify left atrial thrombus, although the sensitivity is low. Transesophageal echocardiography is much more sensitive for identifying thrombi in the left atrium or left atrial appendage and can be used to determine the need for anticoagulation prior to any attempt at pharmacologic or electrical cardioversion. (See "Role of echocardiography in atrial fibrillation" and 'Anticoagulation' below.) Additional cardiac testing We refer patients with signs or symptoms of ischemic heart disease for exercise testing. (See "Exercise ECG testing: Performing the test and interpreting the ECG results" and "Stress testing for the diagnosis of obstructive coronary heart disease".) Exercise testing is useful to help guide pharmacotherapy for AF, as some antiarrhythmic medications are contraindicated in patients with coronary artery disease. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Selecting an antiarrhythmic drug'.) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 9/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Ambulatory cardiac monitoring with event recorders, adhesive extended time event monitors, or insertable cardiac monitors (also sometimes referred to as implantable cardiac monitors or implantable loop recorders) can be used to identify the arrhythmia if it is intermittent and not captured on routine ECG. Ambulatory ECG monitoring can also be utilized to correlate symptoms to the arrhythmia along with assessment of the AF burden. Twenty-four- to 48-hour Holter monitoring mainly aids in the evaluation of overall ventricular response rates in individuals where a rate control strategy has been chosen and there is concern for inadequate heart rate control or bradycardia. (See "Ambulatory ECG monitoring".) Laboratory testing We obtain a complete blood count, serum electrolytes, and assessment of renal function, particularly in patients for whom a nonvitamin oral anticoagulant might be started. We do not order troponin unless acute ischemia is suspected. Clinical or subclinical hyperthyroidism is present in less than 5 percent of patients with AF [23]. A thyroid-stimulating hormone and free T4 levels should be obtained in all patients with a first episode of AF, or in those who develop an increase in AF frequency. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Hyperthyroidism'.) Other important baseline tests include a complete blood count to assess for underlying anemia or sign of infection and evaluation for diabetes mellitus [24]. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".) Other tests A chest radiograph may be a useful diagnostic test in selected patients with evidence of dyspnea and potential heart failure or risk of pneumonia. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Chest radiograph'.) INITIAL MANAGEMENT A useful framework for the general care of AF patients (including those with new-onset as well as longstanding AF) is the ABC (Atrial Fibrillation Better Care) pathway [25,26]. "A" can be considered for anticoagulation "B" for better symptom management "C" for cardiovascular risk factor and comorbid disease assessment and management. Observational studies [27,28], a post-hoc analysis of the AFFIRM trial [29], and a prospective randomized trial using a mobile application [30] suggest that the implementation of such a framework of care for AF patients may have a salutary impact on adverse cardiovascular events and hospitalizations, while being cost saving for healthcare systems [31]. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 10/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Management setting Outpatient versus emergency department Whereas most patients with newly diagnosed AF can often be managed in an outpatient setting, some unstable patients require direct hospital admission or transfer to emergency department from an outpatient setting. Indications for transfer to a facility with emergency services include the following: Hemodynamic instability and/or shock (manifested as hypotension, confusion, acute kidney injury, etc). Suspected or confirmed myocardial ischemia/infarction. Suspected or confirmed heart failure. (See "The management of atrial fibrillation in patients with heart failure".) Evidence of pre-excitation (eg, Wolff-Parkinson-White syndrome) on the ECG. Extreme, uncontrolled tachycardia. Severe symptoms that may require more urgent rate or rhythm control. Hypotension for which AF is suspected to be causal or contributory and for which standard therapy to treat underlying causes and hypotension have failed. Care must be given to other potentially inciting factors such as sepsis, fluid depletion, or vasodilation. For patients whose AF is thought to be secondary to an initiating comorbidity such as pneumonia, treatment of the underlying cause of AF is important and may reduce the long- term risk of recurrent AF. Finally, for those patients who require urgent management, we generally obtain the same baseline diagnostic tests as in stable patients unless other clinical characteristics suggest otherwise. In this case, the diagnostic approach should also include work-up for the suspected underlying condition (eg, pneumonia, pulmonary embolus, etc). Indications for hospitalization Many patients with new-onset AF who are evaluated in an emergency room may not need to be hospitalized. However, indications for hospitalization in these patients include: Patients in whom ablation of an accessory pathway is being considered, particularly if the AF was highly symptomatic and associated with hemodynamic collapse and rapid ventricular response rate. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 11/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Severe bradycardia or prolonged pauses, including after cardioversion. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Treatment of an associated medical problem, which is often the reason for the arrhythmia (eg, hypertension, infection, exacerbation of chronic obstructive pulmonary disease, pulmonary embolism, pericarditis, persistent myocardial ischemia). It should be noted that AF alone is not an indication to rule out myocardial infarction. Further management of heart failure or hypotension after control of the rhythm or rate. Initiation of antiarrhythmic drug therapy (if patient and drug characteristics necessitate hospitalization). Difficult-to-control ventricular rates with evidence of ischemia, congestive heart failure symptoms or signs, and severe symptoms are indications for at least a 24-hour admission. Referral to cardiologist AF is a common medical problem and can often be managed by primary care physicians without need for consultation with a cardiologist. We suggest patient referral when the physician is not comfortable with decision-making or when catheter ablation of AF is under consideration. Also, when cardioversion or antiarrhythmic drugs are contemplated, cardiology consultation is advantageous. Anticoagulation Every patient with AF should be evaluated for the need for antithrombotic therapy to prevent systemic embolization even for the first AF episode. This is accomplished by use of a risk-scoring system for incident stroke called the CHA DS -VASc score ( table 1). Other 2 2 factors that may improve prediction of risk of stroke for an individual patient with burden of AF include left atrial size and function and certain biomarkers (ie, NT-proBNP and high-sensitivity troponin-T) [32]. Patients who require antithrombotic therapy include those in whom cardioversion (whether electrically or pharmacologically) to sinus rhythm is being considered (regardless of the CHA DS -VASc score or method of cardioversion [electrical or pharmacologic]) 2 2 and those who meet criteria for long-term anticoagulation. All patients whose risk of embolization exceeds the risk of bleeding are candidates for long-term antithrombotic therapy. These issues are discussed in detail elsewhere. (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Triggers In some cases, onset of AF is triggered by another acute medical diagnosis: hyperthyroidism, acute pulmonary embolism, myopericarditis, pneumonia, after cardiac surgery, and certain drugs or supplements. Treatment of specific triggers or elimination of inciting factors may lead to years or even a lifetime without further episodes of AF. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 12/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate The treatment of a suspected precipitating cause may result in reversion to sinus rhythm. For patients with severe hyperthyroidism, the main goal of therapy initially is rate control, anticoagulation, treatment of hyperthyroidism, and restoration of sinus rhythm once they are euthyroid. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Therapeutic approach'.) Treatment of AF in patients with heart failure and/or chronic obstructive pulmonary disease should generally be undertaken simultaneously with treatment of their other condition. (See "The management of atrial fibrillation in patients with heart failure", section on 'Correction of reversible causes'.) Cardiovascular risk factors Identifying and treating risk factors and comorbidities may help with AF symptoms and burden. Common risk factors and comorbidities that can lead to the development of AF include advanced age, hypertension, diabetes, obstructive sleep apnea, heart failure, and obesity. For most identified risk factors, we believe that treating the risk factor may reduce but not eliminate the likelihood of subsequent episodes of AF. A comprehensive description of risk factors for AF is discussed separately. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Chronic disease associations' and "Overview of established risk factors for cardiovascular disease".) Symptom and hemodynamic management Unstable patients In some hemodynamically unstable patients who manifest with signs or symptoms such as hypotension, altered mental status, or heart failure, we attempt ventricular rate control. Slowing of the ventricular rate will sometimes lead to spontaneous reversion to sinus rhythm. Rate control is usually performed with a beta blocker or calcium channel blocker (verapamil or diltiazem). This is discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) For patients with AF and heart failure, ventricular rate control strategies are discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction'.) If the patient remains hemodynamically unstable, emergency cardioversion should be performed, particularly if the hemodynamic compromise is due to an uncontrolled rapid ventricular rate and/or we believe that the lack of atrial contraction is impairing cardiac output. Emergent therapy with rate control and/or cardioversion for unstable patients is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Unstable patients' and "Control of https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 13/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Determining urgency'.) Unless AF reverts spontaneously, a decision is made whether, when, and how cardioversion will be performed. Management of thromboembolic risk is a key consideration when cardioversion is considered. (See "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) If we decide to perform emergency cardioversion, the risk for a thromboembolic event needs to be considered. Most patients who will undergo cardioversion should be anticoagulated as soon as the decision is made to cardiovert or after assessment of their clinical thromboembolic risk based on their CHA DS -VASc score. Issues related to anticoagulation around the time of 2 2 cardioversion are discussed in detail separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours' and "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Once the patient becomes hemodynamically stable, the remainder of the acute and long-term management is similar to that of stable patients. Stable patients For stable patients with new-onset AF who do not meet the above criteria for emergency management and in whom we have performed an evaluation, we try to accomplish the following in the outpatient setting: Evaluate the need to slow the ventricular rate. Discuss the possible need for cardioversion with the patient. If the patient is highly symptomatic or if there is new-onset AF even in the absence of symptoms, we usually attempt cardioversion. Among patients with new-onset AF, even if cardioversion is contemplated, it usually does not need to be performed urgently; the majority of these patients will spontaneously convert to sinus rhythm within 48 to 72 hours [33]. Among 1822 patients admitted to the hospital because of AF, 356 had an arrhythmia duration less than 72 hours. Sixty-eight percent of the patients with this short AF duration spontaneously reverted to sinus rhythm [33]. Two-thirds of those with spontaneous reversion had AF duration of less than 24 hours; AF duration less than 24 hours was the only predictor of spontaneous reversion. A detailed discussion of cardioversion, including reasons to not cardiovert, is found elsewhere. (See "Atrial fibrillation: Cardioversion" and "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 14/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate The choice of electrical or pharmacologic cardioversion requires consideration of the efficacy and safety of the approach, comorbidities, stability, preferences of the patient, and comfort of the clinician to use one or the other approach. This issue is discussed in detail elsewhere. (See "Atrial fibrillation: Cardioversion", section on 'Electrical versus pharmacologic cardioversion'.) Determine the need for acute and long-term anticoagulant therapy. Discuss the cause (if known) and natural history of AF. (See 'Sequelae' below.) Consider consultation with a cardiologist. Reasons to consult a cardiologist include the need for cardioversion or the need to treat with antiarrhythmic drugs or catheter ablation. (See 'Management setting' above.) Schedule follow-up. (See 'Long-term management' below.) LONG-TERM MANAGEMENT Early follow-up Follow-up after an episode of acute AF is necessary to evaluate the safety and efficacy of rate or rhythm control, patient adherence with anticoagulant and antiarrhythmic therapy, need for continued therapies for AF, to discuss any strategies to reduce AF recurrence, and to assess the functional status of the patient. For many patients, a one-week follow-up visit, or as soon as possible if one week is not realistic for a particular patient, is a reasonable strategy. This early return is particularly important for patients started on antiarrhythmic drug therapy to assess safety, efficacy, and side effects that can be specific to their therapy. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Prevention of thromboembolism Following initial pre- and postcardioversion anticoagulation, the decision to continue long-term anticoagulation following a single reversible incident is debatable, and the decision is highly individualized based on the presumed future risk of recurrent AF in that individual (vis a vis CHA DS -VASc score). It is also reasonable to take 2 2 an observational approach following a reversible cause of AF involving clinical follow-up of symptoms and ambulatory monitoring for surveillance for possible recurrence. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation shared-decision making The shared decision-making between patients and providers includes benefits versus risks of taking anticoagulation and tradeoffs between warfarin and DOAC; providers should also be prepared to address patients https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 15/35 7/6/23, 2:49 PM

reversible causes'.) Cardiovascular risk factors Identifying and treating risk factors and comorbidities may help with AF symptoms and burden. Common risk factors and comorbidities that can lead to the development of AF include advanced age, hypertension, diabetes, obstructive sleep apnea, heart failure, and obesity. For most identified risk factors, we believe that treating the risk factor may reduce but not eliminate the likelihood of subsequent episodes of AF. A comprehensive description of risk factors for AF is discussed separately. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Chronic disease associations' and "Overview of established risk factors for cardiovascular disease".) Symptom and hemodynamic management Unstable patients In some hemodynamically unstable patients who manifest with signs or symptoms such as hypotension, altered mental status, or heart failure, we attempt ventricular rate control. Slowing of the ventricular rate will sometimes lead to spontaneous reversion to sinus rhythm. Rate control is usually performed with a beta blocker or calcium channel blocker (verapamil or diltiazem). This is discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) For patients with AF and heart failure, ventricular rate control strategies are discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction'.) If the patient remains hemodynamically unstable, emergency cardioversion should be performed, particularly if the hemodynamic compromise is due to an uncontrolled rapid ventricular rate and/or we believe that the lack of atrial contraction is impairing cardiac output. Emergent therapy with rate control and/or cardioversion for unstable patients is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Unstable patients' and "Control of https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 13/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Determining urgency'.) Unless AF reverts spontaneously, a decision is made whether, when, and how cardioversion will be performed. Management of thromboembolic risk is a key consideration when cardioversion is considered. (See "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) If we decide to perform emergency cardioversion, the risk for a thromboembolic event needs to be considered. Most patients who will undergo cardioversion should be anticoagulated as soon as the decision is made to cardiovert or after assessment of their clinical thromboembolic risk based on their CHA DS -VASc score. Issues related to anticoagulation around the time of 2 2 cardioversion are discussed in detail separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours' and "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Once the patient becomes hemodynamically stable, the remainder of the acute and long-term management is similar to that of stable patients. Stable patients For stable patients with new-onset AF who do not meet the above criteria for emergency management and in whom we have performed an evaluation, we try to accomplish the following in the outpatient setting: Evaluate the need to slow the ventricular rate. Discuss the possible need for cardioversion with the patient. If the patient is highly symptomatic or if there is new-onset AF even in the absence of symptoms, we usually attempt cardioversion. Among patients with new-onset AF, even if cardioversion is contemplated, it usually does not need to be performed urgently; the majority of these patients will spontaneously convert to sinus rhythm within 48 to 72 hours [33]. Among 1822 patients admitted to the hospital because of AF, 356 had an arrhythmia duration less than 72 hours. Sixty-eight percent of the patients with this short AF duration spontaneously reverted to sinus rhythm [33]. Two-thirds of those with spontaneous reversion had AF duration of less than 24 hours; AF duration less than 24 hours was the only predictor of spontaneous reversion. A detailed discussion of cardioversion, including reasons to not cardiovert, is found elsewhere. (See "Atrial fibrillation: Cardioversion" and "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 14/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate The choice of electrical or pharmacologic cardioversion requires consideration of the efficacy and safety of the approach, comorbidities, stability, preferences of the patient, and comfort of the clinician to use one or the other approach. This issue is discussed in detail elsewhere. (See "Atrial fibrillation: Cardioversion", section on 'Electrical versus pharmacologic cardioversion'.) Determine the need for acute and long-term anticoagulant therapy. Discuss the cause (if known) and natural history of AF. (See 'Sequelae' below.) Consider consultation with a cardiologist. Reasons to consult a cardiologist include the need for cardioversion or the need to treat with antiarrhythmic drugs or catheter ablation. (See 'Management setting' above.) Schedule follow-up. (See 'Long-term management' below.) LONG-TERM MANAGEMENT Early follow-up Follow-up after an episode of acute AF is necessary to evaluate the safety and efficacy of rate or rhythm control, patient adherence with anticoagulant and antiarrhythmic therapy, need for continued therapies for AF, to discuss any strategies to reduce AF recurrence, and to assess the functional status of the patient. For many patients, a one-week follow-up visit, or as soon as possible if one week is not realistic for a particular patient, is a reasonable strategy. This early return is particularly important for patients started on antiarrhythmic drug therapy to assess safety, efficacy, and side effects that can be specific to their therapy. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Prevention of thromboembolism Following initial pre- and postcardioversion anticoagulation, the decision to continue long-term anticoagulation following a single reversible incident is debatable, and the decision is highly individualized based on the presumed future risk of recurrent AF in that individual (vis a vis CHA DS -VASc score). It is also reasonable to take 2 2 an observational approach following a reversible cause of AF involving clinical follow-up of symptoms and ambulatory monitoring for surveillance for possible recurrence. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation shared-decision making The shared decision-making between patients and providers includes benefits versus risks of taking anticoagulation and tradeoffs between warfarin and DOAC; providers should also be prepared to address patients https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 15/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate questions about out-of-pocket costs, as failure to do so could lead to patient harm. A qualitative study of 37 recorded clinical encounters showed that providers rarely are prepared to adequately address patient questions related to medication cost [34]. Among patients with AF, thrombus in the left atrial appendage is the primary source for thromboemboli. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial stunning'.) A subset of patients who require long-term anticoagulation may be unable to take it due to high bleeding risk or poor adherence. In such patients, occlusion of the left atrial appendage may be considered. After left atrial appendage occlusion, patients are required to be on short-term anticoagulation. Left atrial appendage occlusion is described in detail separately. (See "Atrial fibrillation: Left atrial appendage occlusion".) AF recurrence Continuous cardiac monitoring studies have shown that approximately 90 percent of patients with AF have recurrent episodes of AF [35]. However, up to 90 percent of episodes are not recognized by the patient [36], and asymptomatic episodes lasting more than 48 hours are not uncommon, occurring in 17 percent of patients in a study that used continuous ECG monitoring to detect AF [35]. The latter study also showed that 40 percent of patients had episodes of AF-like symptoms in the absence of AF. (See "Paroxysmal atrial fibrillation", section on 'Natural history'.) Some methods to reduce AF recurrence and/or burden including the following: Alcohol reduction Alcohol is a modifiable risk factor for AF, and among people who consume an excessive amount of alcohol, reduction and abstinence appear to decrease the risk of recurrent AF and time in AF. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Alcohol'.) In one study, 140 symptomatic patients with paroxysmal or persistent AF who were in sinus rhythm at baseline and who consumed 10 or more standard drinks per week (about 120 g of pure alcohol) were randomly assigned to alcohol abstention or usual alcohol consumption [37]. After six months, patients underwent comprehensive rhythm monitoring. Patients assigned to abstinence had: Greater reduction in their alcohol intake from 16.8 to 2.1 standard drinks per week, while those in the usual consumption group reduced their consumption from 16.4 to 13.2 per week. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 16/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Lower rates of recurrent AF (53 versus 73 percent of the two groups). Recurrence of AF was also delayed in the abstinence group, and the AF burden was significantly lower. Weight loss and physical activity Among patients with AF, both of these measures can lead to healthy cardiac remodeling [38] and reduce AF burden [38,39] and cardiovascular mortality [40,41]: In one study, 150 patients with symptomatic AF and a body mass index in the 2 overweight or greater range ( 25 kg/m ) were randomized to a weight management intervention or general lifestyle advice [38]. After 15 months, participants assigned the intervention showed a greater reduction in weight compared with the general lifestyle advice group (14.3 versus 3.6 kg). The intervention group also had a greater reduction in AF symptom burden (11.8 versus 2.6 points), symptom severity scores (8.4 versus 1.7 points), number of AF episodes (2.5 fewer versus no change), and cumulative AF duration (692-minute decline versus 419-minute increase). Echocardiographic cardiac remodeling parameters also improved in the intervention versus control group (ie, reduction in interventricular septal thickness [1.1 and 0.6 mm] and reduction in left 2 atrial area [3.5 and 1.9 cm ]). In a nonrandomized intervention study, 149 patients undergoing a catheter ablation for symptomatic AF were offered a three-month cardiovascular risk factor management 2 program [39]. Patients had a body mass index of 27 kg/m plus at least one additional cardiovascular risk factor. Sixty-one patients opted for the risk factor management intervention and 88 did not (the control group). On follow-up, patients who chose the intervention lost weight, whereas the control group gained weight (-13.2 versus +1.5 kg). The intervention group had a mean systolic blood pressure reduction, whereas the control group had a blood pressure increase (-34.1 versus 20.6). Control of dyslipidemia was higher in the intervention compared with control group (46 versus 17 percent). More patients in the control group experienced AF recurrence (32.9 versus 9.7 percent; hazard ratio [HR] 2.6; 95 %CI, 1.7-4.0) compared with the intervention group. Among patients with AF, physical activity may lower cardiovascular mortality [40,41]. (See 'Benefit of physical activity' below.) Rate or rhythm control Once ventricular rate control is achieved, a decision regarding the long-term management (rhythm versus rate control) of AF should be made; this decision depends on many factors. These are discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) The following points should be kept in mind irrespective of the strategy chosen: https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 17/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Both strategies can fail in the short and long term. Consequently, many patients need to be reconsidered for the alternate strategy as the natural history of their disease progresses. All patients with AF, irrespective of strategy chosen/rhythm, should have their thromboembolic risk assessed and be managed accordingly. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) For patients who are managed with a rhythm-control strategy, rate control is necessary due to the possibility of recurrence of AF. The advantages and disadvantages of rhythm and rate control, and subgroups of patients for whom one or the other is preferred, are discussed in greater detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) A rhythm-control strategy uses either antiarrhythmic drug therapy, percutaneous catheter ablation, and/or a surgical procedure. Electrical cardioversion may be necessary to restore sinus rhythm. Antiarrhythmic medications are generally started before cardioversion and continued to maintain sinus rhythm (in the event of AF recurrence). (See "Atrial fibrillation: Surgical ablation", section on 'Maze procedure' and "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) The decision regarding which of the above rhythm-control methods to pursue is discussed in detail separately. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) Among patients undergoing cardiac surgery for another reason (eg, mitral valve or coronary artery bypass surgery), surgical ablation to control refractory AF can be done during the same procedure. Several surgical techniques have been developed for the control of refractory AF and maintenance of sinus rhythm. These surgical procedures appear effective at eliminating or reducing the frequency of AF in a high percentage of patients. For patients who are at high risk for stroke, long-term anticoagulation is still continued. This is discussed in detail separately. (See "Atrial fibrillation: Surgical ablation".) A rate-control strategy generally uses drugs that slow conduction across the atrioventricular node such as beta blockers, nondihydropyridine calcium channel blockers, or digoxin. Atrioventricular junction ablation with pacemaker placement is used in patients with persistent tachycardia, hemodynamic instability, and poorly tolerated and/or highly symptomatic AF, in whom rate control has not been successful. These approaches to ventricular rate control in AF are discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Atrial fibrillation: Atrioventricular node ablation".) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 18/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Most patients who present with AF will require slowing of the ventricular rate to improve symptoms. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Long-term follow-up Patients with paroxysmal, persistent, longstanding persistent, or permanent AF will need periodic care and occasional urgent evaluation during the natural history of their disease. (See 'Classification and terminology' above.) We suggest routine follow-up every 12 months in stable patients and sooner if there are changes in symptoms. Patients on high-risk antiarrhythmic therapy, such as dofetilide or sotalol, are often seen every six months. These patients may need to be under the care of a cardiologist and/or electrophysiology specialist for management of antiarrhythmic medications. From time to time, patients should be monitored for the following: Efficacy and safety of antithrombotic therapy (international normalized ratio for patients on warfarin and creatinine clearance for patients on antiarrhythmic therapy and other newer anticoagulants). Functional status, including change in symptoms (history). Efficacy and safety of antiarrhythmic drug therapy (eg, ECG, assessment of renal and hepatic function). (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Efficacy of rate control (history, ECG, and extended Holter monitoring if variability in heart rate is suspected). (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) In active patients with AF, we use stress testing to gauge adequacy of heart rate control in AF during exercise. Insufficient heart rate control in AF is a major factor for exercise intolerance in AF. (See "Ambulatory ECG monitoring".) Laboratory testing We obtain a complete blood count, serum electrolytes, and assessment of renal function, particularly in patients for whom a nonvitamin oral anticoagulant might be started. We do not order troponin unless acute ischemia is suspected. Clinical or subclinical hyperthyroidism is present in less than 5 percent of patients with AF [23]. A thyroid-stimulating hormone and free T4 levels should be obtained in all patients with a first episode of AF, or in those who develop an increase in AF frequency. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Hyperthyroidism'.) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 19/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate SEQUELAE Myocardial infarction Myocardial infarction has been shown to occur as a result of a coronary artery thromboembolism resulting from AF [42,43]. However, large studies of this sequelae of AF are lacking. Also, myocardial infarction from demand ischemia (also called type 2 myocardial infarction) can also result from AF, usually in the setting of a rapid ventricular rate. (See "Diagnosis of acute myocardial infarction", section on 'Comparing type 1 and 2 myocardial infarction'.) Whereas tachyarrhythmias have been shown to account for about 25 percent of type 2 myocardial infarction [44], studies specifically studying AF and type 2 myocardial infarction are lacking. In patients with a recent myocardial infarction, the subsequent development of AF increases mortality [45,46]. This effect is primarily due to associated risk factors such as heart failure and cardiogenic shock and not due to AF itself [46,47]. Mortality AF and mortality AF is an independent risk factor for mortality across a wide age range and in both males and females, but the evidence is insufficient to establish AF as a cause of excess mortality rather than just a marker of high risk [48]. Rhythm-control trials among patients with AF suggest that those in sinus rhythm had lower mortality compared with those in AF [49,50]. In a secondary analysis of the randomized controlled AFFIRM trial of rhythm versus rate control in AF, the presence of sinus rhythm was associated with a significant reduction in mortality (hazard ratio [HR] 0.54; 95% CI 0.42-0.70) [49]. A similar benefit from being in sinus rhythm (relative risk 0.44; 95% CI 0.4-0.64) was noted in a separate trial of dofetilide in patients with reduced left ventricular function [50]. Strength of association Observational cohort studies have also shown that AF is associated with increased mortality [51-54]. In a post-hoc analysis of the Women's Health Study of 34,772 women with a median age of 53 who were free of AF, 2.9 percent developed AF at a median follow-up of 15.4 years [51]. New-onset AF was associated with a significantly increased adjusted risk of all-cause, cardiovascular, and noncardiovascular mortality (HR 2.14, 95% CI 1.64-2.77; HR 4.18, 95% CI 2.69-6.51; and HR 1.66, 95% CI 1.19- 2.30, respectively). Adjustment for nonfatal cardiovascular events such as myocardial infarction, stroke, or heart failure lowered these risks, but incident AF remained https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 20/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate significantly associated with all types of mortality (HR 1.7, HR 2.57, HR and 1.42, respectively). Sex difference Several observational studies have suggested that the association between AF and death is greater in women with AF compared with men [52,53]. In a retrospective study of 272,186 patients with incidental AF at the time of hospitalization and 544,344 matched AF-free controls, the adjusted relative risk of death with AF was higher in females compared with males across all age categories (2.15 versus 1.76 for those <65 years, 1.72 versus 1.36 for those ages 65 to 74 years, and 1.44 versus 1.24 for those 75 to 85 years) [52]. In 621 participants in the Framingham Heart Study, having AF led to an almost doubling of the risk of death in both men and women (adjusted odds ratio 1.9 for women and 1.5 for men) ( figure 1) [53]. This sex difference in the association between AF and mortality was also shown in a separate study of 15,000 men and women [54]. Cause of excess mortality In participants with AF in the Framingham Heart Study, both heart failure and stroke contributed to the excess mortality [53]. In addition, in an observational study of over 20,000 individuals in two cohorts, incident AF was associated with an increased risk of sudden cardiac death (HR 2.47; 95% CI 1.95-3.13) as well as nonsudden cardiac death (HR 2.98; 95% CI 2.52-3.53) [55]. The specific causes of death, as well as their frequency and predictors, were evaluated using follow-up data from the RE-LY trial comparing dabigatran with warfarin [56]. Among 18,113 randomized patients with a median follow-up of two years, the annual mortality rate was 3.84 percent. Cardiac deaths (sudden cardiac death and progressive heart failure) accounted for 37.4 percent of these; stroke and hemorrhagic death accounted for 9.9 percent. Predictors of mortality in patients with AF In the RE-LY trial , the strongest independent clinical predictors of cardiac death were heart failure, intraventricular conduction delay on an ECG, and prior myocardial infarction [56]. In a post-hoc analysis of the RACE II trial, the risk of cardiovascular morbidity and mortality was highest in those with the greatest symptom burden as assessed with the Toronto AF Severity Scale [57]. This finding was driven by the increased rate of heart failure hospitalizations. Benefit of physical activity As in the general population, among patients with AF, physical activity can significantly reduce cardiovascular mortality [40,41]. (See "The benefits and risks of aerobic exercise", section on 'Mortality'.) In a prospective Danish study of over 1100 individuals with AF, metabolic equivalents were used to estimate cardiorespiratory fitness, and patients were followed for up to nine years for mortality outcomes. This study observed that each one-metabolic equivalent task higher was https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 21/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate associated with a lower risk of all-cause mortality (HR 0.88; 95% CI 0.81-0.95) and cardiovascular disease mortality (HR 0.85; 95% CI 0.76-0.95) [40]. Patients meeting European Society of Cardiology physical activity recommendations had a lower risk of cardiovascular mortality compared with inactive patients (HR 0.54; 95% CI 0.34-0.86) [41]. Stroke and silent cerebral ischemia Stroke Stroke is the most frequent major complication of AF; this topic is discussed in detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Silent cerebral ischemia Silent cerebral ischemia occurs in a patient who has specific lesions on imaging studies in the absence of clinical complaints or findings. Among patients with AF, these lesions are relatively common; this is discussed in detail separately. (See "Stroke in patients with atrial fibrillation", section on 'Silent cerebral infarction'.) Cognitive impairment and dementia AF increases the risk of cognitive impairment, all- cause dementia, vascular dementia, and Alzheimer's disease [58,59]. It is uncertain whether anticoagulation protects against dementia [59,60]. This is discussed in detail separately. (See "Risk factors for cognitive decline and dementia", section on 'Atrial fibrillation'.) Heart failure AF is a risk factor for new-onset heart failure. This is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Epidemiology'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 22/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Coping with high drug prices (The Basics)" and "Patient education: Heart failure and atrial fibrillation (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Background Atrial fibrillation (AF) is the most common cardiac arrhythmia that can have adverse consequences related to a reduction in cardiac output (symptoms) and atrial and atrial appendage thrombus formation (stroke and peripheral embolization) ( waveform 1). Classification Patients are classified as having paroxysmal, persistent, longstanding persistent, or permanent AR. Other classifications include subclinical or occult AF. (See 'Classification and terminology' above.) Screening We do not screen asymptomatic patients for AF. There is no sufficient evidence that screening for AF will substantially detect more AF or protect against cardiac events. Electrocardiograms (ECGs) do not appear more effective than pulse palpation at AF detection. (See 'Screening' above.) Presentation and Evaluation A new diagnosis of AF can present in a variety of ways; sometimes the patient has symptoms of AF and other times it is picked up incidentally. (See 'Common scenarios' above.) Essential information from the patient's symptoms and past medical history, physical examination, electrocardiogram (ECG), and a transthoracic echocardiogram (TTE) should be obtained at the time of diagnosis and periodically during the course of the disease. Additional laboratory testing, such as thyroid stimulating hormone assay, and ambulatory https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 23/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate ECG monitoring may be necessary. (See 'History and physical examination' above and 'Laboratory testing' above.) Initial steps in all patients It is important to decide whether the patient should be managed as an outpatient or in the emergency room or acute hospital setting. When deciding, we take the patient's presentation, symptom burden, and associated conditions into consideration. (See 'Management setting' above.) Other initial steps for all patients include consideration of antithrombotic therapy, treatment of potentially reversible triggers of AF, and cardiovascular risk factor management. (See 'Initial management' above.) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Acute symptom management Symptom management starts with rate control of acute AF episodes and early decision-making regarding the need for cardioversion. Unstable patients In some hemodynamically unstable patients, ventricular rate control can be attempted; slowing of the ventricular rate sometimes leads to spontaneous reversion to sinus rhythm. If rate control does not work and the patient remains hemodynamically unstable, we pursue cardioversion; if we decide to perform emergency cardioversion, the risk for a thromboembolic event needs to be considered. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours'.) Stable patients For stable patients, usually in the nonacute care setting, we discuss the need for possible cardioversion, need for acute and long-term anticoagulant therapy, the cause (if known), and natural history of AF. (See 'Sequelae' above.) We consider consultation with a cardiologist. Reasons to consult a cardiologist include the need for cardioversion or the need to treat with antiarrhythmic drugs or catheter ablation. (See 'Management setting' above.) Long-term management Follow-up after an episode of acute AF is necessary to evaluate the safety and efficacy of rate or rhythm control, patient adherence with anticoagulant and antiarrhythmic therapy, need for continued therapies for AF, to discuss any strategies to reduce AF recurrence, and to assess the functional status of the patient. Lifestyle modification with reducing alcohol consumption, weight reduction, and increasing physical https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 24/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate activity can reduce AF burden and decrease recurrence. (See 'Long-term management' above.) Sequelae In the absence of a reversible precipitant, AF is typically recurrent. AF is associated with increased risk of mortality, stroke, silent cerebral ischemia, cognitive impairment, dementia, and heart failure. Physical activity and higher cardiorespiratory fitness may protect against mortality in AF. (See 'Sequelae' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alan Cheng, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 2. Wyse DG, Van Gelder IC, Ellinor PT, et al. Lone atrial fibrillation: does it exist? J Am Coll Cardiol 2014; 63:1715. 3. Svennberg E, Friberg L, Frykman V, et al. Clinical outcomes in systematic screening for atrial fibrillation (STROKESTOP): a multicentre, parallel group, unmasked, randomised controlled trial. Lancet 2021; 398:1498. 4. Svendsen JH, Diederichsen SZ, H jberg S, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial. Lancet 2021; 398:1507. 5. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for Atrial Fibrillation: US Preventive Services Task Force Recommendation Statement. JAMA 2022; 327:360. 6. Lyth J, Svennberg E, Bernfort L, et al. Cost-effectiveness of population screening for atrial fibrillation: the STROKESTOP study. Eur Heart J 2023; 44:196. 7. Lubitz SA, Atlas SJ, Ashburner JM, et al. Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF Randomized Controlled Trial. Circulation 2022; 145:946. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 25/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 8. Perez MV, Mahaffey KW, Hedlin H, et al. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. N Engl J Med 2019; 381:1909. 9. Diederichsen SZ, Haugan KJ, Kronborg C, et al. Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights From Patients at Risk Monitored Long Term With an Implantable Loop Recorder. Circulation 2020; 141:1510. 10. Jonas DE, Kahwati LC, Yun JDY, et al. Screening for Atrial Fibrillation With Electrocardiography: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2018; 320:485. 11. Christophersen IE, Yin X, Larson MG, et al. A comparison of the CHARGE-AF and the CHA2DS2-VASc risk scores for prediction of atrial fibrillation in the Framingham Heart Study. Am Heart J 2016; 178:45. 12. Marston NA, Garfinkel AC, Kamanu FK, et al. A polygenic risk score predicts atrial fibrillation in cardiovascular disease. Eur Heart J 2023; 44:221. 13. Bano A, Rodondi N, Beer JH, et al. Association of Diabetes With Atrial Fibrillation Phenotype and Cardiac and Neurological Comorbidities: Insights From the Swiss-AF Study. J Am Heart Assoc 2021; 10:e021800. 14. Echouffo-Tcheugui JB, Shrader P, Thomas L, et al. Care Patterns and Outcomes in Atrial Fibrillation Patients With and Without Diabetes: ORBIT-AF Registry. J Am Coll Cardiol 2017; 70:1325. 15. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370:2478. 16. Noseworthy PA, Kaufman ES, Chen LY, et al. Subclinical and Device-Detected Atrial Fibrillation: Pondering the Knowledge Gap: A Scientific Statement From the American Heart Association. Circulation 2019; 140:e944. 17. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366:120. 18. Walkey AJ, Benjamin EJ, Lubitz SA. New-onset atrial fibrillation during hospitalization. J Am Coll Cardiol 2014; 64:2432. 19. Tung P, Levitzky YS, Wang R, et al. Obstructive and Central Sleep Apnea and the Risk of Incident Atrial Fibrillation in a Community Cohort of Men and Women. J Am Heart Assoc 2017; 6. 20. Lavie CJ, Pandey A, Lau DH, et al. Obesity and Atrial Fibrillation Prevalence, Pathogenesis, and Prognosis: Effects of Weight Loss and Exercise. J Am Coll Cardiol 2017; 70:2022. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 26/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 21. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA 2004; 292:2471. 22. Wynn GJ, Todd DM, Webber M, et al. The European Heart Rhythm Association symptom classification for atrial fibrillation: validation and improvement through a simple modification. Europace 2014; 16:965. 23. Krahn AD, Klein GJ, Kerr CR, et al. How useful is thyroid function testing in patients with recent-onset atrial fibrillation? The Canadian Registry of Atrial Fibrillation Investigators. Arch Intern Med 1996; 156:2221. 24. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. 25. Lip GYH. The ABC pathway: an integrated approach to improve AF management. Nat Rev Cardiol 2017; 14:627. 26. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 27. Yoon M, Yang PS, Jang E, et al. Improved Population-Based Clinical Outcomes of Patients with Atrial Fibrillation by Compliance with the Simple ABC (Atrial Fibrillation Better Care) Pathway for Integrated Care Management: A Nationwide Cohort Study. Thromb Haemost 2019; 119:1695. 28. Pastori D, Pignatelli P, Menichelli D, et al. Integrated Care Management of Patients With Atrial Fibrillation and Risk of Cardiovascular Events: The ABC (Atrial fibrillation Better Care)

fibrillation", section on 'AF duration less than 48 hours'.) Stable patients For stable patients, usually in the nonacute care setting, we discuss the need for possible cardioversion, need for acute and long-term anticoagulant therapy, the cause (if known), and natural history of AF. (See 'Sequelae' above.) We consider consultation with a cardiologist. Reasons to consult a cardiologist include the need for cardioversion or the need to treat with antiarrhythmic drugs or catheter ablation. (See 'Management setting' above.) Long-term management Follow-up after an episode of acute AF is necessary to evaluate the safety and efficacy of rate or rhythm control, patient adherence with anticoagulant and antiarrhythmic therapy, need for continued therapies for AF, to discuss any strategies to reduce AF recurrence, and to assess the functional status of the patient. Lifestyle modification with reducing alcohol consumption, weight reduction, and increasing physical https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 24/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate activity can reduce AF burden and decrease recurrence. (See 'Long-term management' above.) Sequelae In the absence of a reversible precipitant, AF is typically recurrent. AF is associated with increased risk of mortality, stroke, silent cerebral ischemia, cognitive impairment, dementia, and heart failure. Physical activity and higher cardiorespiratory fitness may protect against mortality in AF. (See 'Sequelae' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alan Cheng, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 2. Wyse DG, Van Gelder IC, Ellinor PT, et al. Lone atrial fibrillation: does it exist? J Am Coll Cardiol 2014; 63:1715. 3. Svennberg E, Friberg L, Frykman V, et al. Clinical outcomes in systematic screening for atrial fibrillation (STROKESTOP): a multicentre, parallel group, unmasked, randomised controlled trial. Lancet 2021; 398:1498. 4. Svendsen JH, Diederichsen SZ, H jberg S, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial. Lancet 2021; 398:1507. 5. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for Atrial Fibrillation: US Preventive Services Task Force Recommendation Statement. JAMA 2022; 327:360. 6. Lyth J, Svennberg E, Bernfort L, et al. Cost-effectiveness of population screening for atrial fibrillation: the STROKESTOP study. Eur Heart J 2023; 44:196. 7. Lubitz SA, Atlas SJ, Ashburner JM, et al. Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF Randomized Controlled Trial. Circulation 2022; 145:946. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 25/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 8. Perez MV, Mahaffey KW, Hedlin H, et al. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. N Engl J Med 2019; 381:1909. 9. Diederichsen SZ, Haugan KJ, Kronborg C, et al. Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights From Patients at Risk Monitored Long Term With an Implantable Loop Recorder. Circulation 2020; 141:1510. 10. Jonas DE, Kahwati LC, Yun JDY, et al. Screening for Atrial Fibrillation With Electrocardiography: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2018; 320:485. 11. Christophersen IE, Yin X, Larson MG, et al. A comparison of the CHARGE-AF and the CHA2DS2-VASc risk scores for prediction of atrial fibrillation in the Framingham Heart Study. Am Heart J 2016; 178:45. 12. Marston NA, Garfinkel AC, Kamanu FK, et al. A polygenic risk score predicts atrial fibrillation in cardiovascular disease. Eur Heart J 2023; 44:221. 13. Bano A, Rodondi N, Beer JH, et al. Association of Diabetes With Atrial Fibrillation Phenotype and Cardiac and Neurological Comorbidities: Insights From the Swiss-AF Study. J Am Heart Assoc 2021; 10:e021800. 14. Echouffo-Tcheugui JB, Shrader P, Thomas L, et al. Care Patterns and Outcomes in Atrial Fibrillation Patients With and Without Diabetes: ORBIT-AF Registry. J Am Coll Cardiol 2017; 70:1325. 15. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370:2478. 16. Noseworthy PA, Kaufman ES, Chen LY, et al. Subclinical and Device-Detected Atrial Fibrillation: Pondering the Knowledge Gap: A Scientific Statement From the American Heart Association. Circulation 2019; 140:e944. 17. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366:120. 18. Walkey AJ, Benjamin EJ, Lubitz SA. New-onset atrial fibrillation during hospitalization. J Am Coll Cardiol 2014; 64:2432. 19. Tung P, Levitzky YS, Wang R, et al. Obstructive and Central Sleep Apnea and the Risk of Incident Atrial Fibrillation in a Community Cohort of Men and Women. J Am Heart Assoc 2017; 6. 20. Lavie CJ, Pandey A, Lau DH, et al. Obesity and Atrial Fibrillation Prevalence, Pathogenesis, and Prognosis: Effects of Weight Loss and Exercise. J Am Coll Cardiol 2017; 70:2022. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 26/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 21. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA 2004; 292:2471. 22. Wynn GJ, Todd DM, Webber M, et al. The European Heart Rhythm Association symptom classification for atrial fibrillation: validation and improvement through a simple modification. Europace 2014; 16:965. 23. Krahn AD, Klein GJ, Kerr CR, et al. How useful is thyroid function testing in patients with recent-onset atrial fibrillation? The Canadian Registry of Atrial Fibrillation Investigators. Arch Intern Med 1996; 156:2221. 24. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. 25. Lip GYH. The ABC pathway: an integrated approach to improve AF management. Nat Rev Cardiol 2017; 14:627. 26. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 27. Yoon M, Yang PS, Jang E, et al. Improved Population-Based Clinical Outcomes of Patients with Atrial Fibrillation by Compliance with the Simple ABC (Atrial Fibrillation Better Care) Pathway for Integrated Care Management: A Nationwide Cohort Study. Thromb Haemost 2019; 119:1695. 28. Pastori D, Pignatelli P, Menichelli D, et al. Integrated Care Management of Patients With Atrial Fibrillation and Risk of Cardiovascular Events: The ABC (Atrial fibrillation Better Care) Pathway in the ATHERO-AF Study Cohort. Mayo Clin Proc 2019; 94:1261. 29. Proietti M, Romiti GF, Olshansky B, et al. Improved Outcomes by Integrated Care of Anticoagulated Patients with Atrial Fibrillation Using the Simple ABC (Atrial Fibrillation Better Care) Pathway. Am J Med 2018; 131:1359. 30. Guo Y, Lane DA, Wang L, et al. Mobile Health Technology to Improve Care for Patients With Atrial Fibrillation. J Am Coll Cardiol 2020; 75:1523. 31. Pastori D, Farcomeni A, Pignatelli P, et al. ABC (Atrial fibrillation Better Care) Pathway and Healthcare Costs in Atrial Fibrillation: The ATHERO-AF Study. Am J Med 2019; 132:856. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 27/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 32. Alkhouli M, Friedman PA. Ischemic Stroke Risk in Patients With Nonvalvular Atrial Fibrillation: JACC Review Topic of the Week. J Am Coll Cardiol 2019; 74:3050. 33. Danias PG, Caulfield TA, Weigner MJ, et al. Likelihood of spontaneous conversion of atrial fibrillation to sinus rhythm. J Am Coll Cardiol 1998; 31:588. 34. Martinez KA, Hurwitz HM, Rothberg MB. Qualitative Analysis of Patient-Physician Discussions Regarding Anticoagulation for Atrial Fibrillation. JAMA Intern Med 2022; 182:1260. 35. Israel CW, Gr nefeld G, Ehrlich JR, et al. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient care. J Am Coll Cardiol 2004; 43:47. 36. Page RL, Wilkinson WE, Clair WK, et al. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation 1994; 89:224. 37. Voskoboinik A, Kalman JM, De Silva A, et al. Alcohol Abstinence in Drinkers with Atrial Fibrillation. N Engl J Med 2020; 382:20. 38. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA 2013; 310:2050. 39. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014; 64:2222. 40. Garnvik LE, Malmo V, Janszky I, et al. Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study. Eur Heart J 2020; 41:1467. 41. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37:2315. 42. Schmitt J, Duray G, Gersh BJ, Hohnloser SH. Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 2009; 30:1038. 43. Garg RK, Jolly N. Acute myocardial infarction secondary to thromboembolism in a patient with atrial fibrillation. Int J Cardiol 2007; 123:e18. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 28/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 44. Belkouche A, Yao H, Putot A, et al. The Multifaceted Interplay between Atrial Fibrillation and Myocardial Infarction: A Review. J Clin Med 2021; 10. 45. Crenshaw BS, Ward SR, Granger CB, et al. Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries. J Am Coll Cardiol 1997; 30:406. 46. Eldar M, Canetti M, Rotstein Z, et al. Significance of paroxysmal atrial fibrillation complicating acute myocardial infarction in the thrombolytic era. SPRINT and Thrombolytic Survey Groups. Circulation 1998; 97:965. 47. Goldberg RJ, Seeley D, Becker RC, et al. Impact of atrial fibrillation on the in-hospital and long-term survival of patients with acute myocardial infarction: a community-wide perspective. Am Heart J 1990; 119:996. 48. Leong DP, Eikelboom JW, Healey JS, Connolly SJ. Atrial fibrillation is associated with increased mortality: causation or association? Eur Heart J 2013; 34:1027. 49. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 2004; 109:1509. 50. Pedersen OD, Bagger H, Keller N, et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation 2001; 104:292. 51. Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. JAMA 2011; 305:2080. 52. Andersson T, Magnuson A, Bryngelsson IL, et al. All-cause mortality in 272,186 patients hospitalized with incident atrial fibrillation 1995-2008: a Swedish nationwide long-term case-control study. Eur Heart J 2013; 34:1061. 53. Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946. 54. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med 2002; 113:359. 55. Chen LY, Sotoodehnia N, B kov P, et al. Atrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study. JAMA Intern Med 2013; 173:29. 56. Marijon E, Le Heuzey JY, Connolly S, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long- https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 29/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate term anticoagulant therapy study. Circulation 2013; 128:2192. 57. Vermond RA, Crijns HJ, Tijssen JG, et al. Symptom severity is associated with cardiovascular outcome in patients with permanent atrial fibrillation in the RACE II study. Europace 2014; 16:1417. 58. Papanastasiou CA, Theochari CA, Zareifopoulos N, et al. Atrial Fibrillation Is Associated with Cognitive Impairment, All-Cause Dementia, Vascular Dementia, and Alzheimer's Disease: a Systematic Review and Meta-Analysis. J Gen Intern Med 2021; 36:3122. 59. Kim D, Yang PS, Yu HT, et al. Risk of dementia in stroke-free patients diagnosed with atrial fibrillation: data from a population-based cohort. Eur Heart J 2019; 40:2313. 60. Moffitt P, Lane DA, Park H, et al. Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review. Age Ageing 2016; 45:767. Topic 1022 Version 82.0 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 30/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate GRAPHICS 12 lead ECG of atrial fibrillation The 12 lead ECG shows atrial fibrillation. The QRS complex is narrow, P waves are absent, and the baseline between successive QRS complexes shows irregular coarse "fibrillatory waves." The QRS complexes occur at irregularly irregular intervals. Reproduced with permission by Samuel Levy, MD. Graphic 64217 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 31/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) 2 2 CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients Stroke and 2 2 (n = 73,538) thromboembolism event rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 5 8942 15.26 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 32/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 33/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Atrial fibrillation increases mortality in men and women Among 5209 subjects in the Framingham Heart Study, the mortality after a 10-year follow-up was higher in both men and women, aged 55 to 74, who had atrial fibrillation (AF) compared to those without AF (p <0.001) A similar relationship was seen in subjects between the ages of 75 and 94 (not shown). Data from Benjamin EJ, Wolf PA, D'Agostino RB, et al. Circulation 1998; 98:946. Graphic 71640 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 34/35 7/6/23, 2:49 PM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 35/35

7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Surgical ablation : Richard Lee, MD, MBA : Gabriel S Aldea, MD, Edward Verrier, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 11, 2023. INTRODUCTION Atrial fibrillation (AF) is associated with an increased risk for stroke, heart failure, and death. An attempt to maintain sinus rhythm is made in patients based on the presence or absence of symptoms and evidence that myocardial function is being compromised. This may involve pharmacologic and nonpharmacologic strategies. The most commonly performed invasive procedure used in an attempt to maintain sinus rhythm is catheter ablation performed by an electrophysiologist in a specially designed hospital procedure room. This technique is discussed in detail elsewhere. (See "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) This chapter focuses on surgical ablation for the prevention of recurrent atrial fibrillation. The role of nonpharmacologic strategies for rate control in AF or to minimize thrombotic risk by left atrial appendage ligation, and an overview of the management of patients with AF, are presented separately. (See "Atrial fibrillation: Atrioventricular node ablation" and "Atrial fibrillation: Left atrial appendage occlusion" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) RATIONALE Work on the arrhythmic mechanisms for atrial fibrillation (AF) has led to a greater appreciation for the underlying process by which premature atrial complex (PAC; also referred to a premature https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 1/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate atrial beat, premature supraventricular complex, or premature supraventricular beat) can promote areas of microreentry within the atrium that ultimately lead to AF. (See "Mechanisms of atrial fibrillation".) Several surgical techniques have been developed to maintain sinus rhythm. In most cases, these techniques are employed in patients who are undergoing other cardiac surgery for some other reason (valve repair or replacement, coronary bypass grafting, or corrective surgery for congenital heart disease). The three principal goals of surgical intervention include [1]: Creation of conduction block to disrupt all micro- and macroreentrant circuits. (See "Mechanisms of atrial fibrillation", section on 'Mechanisms of atrial fibrillation: triggers and substrates'.) Reestablishment or maintenance of electrical atrioventricular synchrony. Restoration of atrial mechanical function in order to improve diastolic filling. MAZE PROCEDURE Developed in the 1980s, the Maze procedure aims to create a "maze" of functional myocardium within the atrium that allows for propagation of atrial depolarization while reducing the likelihood that the wavefront would promote microreentry. (See "Mechanisms of atrial fibrillation".) The most commonly performed procedure is referred to as the Cox-Maze IV and it consists of a pattern of linear scars created by incision or ablative technology such as radiofrequency or cryothermal ablation [2]. Most commonly, the procedure is performed at the time of other cardiac surgery, such as mitral valve surgery or coronary artery bypass graft surgery; the patient is on cardiopulmonary bypass. (See 'Indications' below.) Traditional approach The Maze procedure has evolved over the last 20 years. It originally created lines of scar by making several small incisions (referred to as "cut and sew") around the sinoatrial node as well as one to the atrial-superior vena caval junction (Maze I) through the sinus tachycardia region of the sinoatrial node. This unintentionally resulted in chronotropic incompetence and resulted in the Maze II procedure that modified the location of the incision to prevent this. The technical challenges of the Maze II procedure (eg, approach to the left atrium) eventually resulted in Maze III, which reduced the frequency of chronotropic incompetence, improved atrial transport function, and shortened procedure times ( figure 1) [3-9]. Eventually, https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 2/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate with the introduction of new technologies that created scar without incisions, such as cryothermia and radiofrequency, procedures were simplified and shortened. The "cut and sew" techniques became less frequently utilized and are now rarely performed. Although they are more complex and slightly more time consuming, approaches that treat both atria appear to be more effective [10]. However, it is important to point out that long-term follow-up on the efficacy of these procedures is limited. The "gold standard" is considered to be the Cox-Maze IV procedure, in which lines of ablation are created using bipolar radiofrequency and/or cryothermal energy devices. Several lines of scar are created from the superior vena cava to the inferior vena cava on the right atrium, which is then connected to the tricuspid annulus. On the left, the posterior wall of the left atrium containing all four pulmonary veins is isolated as a box. The box is then connected to the mitral valve annulus. In addition, the left atrial appendage is removed. The Maze procedure meets the three criteria for an ideal treatment of atrial fibrillation (AF) outlined above (see 'Rationale' above). In a five-year experience of 75 patients in one center, the procedure cured AF, restored atrioventricular synchrony, and preserved atrial transport function in all but one patient; six patients (9 percent) required antiarrhythmic medications [6]. Postoperative atrial pacemakers were implanted in 40 percent, mostly for preoperative sinus node dysfunction but occasionally for iatrogenic sinus node injury. This is a higher percent than has been observed in most contemporary series (see 'Need for pacemaker' below). Patients note a significant improvement in health-related quality of life, especially when compared with other cardiac procedures [8,11]. The addition of a Maze procedure does not appear to adversely impact outcomes after cardiac surgery. In a propensity-matched comparison of 485 patients undergoing Maze procedure and aortic valve replacement or coronary artery bypass graft surgery, there was no difference in any major morbidity or mortality. However, patients were on cardiopulmonary bypass longer and had a higher need for pacemakers [12]. Similar findings after mitral valve surgery have been reported in randomized trials [13]. A few studies have suggested that correcting AF at the time of cardiac surgery improves survival. In one study of 744 propensity-matched patients undergoing AF surgery at the time of other cardiac surgeries, patients who were successfully treated and free from antiarrhythmic medications at one year appeared to have improved survival, similar to patients without a history of AF. Those that remained in AF had a survival that was worse [14]. In another propensity-matched series of similar size, Maze-treated patients had a 10-year survival of 63 percent as compared with a 55 percent 10-year survival in similar patients whose AF was untreated [15]. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 3/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate Radial approach The radial approach was developed after the Maze procedure to provide a more physiologic atrial activation-contraction sequence, thereby reducing the degree of left atrial dysfunction and optimizing the atrial contribution to left ventricular filling [16]. In contrast to the Maze procedure, in which the incisions desynchronize the activation sequence and often cut across the atrial coronary arteries, the incisions produced by the radial approach radiate from the sinus node toward the atrioventricular annular margins, paralleling the activation sequence and the atrial coronary arteries ( figure 2A-B) [17]. Left versus biatrial lesion set Some controversy exists as to the most appropriate lesion set. If only the left atrium is open in the case of a mitral valve repair or replacement without a tricuspid intervention, some surgeons have advocated a left-atrial-only approach [18]. In a series of 305 patients, there was an equal efficacy of a left-only approach, but a higher pacemaker implantation in those who underwent a biatrial lesion set [18]. Both of these findings were confirmed on a meta-analysis of 2225 patients from 10 studies [19]. The equivalent sinus restoration is supported by a randomized subgroup analysis of mitral valve patients that compared patients undergoing biatrial Mazes with pulmonary vein isolation alone [13]. However, in a 2008 analysis of 1723 patients, absence of a biatrial lesion set was a predictor of failure at 48 months [20]. This finding was also supported by a 2006 meta-analysis of 5885 patients in 69 studies [10]. More investigation may lead to a better understanding of which patients benefit from the biatrial lesion set. One study compared the outcome of 23 patients who underwent a radial approach with 13 who had a traditional Maze procedure [21]. The radial approach was technically easier than the Maze, was equally likely to restore sinus rhythm (90 versus 92 percent for the Maze), and was associated with better left atrial transport function after surgery, as assessed with Doppler echocardiography. However, this approach has not yet been widely adopted by the majority of surgeons. Minimally invasive approach While the Maze procedure is usually performed at the time of cardiac surgery using a sternotomy, it has also been performed through a thoracotomy with a minimally invasive approach to mitral valves [22,23]. However, there are limited data available on the efficacy of using this approach. Limitations and complications Atrial transport function One potential limitation to the Maze procedure is extensive damage to the atrial myocardium with resultant atrial dysfunction that may limit the hemodynamic benefit. In one series of 21 patients, the technique was effective in restoring sinus rhythm in 17 (85 percent) but atrial contractility improved in only 12 (71 percent) [24]. In one https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 4/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate series of 150 patients who had successful return of electrical sinus, poor atrial contraction resulted in a significant rate of late stroke [25]. In a series of 31 patients, echocardiography demonstrated left atrial function in 71 percent and right atrial function in 81 percent; however, function was reduced compared with age-matched control subjects [26]. A successful Maze procedure may improve atrial transport, but the degree of improvement will likely be dependent on preoperative dysfunction. Need for pacemaker A common complication is the need for postoperative pacemaker, which usually occurs in approximately 10 percent of patients in most reports. As with simple electrical cardioversion, the mere restoration of sinus rhythm in patients with long-standing persistent AF can result in sinus node dysfunction unrelated to the surgery itself. Sinus node dysfunction may manifest as severe sinus bradycardia, sinus pauses or sinus arrest, sinoatrial exit block, atrial tachyarrhythmias, alternating periods of atrial bradyarrhythmias and tachyarrhythmias, and inappropriate heart rate responses during exercise or emotional stress. These arrhythmias probably result from partial denervation of the sympathetic and parasympathetic systems of the heart [27]. However, there may be some association with the extent of AF procedure performed. The published results are highly variable, with early studies reporting a postoperative need for pacemaker as high as 40 percent. Another study found pacemaker placement in 20 percent [6,13]. As surgeons learn to avoid the sinus node on the right side, the pacemaker rate may fall further. The manifestations of sinus node dysfunction after the modified Maze surgical technique are time dependent and, in one series, resolved within 12 months after surgery [28]; resolution correlated with functional reinnervation [27]. However, in another study, sick sinus syndrome developed in 7 of 87 patients (8.4 percent) and a pacemaker was required in 70 percent [29]. Pacemakers are rarely required after pulmonary vein isolation alone. In one series, there were more pacemakers required after biatrial lesion sets were employed, as compared with left atrial lesion sets alone [18]. This suggests that not all pacemakers are due to native sinus node dysfunction and that at least some are related to the creation of the right-sided lesions. There may be a balance between procedural efficacy and pacemaker requirement. METHODS Endocardial surgical ablation Endocardial ablation is most often performed in an electrophysiologic suite by electrophysiologists using a catheter-based approach. However, the endocardial ablation of atrial tissue can also be performed in the operating room as an adjunct to cardiac surgery for other reasons or as a stand-alone procedure using a minimally invasive approach. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 5/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate The efficacy of the left atrial approach was evaluated in a multicenter controlled trial in which 103 patients undergoing endocardial radiofrequency ablation during cardiac surgery for predominantly valvular heart disease were compared with 27 patients who refused radiofrequency ablation [30]. Linear ablation lesions were created around the right and left pulmonary vein ostia, with a lesion connecting the pulmonary vein lesions and another lesion connecting the left pulmonary veins to the mitral annulus. Patients treated with ablation were more likely to be in sinus rhythm at hospital discharge (63 versus 18 percent in the control group) and at one year (81 versus 11 percent). A second study of 70 patients with either chronic or paroxysmal atrial fibrillation (AF) used minimally invasive surgical techniques with linear radiofrequency ablation to create a series of linear ablations around the orifices of the pulmonary veins in the left atrium [31]. During this procedure, the left atrium was accessed through small incisions in the chest (minimally invasive) and the patient was on femoro-femoral cardiopulmonary bypass. The mean intraoperative time was two hours, much shorter than with either the Maze procedure or catheter-based ablation techniques described below. At a mean follow-up of 1.5 years, AF was eliminated in 90 percent of patients. Epicardial procedures A minimally invasive approach using thoracoscopic pulmonary vein (and ganglionated plexi) isolation and ablation has been used to treat patients who have failed or are not candidates for antiarrhythmic drug therapy or catheter-based pulmonary vein catheter ablation (CA) [32-34]. However, we do not use this approach as the first interventional strategy. As a stand-alone procedure, these approaches are limited to pulmonary vein isolation, either as a box or islands around each side. An endocardial approach is necessary to connect any lesion to either the mitral or tricuspid valves. (See "Atrial fibrillation: Catheter ablation".) This procedure is performed with video-assisted thorascopic access to the epicardial space through small, either right-sided or bilateral thoracic incisions and primarily focuses on pulmonary vein isolation. The pulmonary veins are electrically isolated with a bipolar radiofrequency ablation clamp or suction-assisted unidirectional device. Depending on the center, additional ablation of ganglia or the left atrium are also performed epicardially. Individuals are not placed on bypass and linear epicardial lesions are delivered to the pulmonary veins. This technique can be used in a stand-alone fashion or in conjunction with an endocardial approach (see 'Hybrid approach' below). Complications of the traditional endocardial approach to catheter ablation, such as damage to the phrenic nerve and the development of thromboembolism, occur but may be less frequent through an epicardial ablation. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 6/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate The 2020 CASA-AF trial randomly assigned 120 patients with long-standing persistent atrial fibrillation (AF) to thoracoscopic surgical or catheter ablation [35]. The primary outcome of single-procedure freedom from AF/atrial tachycardia 30 seconds without antiarrhythmic drugs at 12 months occurred at a similar rate in both groups (26 versus 28 percent, respectively; odds ratio 1.13, 95% CI 0.46-2.83). One death was reported in the surgical ablation group, and over 12 months it was more expensive and provided fewer quality-adjusted life-years compared with catheter ablation (0.78 versus 0.85; p = 0.02). The FAST trial randomly assigned 124 patients with antiarrhythmic drug-refractory AF with left atrial dilatation and hypertension (33 percent) or failed prior CA (67 percent) to either minimally invasive surgical ablation or CA [36]. At 12 months, the primary end point of freedom from left atrial arrhythmia of greater than 30 seconds without antiarrhythmic drugs was significantly higher in the surgical ablation group (65.6 versus 36.5 percent). However, there were significantly more periprocedural complications, such as pneumothorax, major bleeding, and the need for pacemaker, in the surgical ablation group (35.4 versus 15.9 percent). The need for pacemaker placement was 3 percent after surgery and 0 percent after catheter ablation. Hybrid approach Surgeons and cardiologists are now combining to perform some of the lesions surgically and some in the electrophysiology lab or operating room in a "hybrid" approach. There are three different types of approaches: right thoracotomy [37], subxyphoid [38], and bilateral thoracoscopic [39]. The convergent procedure is a subxyphoid approach that requires both surgery and catheter ablation in a single hospitalization to complete. Long-term follow-up is needed. Both the right and bilateral thoracoscopic approaches allow for a staged or concomitant approach. The right thoracotomy uses unipolar suction-assisted radiofrequency ablation. The bilateral uses bipolar radiofrequency ablation clamps and is the only approach that allows for treatment of the left atrial appendage. Although initially a simultaneous or single-stage approach predominated, there has been a trend toward a staged approach, performing the electrophysiology portion only in the patients that fail initial surgery. In a small single-center series, the staged, bilateral approach has been demonstrated to be as efficacious as a "cut-and-sew" open Maze, but none of the reports is large enough to make definitive recommendations for any of these procedures. However, they do offer the potential for improving the success of treatment in challenging patients without the full extent of surgery or its complications. They may be considered in medically refractory AF patients who are unlikely to be successfully treated with catheter ablation alone. Comparison of methods The relative efficacy and safety of the different procedures has not been well studied. There are no large randomized trials, and available observational data are https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 7/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate inconsistent, as illustrated by the following: In a review of 70 patients, 40 underwent radiofrequency (RF) ablation and 30 underwent the surgical Maze procedure [40]. Those undergoing RF ablation and those undergoing the surgical Maze had similar rates of sinus rhythm at discharge (85 versus 73 percent) and at one year (91 versus 96 percent). A series of 56 patients who underwent RF ablation during surgery were compared with 56 matched historical controls [41]. Patients treated with the conventional surgical Maze were more likely than those treated with RF to be in sinus rhythm at discharge (88 versus 63 percent) and at last follow-up (92 versus 62 percent). In a series of 377 patients from a single institution, 220 underwent a surgical Maze procedure, and the remaining 157 were treated with RF ablation during surgery [42]. Patients treated with the conventional surgical procedure were more likely than those treated with RF to be in sinus rhythm at three months (91 versus 62 percent) and at six months (90 versus 75 percent). However, these results should be interpreted with caution for the following reasons: Each cohort included a heterogeneous mix of patients undergoing different surgeries with a variety of underlying cardiac disease and comorbidities. The RF procedures were not standardized, and in most cases, documentation of effective RF lesions was not performed. In percutaneous ablation procedures, documentation that ablation produces conduction block is an important predictor of success. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) INDICATIONS We believe it is reasonable to attempt to surgically ablate atrial fibrillation (AF) in carefully selected patients with a high burden of AF. Most of these patients will have been referred for cardiac surgery for another reason, such as significant valvular or coronary heart disease. It is uncommon for patients without an indication for open heart surgery to be referred for a surgical ablative procedure. We believe it is reasonable to perform concurrent surgical ablation at the time of mitral valve surgery in patients with a high burden of AF, including those with paroxysmal or persistent AF [2]. In patients undergoing mitral valve surgery, most often for mitral regurgitation, 30 to 50 percent have AF [14,43]. Most studies of the surgical treatment of AF have enrolled patients https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 8/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate undergoing mitral valve surgery, with the PRAGUE-12 randomized study being one exception [44]. The procedure should be performed only when it does not add significant additional surgical risk. Patients with prior cardiac surgery or those who cannot tolerate single lung ventilation are less than ideal candidates. In patients who have failed or are intolerant to antiarrhythmic drug therapy, have failed catheter ablation in the electrophysiology laboratory, and in whom a minimally invasive approach is feasible, it is reasonable to attempt this procedure [45]. (See 'Minimally invasive approach' above.) EFFICACY In most published series that compared patients undergoing surgical treatment of atrial fibrillation (AF) with those not, the burden of AF was lower with surgical treatment. This generally leads to improved quality of life and a lower use of antiarrhythmic drug therapy. Similar to patients undergoing traditional catheter ablation, there is no evidence that survival is improved [13,44,46]. The best evidence of long-term outcomes comparing ablation with no ablation during mitral valve surgery comes from a study of 260 patients with persistent or long-standing persistent AF who were randomly assigned to either surgical ablation or no ablation during the surgery [13]. Patients who were assigned to ablation received either pulmonary vein isolation or a biatrial Maze procedure. All patients underwent closure of the left atrial appendage. The primary end point of freedom from AF at both 6 and 12 months, as assessed by three-day continuous monitoring, occurred more often with ablation (63.2 versus 29.4 percent; p<0.001). There was no significant difference between the two ablation procedures for this outcome. Mortality was 6.8 percent in the ablation group and 8.7 percent in the no ablation group (hazard ratio 0.76, 95% CI 0.32-1.84). There was no significant difference in the rate of a composite secondary outcome that included cardiac or cerebrovascular adverse events, nor were there differences in the end points of functional class, quality-of-life measures, and medication use. However, the rate of implantation of a permanent pacemaker was higher with ablation (21.5 versus 8.1 per 100 patient-years; p = 0.01). Individual patient factors, such as symptom status, should determine whether AF ablation is performed in this setting. It is possible that the restoration of sinus rhythm might lead to improved clinical outcomes with longer follow-up in this relatively small study. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) A number of observational studies have demonstrated that performing a combined procedure with either "cut and sew" Maze [47-52] or catheter ablation [20,30,53-56] leads to a 60 to 80 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 9/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate percent likelihood of freedom from AF at one year. In an observational study of 576 patients who underwent the Cox-Maze IV procedure, overall freedom from AF was 78 percent at five years and freedom from AF off antiarrhythmic drugs was 66 percent [2]. In this study, there was no difference between those with paroxysmal and those with persistent/longstanding AF. The freedom from AF after surgery in single-center series has been reported to be as high as 92, 84, and 77 percent at 1, 5, and 10 years, respectively [57]. TREATMENT FAILURES Surgical approaches to prevent atrial fibrillation (AF) have a high rate of success (see 'Maze procedure' above). However, some patients have recurrent atrial arrhythmias including AF, typical flutter, atypical atrial flutter (often due to reentrant circuits around the surgical scars), and focal atrial tachycardias [58]. Such patients may be candidates for electrophysiology study and catheter ablation. (See "Atrial fibrillation: Catheter ablation", section on 'Management of recurrence' and "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) ANTICOAGULATION First two to three months All patients are anticoagulated with a direct oral anticoagulant (DOAC) or vitamin K antagonist (VKA) for at least two months after surgical ablation, regardless of their CHA DS -VASc score or rhythm status. 2 2 Subsequent anticoagulation decisions In patients who are at risk for stroke, anticoagulation therapy should be continued indefinitely after surgical ablation procedure regardless of the rhythm outcome [59]. Since surgical ablation to prevent AF can restore sinus rhythm long term, some have suggested that it may also reduce stroke risk and therefore the need for long-term anticoagulation, but there is no convincing evidence to support this approach. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Identifying patients at risk for stroke Identifying which patients are at risk for stroke and require long-term anticoagulation is not different in patients who have undergone surgical ablation. This is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".). There is limited information regarding the validity of the CHADS2 stroke score in predicting stroke risk in surgical ablation patients. Observational studies suggest overall low stroke rates following surgical ablation [60-63]. In a Swedish cohort study, 526 patients had a Cox- maze III procedure, including left atrial appendage excision, and were followed for https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 10/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate development of stroke/transient ischemic attack (TIA) [63]. A total of 29 patients had any stroke or TIA. There were 6 intracerebral bleeds, 4 perioperative strokes, 13 ischemic strokes, and six TIAs. The mean onset of postoperative stroke/TIAs was at seven years (incidence of 0.36 percent, 19 events per 5231 patient-years). In all CHADS2 groups, observed ischemic stroke/TIA rates were lower than predicted. Importantly, CHADS2 scores of 2 or greater were associated with increased risk of developing stroke compared with patients with lower scores (hazard ratio [HR] 2.15, 95% CI 0.87-5.32). However, in a separate study of 691 patients who underwent a surgical ablation, CHADS2 did not predict stroke but was related to increased bleeding [64]. Anticoagulant administration As for other patients with AF, a DOAC is generally preferred. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) Patients who are treated with VKA (eg, those with a mechanical valve) who have a subtherapeutic international normalized ratio after the procedure are treated with early bridging anticoagulation with heparin (intravenous unfractionated heparin or low molecular weight heparin). Outcomes with surgical left atrial appendage occlusion (with or without a Maze procedure) are discussed further separately. (See "Atrial fibrillation: Left atrial appendage occlusion".) RECOMMENDATIONS OF OTHERS The Society of Thoracic Surgeons 2017 clinical practice guideline for the surgical treatment of atrial fibrillation (AF) makes the following strong recommendations [65]: Surgical ablation for AF is recommended at the time of concomitant isolated aortic valve replacement, isolated coronary artery bypass graft surgery (CABG), and aortic valve replacement plus CABG to restore sinus rhythm. Surgical ablation for AF is recommended at the time of concomitant mitral operations to restore sinus rhythm. Stand-alone surgical ablation for symptomatic AF without structural heart disease is reasonable in patients who have failed a class I or III antiarrhythmic medication or catheter-based therapy. The following recommendations were made in the Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society/Asia Pacific Heart Rhythm https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 11/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate Society/Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulaci n Card aca y Electrofisiolog a) expert consensus statement on catheter and surgical ablation of atrial fibrillation [66]: Surgical ablation for AF is recommended at the time of concomitant isolated aortic valve replacement, isolated CABG, and aortic valve replacement plus CABG to restore sinus rhythm if the patient is symptomatic and refractory or intolerant to one class I or III antiarrhythmic medication. Surgical ablation for AF is recommended at the time of concomitant mitral operations to restore sinus rhythm for all symptomatic AF patients. Stand-alone surgical ablation is reasonable for persistent and long-standing patients who have failed one or more attempts at catheter ablation who prefer a surgical approach after review of safety and efficacy of options. For paroxysmal AF, it may also be considered after one or more catheter attempts. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 12/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate SUMMARY AND RECOMMENDATIONS Several surgical techniques have been developed for the control of refractory atrial fibrillation (AF) and maintenance of sinus rhythm. In most patients, these techniques are employed as adjunctive therapy in patients undergoing other cardiac surgery for some other reason, such as mitral valve or coronary artery bypass surgery. (See 'Indications' above.) These surgical procedures appear effective at eliminating or reducing the frequency of AF in a high percentage of patients. (See 'Maze procedure' above and 'Endocardial surgical ablation' above.) After surgical ablation, we continue anticoagulation in patients at high risk for stroke. For all others, we often discontinue anticoagulation two to three months after successful restoration of sinus rhythm and particularly in patients at high risk for bleeding. Patients in persistent AF should receive continued anticoagulation. This practice applies only to patients who have had the left atrial appendage removed or ligated. Patients with recurrent AF after one of these procedures may be candidates for electrophysiology study and catheter ablation. (See 'Treatment failures' above and "Atrial fibrillation: Catheter ablation".) ACKNOWLEDGMENT The UpToDate editorial staff thank Alan Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ferguson TB Jr, Cox JL. Surgery for atrial fibrillation. In: Cardiac Electrophysiology: From Cell to Bedside, 2nd ed, Zipes DP, Jalife J (Eds), Saunders, Philadelphia 1995. p.1567. 2. Henn MC, Lancaster TS, Miller JR, et al. Late outcomes after the Cox maze IV procedure for atrial fibrillation. J Thorac Cardiovasc Surg 2015; 150:1168. 3. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 13/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991; 101:406. 4. Cox JL. The surgical treatment of atrial fibrillation. IV. Surgical technique. J Thorac Cardiovasc Surg 1991; 101:584. 5. Cox JL, Boineau JP, Schuessler RB, et al. Electrophysiologic basis, surgical development, and clinical results of the maze procedure for atrial flutter and atrial fibrillation. Adv Card Surg 1995; 6:1. 6. Cox JL, Boineau JP, Schuessler RB, et al. Five-year experience with the maze procedure for atrial fibrillation. Ann Thorac Surg 1993; 56:814. 7. Kosakai Y, Kawaguchi AT, Isobe F, et al. Modified maze procedure for patients with atrial fibrillation undergoing simultaneous open heart surgery. Circulation 1995; 92:II359. 8. L nnerholm S, Blomstr m P, Nilsson L, et al. Effects of the maze operation on health-related quality of life in patients with atrial fibrillation. Circulation 2000; 101:2607. 9. Cox JL, Jaquiss RD, Schuessler RB, Boineau JP. Modification of the maze procedure for atrial flutter and atrial fibrillation. II. Surgical technique of the maze III procedure. J Thorac Cardiovasc Surg 1995; 110:485. 10. Barnett SD, Ad N. Surgical ablation as treatment for the elimination of atrial fibrillation: a meta-analysis. J Thorac Cardiovasc Surg 2006; 131:1029. 11. Grady KL, Lee R, Suba ius H, et al. Improvements in health-related quality of life before and after isolated cardiac operations. Ann Thorac Surg 2011; 91:777. 12. Ad N, Henry L, Hunt S, Holmes SD. Do we increase the operative risk by adding the Cox Maze III procedure to aortic valve replacement and coronary artery bypass surgery? J Thorac Cardiovasc Surg 2012; 143:936. 13. Gillinov AM, Gelijns AC, Parides MK, et al. Surgical ablation of atrial fibrillation during mitral- valve surgery. N Engl J Med 2015; 372:1399. 14. Lee R, McCarthy PM, Wang EC, et al. Midterm survival in patients treated for atrial fibrillation: a propensity-matched comparison to patients without a history of atrial fibrillation. J Thorac Cardiovasc Surg 2012; 143:1341. 15. Musharbash FN, Schill MR, Sinn LA, et al. Performance of the Cox-maze IV procedure is associated with improved long-term survival in patients with atrial fibrillation undergoing cardiac surgery. J Thorac Cardiovasc Surg 2018; 155:159. 16. Nitta T, Lee R, Watanabe H, et al. Radial approach: a new concept in surgical treatment for atrial fibrillation. II. Electrophysiologic effects and atrial contribution to ventricular filling. Ann Thorac Surg 1999; 67:36. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 14/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate 17. Nitta T, Lee R, Schuessler RB, et al. Radial approach: a new concept in surgical treatment for atrial fibrillation I. Concept, anatomic and physiologic bases and development of a procedure. Ann Thorac Surg 1999; 67:27. 18. Soni LK, Cedola SR, Cogan J, et al. Right atrial lesions do not improve the efficacy of a complete left atrial lesion set in the surgical treatment of atrial fibrillation, but they do increase procedural morbidity. J Thorac Cardiovasc Surg 2013; 145:356. 19. Phan K, Xie A, Tsai YC, et al. Biatrial ablation vs. left atrial concomitant surgical ablation for treatment of atrial fibrillation: a meta-analysis. Europace 2015; 17:38. 20. Melo J, Santiago T, Aguiar C, et al. Surgery for atrial fibrillation in patients with mitral valve disease: results at five years from the International Registry of Atrial Fibrillation Surgery. J Thorac Cardiovasc Surg 2008; 135:863. 21. Nitta T, Ishii Y, Ogasawara H, et al. Initial experience with the radial incision approach for atrial fibrillation. Ann Thorac Surg 1999; 68:805. 22. Ad N, Henry L, Friehling T, et al. Minimally invasive stand-alone Cox-maze procedure for patients with nonparoxysmal atrial fibrillation. Ann Thorac Surg 2013; 96:792. 23. Moten SC, Rodriguez E, Cook RC, et al. New ablation techniques for atrial fibrillation and the minimally invasive cryo-maze procedure in patients with lone atrial fibrillation. Heart Lung Circ 2007; 16 Suppl 3:S88.

have failed one or more attempts at catheter ablation who prefer a surgical approach after review of safety and efficacy of options. For paroxysmal AF, it may also be considered after one or more catheter attempts. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 12/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate SUMMARY AND RECOMMENDATIONS Several surgical techniques have been developed for the control of refractory atrial fibrillation (AF) and maintenance of sinus rhythm. In most patients, these techniques are employed as adjunctive therapy in patients undergoing other cardiac surgery for some other reason, such as mitral valve or coronary artery bypass surgery. (See 'Indications' above.) These surgical procedures appear effective at eliminating or reducing the frequency of AF in a high percentage of patients. (See 'Maze procedure' above and 'Endocardial surgical ablation' above.) After surgical ablation, we continue anticoagulation in patients at high risk for stroke. For all others, we often discontinue anticoagulation two to three months after successful restoration of sinus rhythm and particularly in patients at high risk for bleeding. Patients in persistent AF should receive continued anticoagulation. This practice applies only to patients who have had the left atrial appendage removed or ligated. Patients with recurrent AF after one of these procedures may be candidates for electrophysiology study and catheter ablation. (See 'Treatment failures' above and "Atrial fibrillation: Catheter ablation".) ACKNOWLEDGMENT The UpToDate editorial staff thank Alan Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ferguson TB Jr, Cox JL. Surgery for atrial fibrillation. In: Cardiac Electrophysiology: From Cell to Bedside, 2nd ed, Zipes DP, Jalife J (Eds), Saunders, Philadelphia 1995. p.1567. 2. Henn MC, Lancaster TS, Miller JR, et al. Late outcomes after the Cox maze IV procedure for atrial fibrillation. J Thorac Cardiovasc Surg 2015; 150:1168. 3. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 13/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991; 101:406. 4. Cox JL. The surgical treatment of atrial fibrillation. IV. Surgical technique. J Thorac Cardiovasc Surg 1991; 101:584. 5. Cox JL, Boineau JP, Schuessler RB, et al. Electrophysiologic basis, surgical development, and clinical results of the maze procedure for atrial flutter and atrial fibrillation. Adv Card Surg 1995; 6:1. 6. Cox JL, Boineau JP, Schuessler RB, et al. Five-year experience with the maze procedure for atrial fibrillation. Ann Thorac Surg 1993; 56:814. 7. Kosakai Y, Kawaguchi AT, Isobe F, et al. Modified maze procedure for patients with atrial fibrillation undergoing simultaneous open heart surgery. Circulation 1995; 92:II359. 8. L nnerholm S, Blomstr m P, Nilsson L, et al. Effects of the maze operation on health-related quality of life in patients with atrial fibrillation. Circulation 2000; 101:2607. 9. Cox JL, Jaquiss RD, Schuessler RB, Boineau JP. Modification of the maze procedure for atrial flutter and atrial fibrillation. II. Surgical technique of the maze III procedure. J Thorac Cardiovasc Surg 1995; 110:485. 10. Barnett SD, Ad N. Surgical ablation as treatment for the elimination of atrial fibrillation: a meta-analysis. J Thorac Cardiovasc Surg 2006; 131:1029. 11. Grady KL, Lee R, Suba ius H, et al. Improvements in health-related quality of life before and after isolated cardiac operations. Ann Thorac Surg 2011; 91:777. 12. Ad N, Henry L, Hunt S, Holmes SD. Do we increase the operative risk by adding the Cox Maze III procedure to aortic valve replacement and coronary artery bypass surgery? J Thorac Cardiovasc Surg 2012; 143:936. 13. Gillinov AM, Gelijns AC, Parides MK, et al. Surgical ablation of atrial fibrillation during mitral- valve surgery. N Engl J Med 2015; 372:1399. 14. Lee R, McCarthy PM, Wang EC, et al. Midterm survival in patients treated for atrial fibrillation: a propensity-matched comparison to patients without a history of atrial fibrillation. J Thorac Cardiovasc Surg 2012; 143:1341. 15. Musharbash FN, Schill MR, Sinn LA, et al. Performance of the Cox-maze IV procedure is associated with improved long-term survival in patients with atrial fibrillation undergoing cardiac surgery. J Thorac Cardiovasc Surg 2018; 155:159. 16. Nitta T, Lee R, Watanabe H, et al. Radial approach: a new concept in surgical treatment for atrial fibrillation. II. Electrophysiologic effects and atrial contribution to ventricular filling. Ann Thorac Surg 1999; 67:36. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 14/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate 17. Nitta T, Lee R, Schuessler RB, et al. Radial approach: a new concept in surgical treatment for atrial fibrillation I. Concept, anatomic and physiologic bases and development of a procedure. Ann Thorac Surg 1999; 67:27. 18. Soni LK, Cedola SR, Cogan J, et al. Right atrial lesions do not improve the efficacy of a complete left atrial lesion set in the surgical treatment of atrial fibrillation, but they do increase procedural morbidity. J Thorac Cardiovasc Surg 2013; 145:356. 19. Phan K, Xie A, Tsai YC, et al. Biatrial ablation vs. left atrial concomitant surgical ablation for treatment of atrial fibrillation: a meta-analysis. Europace 2015; 17:38. 20. Melo J, Santiago T, Aguiar C, et al. Surgery for atrial fibrillation in patients with mitral valve disease: results at five years from the International Registry of Atrial Fibrillation Surgery. J Thorac Cardiovasc Surg 2008; 135:863. 21. Nitta T, Ishii Y, Ogasawara H, et al. Initial experience with the radial incision approach for atrial fibrillation. Ann Thorac Surg 1999; 68:805. 22. Ad N, Henry L, Friehling T, et al. Minimally invasive stand-alone Cox-maze procedure for patients with nonparoxysmal atrial fibrillation. Ann Thorac Surg 2013; 96:792. 23. Moten SC, Rodriguez E, Cook RC, et al. New ablation techniques for atrial fibrillation and the minimally invasive cryo-maze procedure in patients with lone atrial fibrillation. Heart Lung Circ 2007; 16 Suppl 3:S88. 24. Sandoval N, Velasco VM, Orjuela H, et al. Concomitant mitral valve or atrial septal defect surgery and the modified Cox-maze procedure. Am J Cardiol 1996; 77:591. 25. Buber J, Luria D, Sternik L, et al. Left atrial contractile function following a successful modified Maze procedure at surgery and the risk for subsequent thromboembolic stroke. J Am Coll Cardiol 2011; 58:1614. 26. Albirini A, Scalia GM, Murray RD, et al. Left and right atrial transport function after the Maze procedure for atrial fibrillation: an echocardiographic Doppler follow-up study. J Am Soc Echocardiogr 1997; 10:937. 27. Pasic M, Musci M, Siniawski H, et al. The Cox maze iii procedure: parallel normalization of sinus node dysfunction, improvement of atrial function, and recovery of the cardiac autonomic nervous system. J Thorac Cardiovasc Surg 1999; 118:287. 28. Pasic M, Musci M, Siniawski H, et al. Transient sinus node dysfunction after the Cox-maze III procedure in patients with organic heart disease and chronic fixed atrial fibrillation. J Am Coll Cardiol 1998; 32:1040. 29. Izumoto H, Kawazoe K, Kitahara H, Kamata J. Operative results after the Cox/maze procedure combined with a mitral valve operation. Ann Thorac Surg 1998; 66:800. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 15/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate 30. Mantovan R, Raviele A, Buja G, et al. Left atrial radiofrequency ablation during cardiac surgery in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2003; 14:1289. 31. Kottkamp H, Hindricks G, Autschbach R, et al. Specific linear left atrial lesions in atrial fibrillation: intraoperative radiofrequency ablation using minimally invasive surgical techniques. J Am Coll Cardiol 2002; 40:475. 32. Krul SP, Driessen AH, van Boven WJ, et al. Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: first results of a hybrid surgical-electrophysiological approach for atrial fibrillation. Circ Arrhythm Electrophysiol 2011; 4:262. 33. Edgerton JR, Brinkman WT, Weaver T, et al. Pulmonary vein isolation and autonomic denervation for the management of paroxysmal atrial fibrillation by a minimally invasive surgical approach. J Thorac Cardiovasc Surg 2010; 140:823. 34. Beyer E, Lee R, Lam BK. Point: Minimally invasive bipolar radiofrequency ablation of lone atrial fibrillation: early multicenter results. J Thorac Cardiovasc Surg 2009; 137:521. 35. Haldar S, Khan HR, Boyalla V, et al. Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial. Eur Heart J 2020; 41:4471. 36. Boersma LV, Castella M, van Boven W, et al. Atrial fibrillation catheter ablation versus surgical ablation treatment (FAST): a 2-center randomized clinical trial. Circulation 2012; 125:23. 37. Muneretto C, Bisleri G, Bontempi L, et al. Successful treatment of lone persistent atrial fibrillation by means of a hybrid thoracoscopic-transcatheter approach. Innovations (Phila) 2012; 7:254. 38. Kiser AC, Landers MD, Boyce K, et al. Simultaneous catheter and epicardial ablations enable a comprehensive atrial fibrillation procedure. Innovations (Phila) 2011; 6:243. 39. Lee R, McCarthy PM, Passman RS, et al. Surgical treatment for isolated atrial fibrillation: minimally invasive vs. classic cut and sew maze. Innovations (Phila) 2011; 6:373. 40. Chiappini B, Mart n-Su rez S, LoForte A, et al. Cox/Maze III operation versus radiofrequency ablation for the surgical treatment of atrial fibrillation: a comparative study. Ann Thorac Surg 2004; 77:87. 41. Stulak JM, Dearani JA, Sundt TM 3rd, et al. Superiority of cut-and-sew technique for the Cox maze procedure: comparison with radiofrequency ablation. J Thorac Cardiovasc Surg 2007; 133:1022. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 16/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate 42. Doty JR, Doty DB, Jones KW, et al. Comparison of standard Maze III and radiofrequency Maze operations for treatment of atrial fibrillation. J Thorac Cardiovasc Surg 2007; 133:1037. 43. Gillinov AM, Saltman AE. Ablation of atrial fibrillation with concomitant cardiac surgery. Semin Thorac Cardiovasc Surg 2007; 19:25. 44. Budera P, Straka Z, Osman k P, et al. Comparison of cardiac surgery with left atrial surgical ablation vs. cardiac surgery without atrial ablation in patients with coronary and/or valvular heart disease plus atrial fibrillation: final results of the PRAGUE-12 randomized multicentre study. Eur Heart J 2012; 33:2644. 45. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012; 14:528. 46. Abo-Salem E, Lockwood D, Boersma L, et al. Surgical Treatment of Atrial Fibrillation. J Cardiovasc Electrophysiol 2015; 26:1027. 47. Sueda T, Imai K, Ishii O, et al. Efficacy of pulmonary vein isolation for the elimination of chronic atrial fibrillation in cardiac valvular surgery. Ann Thorac Surg 2001; 71:1189. 48. de Lima GG, Kalil RA, Leiria TL, et al. Randomized study of surgery for patients with permanent atrial fibrillation as a result of mitral valve disease. Ann Thorac Surg 2004; 77:2089. 49. Yuda S, Nakatani S, Kosakai Y, et al. Long-term follow-up of atrial contraction after the maze procedure in patients with mitral valve disease. J Am Coll Cardiol 2001; 37:1622. 50. Kim KB, Cho KR, Sohn DW, et al. The Cox-Maze III procedure for atrial fibrillation associated with rheumatic mitral valve disease. Ann Thorac Surg 1999; 68:799. 51. Handa N, Schaff HV, Morris JJ, et al. Outcome of valve repair and the Cox maze procedure for mitral regurgitation and associated atrial fibrillation. J Thorac Cardiovasc Surg 1999; 118:628. 52. Fujita T, Kobayashi J, Toda K, et al. Long-term outcome of combined valve repair and maze procedure for nonrheumatic mitral regurgitation. J Thorac Cardiovasc Surg 2010; 140:1332. 53. Deneke T, Khargi K, Grewe PH, et al. Left atrial versus bi-atrial Maze operation using intraoperatively cooled-tip radiofrequency ablation in patients undergoing open-heart surgery: safety and efficacy. J Am Coll Cardiol 2002; 39:1644. 54. Sie HT, Beukema WP, Elvan A, Ramdat Misier AR. Long-term results of irrigated radiofrequency modified maze procedure in 200 patients with concomitant cardiac surgery: six years experience. Ann Thorac Surg 2004; 77:512. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 17/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate 55. Gaita F, Riccardi R, Caponi D, et al. Linear cryoablation of the left atrium versus pulmonary vein cryoisolation in patients with permanent atrial fibrillation and valvular heart disease: correlation of electroanatomic mapping and long-term clinical results. Circulation 2005; 111:136. 56. Deneke T, Khargi K, Grewe PH, et al. Efficacy of an additional MAZE procedure using cooled- tip radiofrequency ablation in patients with chronic atrial fibrillation and mitral valve disease. A randomized, prospective trial. Eur Heart J 2002; 23:558. 57. Khiabani AJ, MacGregor RM, Bakir NH, et al. The long-term outcomes and durability of the Cox-Maze IV procedure for atrial fibrillation. J Thorac Cardiovasc Surg 2022; 163:629. 58. McElderry HT, McGiffin DC, Plumb VJ, et al. Proarrhythmic aspects of atrial fibrillation surgery: mechanisms of postoperative macroreentrant tachycardias. Circulation 2008; 117:155. 59. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 60. McCarthy PM, Gillinov AM, Castle L, et al. The Cox-Maze procedure: the Cleveland Clinic experience. Semin Thorac Cardiovasc Surg 2000; 12:25. 61. Lapenna E, De Bonis M, Giambuzzi I, et al. Long-term Outcomes of Stand-Alone Maze IV for Persistent or Long-standing Persistent Atrial Fibrillation. Ann Thorac Surg 2020; 109:124. 62. Alb ge A, Jid us L, St hle E, et al. Early and long-term mortality in 536 patients after theCox- maze III procedure: a national registry-based study. Ann Thorac Surg 2013; 95:1626. 63. Alb ge A, Sartipy U, Kenneb ck G, et al. Long-Term Risk of Ischemic Stroke After the Cox- Maze III Procedure for Atrial Fibrillation. Ann Thorac Surg 2017; 104:523. 64. Ad N, Henry L, Shuman DJ, Holmes SD. A more specific anticoagulation regimen is required for patients after the cox-maze procedure. Ann Thorac Surg 2014; 98:1331. 65. Badhwar V, Rankin JS, Damiano RJ Jr, et al. The Society of Thoracic Surgeons 2017 Clinical Practice Guidelines for the Surgical Treatment of Atrial Fibrillation. Ann Thorac Surg 2017; 103:329. 66. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:e275. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 18/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate Topic 1046 Version 36.0 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 19/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate GRAPHICS MAZE III procedure Modification of the posterior incisions to the vena cava and placement of the septal incision posterior to the orifice of the superior vena cava (SVC) are noted. CS: coronary sinus; FO: foramen ovale; IVC: inferior vena cava; LAA: left atrial appendage; MV: mitral valve; RAA: right atrial appendage; SAN: sinoatrial node; TV: tricuspid valve. Reproduced from: Cheng A, Shah A, Hogue CW. Cardiac electrophysiology: Diagnosis and treatment. In: Kaplan's Cardiac Anesthesia, 6th ed, Kaplan JA, Reich DL, Lake CL, Konstadt SN (Eds), Saunders, Philadelphia 2011. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 58985 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 20/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate Schema of the maze procedure and the radial approach for atrial fibrillation The large outer circle denotes the atria and its outer limit is bounded by the atrioventricular annular margins. The small circle indicates the sinoatrial node (SAN), the shaded area indicates the isolated portion of the atrium, and the atrial coronary arteries, arising at the atrioventricular groove, are also schematically drawn. Arrows indicate the activation wavefront from the sinoatrial node, radiating toward the annular margins. The radial approach (right panel) preserves a more physiologic activation sequence and the blood supply to most atrial segments, whereas the atrial incisions of the maze procedure (left panel) desynchronize the activation sequence, and some of the incisions cross the atrial coronary arteries. Reprinted with permission from the Society of Thoracic Surgeons. Netta T, Cox R, Schuessler RB, et al. Ann Thorac Surg 1999; 67:27. http://www.elsevier.com/locate/jacc http://www.sciencedirect.com Graphic 69962 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 21/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate Schematic representation of atrial activation in sinus rhythm and after the maze procedure or the radial approach The normal activation sequence of the left atrium is maintained with the radial approach while it is altered with the Maze procedure. Thick lines represent the surgical incisions and the solid areas represent parts of the atria surgically isolated or excised; dashed lines represent normal conduction pathways between the atrial appendages, the interatrial septum, and the crista terminalis. Arrows indicate the activation sequence. AVN: atrioventricular node; SAN: sinoatrial node; RAA: right atrial appendage; LAA: left atrial appendage; SVC: superior vena cava; IVC: inferior vena cava; PVs: pulmonary veins. Reprinted with permission from the Society of Thoracic Surgeons. Netta T, Cox R, Schuessler RB, et al. Ann Thorac Surg 1999; 67:27. Graphic 50845 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 22/23 7/6/23, 2:50 PM Atrial fibrillation: Surgical ablation - UpToDate Contributor Disclosures Richard Lee, MD, MBA No relevant financial relationship(s) with ineligible companies to disclose. Gabriel S Aldea, MD No relevant financial relationship(s) with ineligible companies to disclose. Edward Verrier, MD No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 23/23

7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial flutter: Maintenance of sinus rhythm : Jordan M Prutkin, MD, MHS, FHRS : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 30, 2023. INTRODUCTION Atrial flutter is a relatively common supraventricular arrhythmia that can impact quality of life and cause stroke or systemic embolization. Restoration and maintenance of sinus rhythm improves symptoms and decreases the risk of embolization if atrial flutter recurrence does not occur. (See "Overview of atrial flutter", section on 'Clinical manifestations' and "Embolic risk and the role of anticoagulation in atrial flutter", section on 'Embolic risk'.) Issues related to the indications and therapeutic options for the maintenance of sinus rhythm in atrial flutter will be reviewed here. Causes of atrial flutter, rate control therapy, the restoration of sinus rhythm after cardioversion, and the role of anticoagulation in atrial flutter are discussed separately. (See "Overview of atrial flutter", section on 'Etiology and risk factors' and "Restoration of sinus rhythm in atrial flutter" and "Embolic risk and the role of anticoagulation in atrial flutter" and "Control of ventricular rate in atrial flutter".) INDICATIONS We attempt to keep most patients with recurrent atrial flutter in sinus rhythm to decrease symptoms, unlike atrial fibrillation (AF) in which rhythm control and rate control are reasonable strategies. In addition, the long-term maintenance of sinus rhythm may decrease the risk of stroke. Rhythm control with either radiofrequency (RF) catheter ablation or antiarrhythmic drug therapy is necessary; in most cases, RF catheter ablation is preferred because of the high rate of success and low rate of complications. Exceptions include individuals identified as having https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 1/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate reversible triggers such as pneumonia, hyperthyroidism, and other acute medical problems. (See "Management of atrial fibrillation: Rhythm control versus rate control".). Atrial flutter is characterized by rapid, regular atrial depolarizations at a characteristic rate of approximately 300 beats/min. In the absence of rate slowing drugs or atrioventricular (AV) nodal disease, every other depolarization passes through the AV node, and the ventricular rate is usually around 150 beats per minute. Unlike AF, attempts to slow this rate are often unsuccessful or require high doses of rate slowing drugs; thus, the maintenance of sinus rhythm is desirable in most patients to control symptoms. In addition, episodes will often be recurrent unless a reversible cause is present. (See "ECG tutorial: Atrial and atrioventricular nodal (supraventricular) arrhythmias", section on 'Atrial fibrillation and atrial flutter' and "Overview of atrial flutter".) The discussion in this topic pertains primarily to patients with typical atrial flutter. The pathogenesis of typical atrial flutter makes it highly amendable to curative therapy with radiofrequency (RF) catheter ablation, though atypical flutters may also be cured with RF ablation. Typical (also called isthmus-dependent) atrial flutter utilizes a large macroreentrant pathway in the right atrium, with the left atrium following passively. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) The negative deflection of the flutter (F) wave in lead II coincides in time with the impulse activating the low right atrial tissue between the inferior vena cava and the tricuspid valve. Activation then travels anteriorly through the region of the low septum, and superiorly and anteriorly up the medial surface of the right atrium, returning along the lateral wall of the right atrium back to the cavotricuspid isthmus (CTI) [1-6]. The cavotricuspid isthmus between the inferior vena cava and the tricuspid annulus (IVC-TA isthmus) is an obligatory route for typical flutter, and, as such, is the best anatomic target for ablation ( waveform 1A-B) [2-5,7-15]. RF CATHETER ABLATION For patients with typical atrial flutter in whom a decision is made to maintain sinus rhythm, radiofrequency catheter ablation is usually preferred to pharmacologic therapy. Technique The femoral approach is generally used and, under fluoroscopic guidance or using a three-dimensional mapping system, an ablation catheter is placed at the CTI where a large ventricular and small atrial electrogram are recorded. RF energy is applied, and the catheter is slowly withdrawn to create a line of ablation from the annulus to the inferior vena cava. https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 2/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate The goal is to create a complete ablation line with the absence of electrical conduction across the CTI both medially to laterally and laterally to medially. This is the best marker for long-term success ( waveform 1A-B). If the patient presents in typical atrial flutter, CTI block should still be assessed with differential pacing on both sides of the ablation line after termination of atrial flutter, since frequently there can still be conduction across the CTI [16,17]. An infusion of isoproterenol during pacing may help to assess the completeness of isthmus block [18]. Alternatively, adenosine may also be given to assess for block across the line [19]. Another method for ablation is the maximum voltage technique [20]. Coronary sinus (CS) ostial pacing is completed and the largest amplitude atrial signal in the CTI is ablated as a point lesion. The next largest signal is then targeted, and the process is repeated until block is seen across the isthmus. Electroanatomic mapping is used in many cases for identifying the appropriate target area for ablation; it is a nonfluoroscopic three-dimensional mapping system. This system permits reconstruction of cardiac anatomy without the use of fluoroscopy. A study of 50 patients with atrial flutter compared isthmus ablation using conventional fluoroscopy for catheter positioning to positioning with electromagnetic mapping [21]. The success rate for complete isthmus blockade after 20 RF pulses or 25 minutes of fluoroscopy time was greater with electromagnetic mapping (96 versus 67 percent). Electromagnetic mapping significantly reduced the overall fluoroscopic time (4 versus 22 minutes) and the fluoroscopic time needed for isthmus mapping (0.2 versus 17.7 minutes). Ablation guided by intracardiac echocardiography (ICE) can also be used, and may be helpful to assess for pouches and ridges in the CTI during difficult cases or repeat procedures [10]. Outcome The initial success rate for RF catheter ablation of typical atrial flutter has ranged from 65 to 100 percent [22,23]. A meta-analysis of a 21 studies examining atrial flutter success rate suggested a single procedure success of 92 percent and multiple procedure success rate of 97 percent [24]. Recurrent atrial flutter or fibrillation Between 7 and 44 percent of patients who undergo flutter ablation have recurrent atrial arrhythmia, though the recurrent arrhythmia is usually AF [22,23]. Thus, some patients should undergo surveillance for recurrent atrial flutter or AF. Our approach to surveillance for recurrent arrhythmia is as follows. For patients who were initially symptomatic and who did not develop a tachycardia mediated cardiomyopathy, we perform testing to document recurrent arrhythmia only for symptoms. If the patient was initially asymptomatic, we perform periodic examinations (every 12 months) at which time we obtain an electrocardiogram, Holter, or event monitor. For those patients who developed tachycardia- https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 3/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate mediated cardiomyopathy, standard heart failure therapy is still indicated unless otherwise contraindicated. Follow-up assessment of left ventricular function by imaging techniques such as echocardiography is warranted. We obtain a repeat echocardiogram three to six months after initiation of therapy. The rate of recurrent AF appears to depend upon the presence or absence of AF before the procedure. In a study of 100 patients, 29 of whom had documented AF before the procedure, AF occurred in 36.4 percent of those with complete follow-up after a mean of almost 15 months [25]. However, in another study of approximately 100 patients without pre-existent AF, new onset AF developed in only 12.9 percent during a mean follow-up of 19 months [26]. Most patients (92 percent) who develop AF after flutter ablation do so within six months. The risk may be as low as 10 percent (mean follow-up of 20 months) in those with no prior AF and a left ventricular ejection fraction >50 percent [27]. The likely reasons for the difference in the rates of recurrence likely has to do with differing populations being studied (eg, symptomatic versus asymptomatic patients) and the intensity of follow-up. In a study of 363 patients who underwent RF ablation for typical atrial flutter, 82 percent developed drug refractory AF during a follow-up period of 39 (+/- 11) months [28]. Elimination of atrial flutter may delay, but does not prevent AF and the two may share common triggers. Therefore, patients may derive a better long-term benefit from additional anatomical ablative treatment, lifestyle modifications, and/or pharmacological therapy of AF. (See 'Patients with atrial fibrillation' below.) Improvement in left ventricular function Persistent atrial flutter can result in a tachycardia-mediated left ventricular cardiomyopathy, similar to what has been seen with AF and other arrhythmias. On the other hand, reversal of the arrhythmia can result in improvement in left ventricular ejection fraction and, in 6 of 11 patients in one report, restoration of normal function [29]. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm" and "Arrhythmia-induced cardiomyopathy", section on 'Atrial fibrillation and atrial flutter'.) Quality of life RF ablation improves the quality of life and reduces symptoms in patients with atrial flutter, particularly if there is no associated AF [23,30]. Other benefits include a reduced frequency of hospitalizations, emergency department visits, need for cardioversion, and the need for antiarrhythmic drugs [31]. Safety RF catheter ablation of atrial flutter is significantly safer than that for atrial fibrillation, in part because the left atrium is not entered and because the procedure is generally shorter due to the fact that ablation in a very limited area that is not adjacent to vulnerable structures https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 4/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate such as the esophagus and pulmonary veins [32]. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) Pericardial effusion, atrioventricular block, and vascular access complications occur infrequently [33]. Procedure-related mortality is very rare and was 0 percent in a meta-analysis of 12 studies [24]. RF ablation versus pharmacologic therapy With the high success rate of radiofrequency (RF) catheter ablation for treating atrial flutter and its low complication rate, pharmacologic therapy is increasingly being replaced by ablation as the preferred strategy in most patients. Improved outcomes with ablation, compared to drug therapy, were illustrated in a randomized trial of 61 patients with at least two episodes of symptomatic atrial flutter within a four-month period [34]. The patients were assigned to conventional antiarrhythmic drug therapy or catheter ablation as a first line treatment. After a mean follow-up of 21 months, the following significant benefits were noted in the patients undergoing ablation: More were in sinus rhythm (80 versus 36 percent with drugs; P<0.01). Fewer required rehospitalization (22 versus 63 percent). Fewer developed AF (29 versus 53 percent). Sense of well-being and function during daily life activities improved with ablation but did not change with drugs. PHARMACOLOGIC THERAPY For most patients with atrial flutter, pharmacologic therapy is not chosen for the long-term maintenance of sinus rhythm. The success rate at one year has been estimated at only 20 to 30 percent, with the risk of recurrence highest in the patient with an enlarged right atrium who is in heart failure. Good prognostic signs for maintaining sinus rhythm are normal atrial size, recent onset, little or no heart failure, and an underlying reversible disorder such as hyperthyroidism, myocardial infarction, or pulmonary embolism. For patients in whom an attempt will be made to maintain sinus rhythm with antiarrhythmic drug therapy, we use the following drugs (with suggested starting doses): dronedarone 400 mg twice daily; flecainide 50 to 100 mg twice daily with an atrioventricular nodal agent; sotalol 80 mg twice daily; dofetilide 500 microgram twice daily; or amiodarone. Our reviewers have differing preferences as to the order in which these are tried. The drugs that are most likely to maintain sinus rhythm are the same as those used for rhythm control in atrial fibrillation (AF) ( algorithm 1). They act by suppressing triggering beats and https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 5/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate arrhythmias and affecting atrial electrophysiologic properties. In a meta-analysis that included 36 patients, flecainide was 50 percent effective in the maintenance of sinus rhythm over variable follow-up [35]. Flecainide can also slow down the atrial flutter rate; thus, atrioventricular (AV) nodal agents should always be used in conjunction to prevent one-to-one atrial flutter. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Selecting an antiarrhythmic drug'.) Oral dofetilide, a class III antiarrhythmic drug available for use in the United States, may be more effective than other agents for maintaining sinus rhythm. In the SAFIRE-D trial, which included 48 patients with atrial flutter, the probability of maintaining sinus rhythm at one year with dofetilide at a dose of 125, 250, or 500 mcg twice daily was 0.40, 0.37, and 0.58 versus 0.25 for placebo [36]. Dronedarone has been studied for the use of atrial flutter, though the major studies all included patients with AF also. In a trial of 2327 patients with AF or atrial flutter who were randomly assigned to either dronedarone 400 mg twice daily or placebo, dronedarone reduced the chances of recurrent AF or flutter by 25 percent and prolonged the time to first recurrence from 498 to 737 days [37]. In those with atrial flutter who had a recurrence, the mean heart rate was reduced by six beats/min, reflecting its rate control properties also. PATIENTS WITH ATRIAL FIBRILLATION Many patients with atrial flutter also have episodes of atrial fibrillation (AF). For many of these patients who have chosen ablation, we recommend atrial fibrillation (with or without atrial flutter ablation) ablation rather than atrial flutter ablation alone. The electrophysiologic substrates of AF and atrial flutter are different, and the addition of atrial flutter ablation to AF ablation adds very little risk. However, in some cases, we believe it is reasonable to perform atrial flutter ablation alone, particularly if atrial flutter is the predominant rhythm and if the rate in flutter is difficult and causing most symptoms. (See "Atrial fibrillation: Catheter ablation".) The optimal approach to ablation in patients with both atrial flutter and atrial fibrillation was evaluated in the single-blind APPROVAL trial, which randomly assigned 360 patients to ablation of AF (with or without atrial flutter ablation) or ablation of flutter alone [38]. Among patients in the first group, 124 received AF ablation only and 58 had both ablation procedures. At nearly 22 months of follow-up, patients assigned to the group that received AF ablation (with or without atrial flutter ablation) had a higher rate of primary end point of freedom from arrhythmia off antiarrhythmic drug therapy during follow-up (64 versus 19 percent). This outcome was similar for the two subpopulations in the first group (AF ablation with or without atrial flutter ablation). https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 6/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate Patients in group one had significant improvement in scores on most quality-of-life measures, whereas those in group two did not. The finding in APPROVAL of similar outcomes between patients who received both AF and atrial flutter ablation and those who received AF ablation alone was noted in an earlier study of 108 patients with both AF and typical atrial flutter who were randomly assigned to either a dual ablative procedure (pulmonary vein isolation [PVI] and CTI ablation, 49 patients) or PVI alone (59 patients) [39]. These findings suggest that pulmonary vein triggers appear to initiate atrial flutter as well as AF. This conclusion is consistent with evidence that atrial flutter commonly starts after a transitional rhythm of variable duration, usually AF [40,41]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) ANTICOAGULATION The discussion of anticoagulation below focuses on patients who undergo radiofrequency (RF) catheter ablation. However, similar issues apply to patients with atrial flutter (and atrial fibrillation) in whom antiarrhythmic drug therapy is to be started. Any therapy that causes conversion of atrial flutter (or fibrillation) to sinus rhythm leads to a measurable increase in the short-term risk of embolization unless proper anticoagulation is in place. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Anticoagulation before RF catheter ablation For patients in atrial flutter scheduled to under RF ablation, anticoagulation is handled, broadly speaking, in a manner similar to that for patients with atrial fibrillation who undergo cardioversion. Most of these patients require at least three to four weeks of adequate anticoagulation before the procedure. (See "Restoration of sinus rhythm in atrial flutter", section on 'Anticoagulation' and "Embolic risk and the role of anticoagulation in atrial flutter", section on 'Radiofrequency catheter ablation'.) For those patients with atrial flutter of less than 48 hours duration, there is disagreement whether a transesophageal echocardiogram (TEE) is necessary to exclude the presence of a left atrial thrombus, as there is not good quality evidence available. If a TEE is performed and no thrombus is found, RF catheter ablation may be performed without prior anticoagulation. For low-risk patients with atrial flutter of less than 48 hours, it may be reasonable to proceed with ablation without a TEE. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours'.) https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 7/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate If the patient is not in atrial flutter at the time of the ablation, therapeutic anticoagulation is not necessary and a TEE is not usually performed. Anticoagulation after RF catheter ablation Anticoagulation for the prevention of embolic events may be necessary, at least on a temporary basis, after flutter ablation due to the potential for the development of recurrent atrial flutter or AF within six months. However, there are limited data to support this approach [42]. We use the following approach: We recommend oral anticoagulation for all patients for at least four weeks after atrial flutter ablation if they were in atrial flutter at the start of the ablation. For patients with evidence of recurrent atrial flutter after atrial flutter ablation, with atrial fibrillation before or after the flutter ablation, or for those patients in sinus rhythm at the time of the ablation, we use the CHA2DS2-VASc score to determine the long-term need for anticoagulation. This may include using no anticoagulation in those at low risk. This issue is discussed in detail elsewhere. (See "Atrial fibrillation: Catheter ablation", section on 'Periprocedural embolic events'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS Indications We attempt to maintain sinus rhythm in most patients with recurrent atrial flutter to decrease symptoms and prevent complications. Unlike atrial fibrillation, the alternative strategy of rate control is usually unsuccessful. (See 'Indications' above.) Radio frequency ablation For most patients with typical atrial flutter in whom a rhythm control strategy is desired, we recommend radiofrequency catheter ablation rather than a pharmacologic approach (Grade 1B). (See 'RF catheter ablation' above and 'RF ablation versus pharmacologic therapy' above.) For patients with both atrial flutter and fibrillation, we recommend radiofrequency catheter ablation of the atrial fibrillation and flutter rather than ablation of atrial flutter alone (Grade 1B). (See 'Patients with atrial fibrillation' above.) https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 8/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate For those patients in whom atrial flutter is the predominant rhythm, atrial flutter ablation alone is a reasonable strategy. Importance of anticoagulation Anticoagulation around the time of radiofrequency catheter ablation or pharmacologic cardioversion is handled in a manner similar to that for patients with atrial flutter or fibrillation scheduled to undergo cardioversion. Most patients will require effective anticoagulation both before and after the procedure. (See 'Anticoagulation' above.) ACKNOWLEDGMENT The UpToDate editorial staff thank Dr. Jie Cheng, who contributed as an author to prior versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wells JL Jr, MacLean WA, James TN, Waldo AL. Characterization of atrial flutter. Studies in man after open heart surgery using fixed atrial electrodes. Circulation 1979; 60:665. 2. Klein GJ, Guiraudon GM, Sharma AD, Milstein S. Demonstration of macroreentry and feasibility of operative therapy in the common type of atrial flutter. Am J Cardiol 1986; 57:587. 3. Cosio FG, Arribas F, Barbero JM, et al. Validation of double-spike electrograms as markers of conduction delay or block in atrial flutter. Am J Cardiol 1988; 61:775. 4. Cosio FG, L pez-Gil M, Goicolea A, Arribas F. Electrophysiologic studies in atrial flutter. Clin Cardiol 1992; 15:667. 5. Olshansky B, Okumura K, Hess PG, Waldo AL. Demonstration of an area of slow conduction in human atrial flutter. J Am Coll Cardiol 1990; 16:1639. 6. Dixit S, Lavi N, Robinson M, et al. Noncontact electroanatomic mapping to characterize typical atrial flutter: participation of right atrial posterior wall in the reentrant circuit. J Cardiovasc Electrophysiol 2011; 22:422. 7. Touboul P, Saoudi N, Atallah G, Kirkorian G. Electrophysiologic basis of catheter ablation in atrial flutter. Am J Cardiol 1989; 64:79J. 8. Feld GK, Fleck RP, Chen PS, et al. Radiofrequency catheter ablation for the treatment of human type 1 atrial flutter. Identification of a critical zone in the reentrant circuit by https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 9/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate endocardial mapping techniques. Circulation 1992; 86:1233. 9. Kirkorian G, Moncada E, Chevalier P, et al. Radiofrequency ablation of atrial flutter. Efficacy of an anatomically guided approach. Circulation 1994; 90:2804. 10. Olgin JE, Kalman JM, Fitzpatrick AP, Lesh MD. Role of right atrial endocardial structures as barriers to conduction during human type I atrial flutter. Activation and entrainment mapping guided by intracardiac echocardiography. Circulation 1995; 92:1839. 11. Poty H, Saoudi N, Abdel Aziz A, et al. Radiofrequency catheter ablation of type 1 atrial flutter. Prediction of late success by electrophysiological criteria. Circulation 1995; 92:1389. 12. Cauchemez B, Haissaguerre M, Fischer B, et al. Electrophysiological effects of catheter ablation of inferior vena cava-tricuspid annulus isthmus in common atrial flutter. Circulation 1996; 93:284. 13. Nath S, Mounsey JP, Haines DE, DiMarco JP. Predictors of acute and long-term success after radiofrequency catheter ablation of type 1 atrial flutter. Am J Cardiol 1995; 76:604. 14. Steinberg JS, Prasher S, Zelenkofske S, Ehlert FA. Radiofrequency catheter ablation of atrial flutter: procedural success and long-term outcome. Am Heart J 1995; 130:85. 15. Fischer B, Haissaguerre M, Garrigues S, et al. Radiofrequency catheter ablation of common atrial flutter in 80 patients. J Am Coll Cardiol 1995; 25:1365. 16. Poty H, Saoudi N, Nair M, et al. Radiofrequency catheter ablation of atrial flutter. Further insights into the various types of isthmus block: application to ablation during sinus rhythm. Circulation 1996; 94:3204. 17. Schwartzman D, Callans DJ, Gottlieb CD, et al. Conduction block in the inferior vena caval- tricuspid valve isthmus: association with outcome of radiofrequency ablation of type I atrial flutter. J Am Coll Cardiol 1996; 28:1519. 18. Nabar A, Rodriguez LM, Timmermans C, et al. Isoproterenol to evaluate resumption of conduction after right atrial isthmus ablation in type I atrial flutter. Circulation 1999; 99:3286. 19. Lehrmann H, Weber R, Park CI, et al. "Dormant transisthmus conduction" revealed by adenosine after cavotricuspid isthmus ablation. Heart Rhythm 2012; 9:1942. 20. Jacobsen PK, Klein GJ, Gula LJ, et al. Voltage-guided ablation technique for cavotricuspid isthmus-dependent atrial flutter: refining the continuous line. J Cardiovasc Electrophysiol 2012; 23:672. 21. Kottkamp H, H gl B, Krauss B, et al. Electromagnetic versus fluoroscopic mapping of the inferior isthmus for ablation of typical atrial flutter: A prospective randomized study. Circulation 2000; 102:2082. https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 10/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate 22. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 2000; 23:1020. 23. Calkins H, Canby R, Weiss R, et al. Results of catheter ablation of typical atrial flutter. Am J Cardiol 2004; 94:437. 24. Spector P, Reynolds MR, Calkins H, et al. Meta-analysis of ablation of atrial flutter and supraventricular tachycardia. Am J Cardiol 2009; 104:671. 25. Anselme F, Saoudi N, Poty H, et al. Radiofrequency catheter ablation of common atrial flutter: significance of palpitations and quality-of-life evaluation in patients with proven isthmus block. Circulation 1999; 99:534. 26. Ng DW, Altemose GT, Wu Q, et al. Typical atrial flutter as a risk factor for the development of atrial fibrillation in patients without otherwise demonstrable atrial tachyarrhythmias. Mayo Clin Proc 2008; 83:646. 27. Paydak H, Kall JG, Burke MC, et al. Atrial fibrillation after radiofrequency ablation of type I atrial flutter: time to onset, determinants, and clinical course. Circulation 1998; 98:315. 28. Ellis K, Wazni O, Marrouche N, et al. Incidence of atrial fibrillation post-cavotricuspid isthmus ablation in patients with typical atrial flutter: left-atrial size as an independent predictor of atrial fibrillation recurrence. J Cardiovasc Electrophysiol 2007; 18:799. 29. Luchsinger JA, Steinberg JS. Resolution of cardiomyopathy after ablation of atrial flutter. J Am Coll Cardiol 1998; 32:205. 30. Lee SH, Tai CT, Yu WC, et al. Effects of radiofrequency catheter ablation on quality of life in patients with atrial flutter. Am J Cardiol 1999; 84:278. 31. O'Callaghan PA, Meara M, Kongsgaard E, et al. Symptomatic improvement after radiofrequency catheter ablation for typical atrial flutter. Heart 2001; 86:167. 32. Bohnen M, Stevenson WG, Tedrow UB, et al. Incidence and predictors of major complications from contemporary catheter ablation to treat cardiac arrhythmias. Heart Rhythm 2011; 8:1661. 33. P rez FJ, Schubert CM, Parvez B, et al. Long-term outcomes after catheter ablation of cavo- tricuspid isthmus dependent atrial flutter: a meta-analysis. Circ Arrhythm Electrophysiol 2009; 2:393. 34. Natale A, Newby KH, Pisan E, et al. Prospective randomized comparison of antiarrhythmic therapy versus first-line radiofrequency ablation in patients with atrial flutter. J Am Coll Cardiol 2000; 35:1898. 35. Hohnloser SH, Zabel M. Short- and long-term efficacy and safety of flecainide acetate for supraventricular arrhythmias. Am J Cardiol 1992; 70:3A. https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 11/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate 36. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000; 102:2385. 37. Page RL, Connolly SJ, Crijns HJ, et al. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). Am J Cardiol 2011; 107:1019. 38. Mohanty S, Mohanty P, Di Biase L, et al. Results from a single-blind, randomized study comparing the impact of different ablation approaches on long-term procedure outcome in coexistent atrial fibrillation and flutter (APPROVAL). Circulation 2013; 127:1853. 39. Wazni O, Marrouche NF, Martin DO, et al. Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein-left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation. Circulation 2003; 108:2479. 40. Waldo AL, Cooper TB. Spontaneous onset of type I atrial flutter in patients. J Am Coll Cardiol 1996; 28:707. 41. Waldo AL. Mechanisms of atrial flutter and atrial fibrillation: distinct entities or two sides of a coin? Cardiovasc Res 2002; 54:217. 42. Nunes-Ferreira A, Alves M, Lima da Silva G, et al. Anticoagulation after typical atrial flutter ablation: Systematic review and meta-analysis. Pacing Clin Electrophysiol 2021; 44:1701. Topic 1065 Version 27.0 https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 12/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate GRAPHICS Intracardiac and surface ECG recordings during electrophysiologic study and radiofrequency catheter ablation of typical atrial flutter Three surface ECG leads (I, aVF, V1) and intracardiac recordings from the high right atrium (HRA), a mapping catheter in the isthmus between the tricuspid valve and inferior vena cava (TV-IVC) (HBE1-2), eight recordings from a catheter extending from the lateral right atrial wall through the TV-IVC isthmus and into the ostium of the coronary sinus (CS15-1 to CS1-2), and right ventricular apex (RVA3-4) in a patient with typical atrial flutter. The tip of the mapping catheter was initially positioned on the tricuspid annulus, and then dragged through the TV-IVC isthmus to the ostium of the IVC during RF application; atrial flutter terminated. Note that the atrial activation (A) blocks between CS7-8 and CS5-6, which on fluoroscopy corresponded to the position of the mapping catheter. Fl: flutter waves; V: ventricular electrogram. Graphic 69946 Version 4.0 https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 13/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate Intracardiac and surface electrocardiogram (ECG) recordings during electrophysiologic study and radiofrequency catheter ablation of atrial flutter showing bidirectional isthmus block Shown are three surface ECG leads (I, aVF, V1) and intracardiac recordings from the high right atrium (HRA), eight recordings from a catheter extending from the lateral right atrial wall through the tricuspid valve-inferior vena cava (TV- IVC) isthmus and into the ostium of the coronary sinus (CS15-16 through CS1- 2), and right ventricular apex (RVA3-4) in a patient who has undergone ablation for atrial flutter. Left panel shows pacing (PA) from the lateral right atrial wall; the impulse is propagated down the lateral wall of the high right atrium, generating an atrial electrogram (A), to the lateral TV-IVC isthmus region (CS13- 14, CS11-12, CS9-10) where conduction is blocked. The medial aspect of the isthmus is not depolarized until a wavefront of activation comes down the interatrial septum or from the low left atrium; the distal poles of the catheter are therefore depolarized late and in the opposite direction, from the coronary sinus ostium back towards the medial TV-IVC isthmus (CS3-4, CS5-6, CS7-8). Right panel shows pacing from the coronary sinus ostium. In this case, the medial isthmus is depolarized promptly (CS3-4, CS5-6), but conduction is blocked within the isthmus (CS7-8). Thus, activation of the lateral wall of the right atrium is delayed until a wavefront travels up the septum and across the roof of the right atrium. Activation of the proximal poles of the catheter is therefore delayed and occurs from high to low (CS15-16, CS13-14, CS11-12, https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 14/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate CS9-10). Patients with bidirectional block across the TC-IVC isthmus have a low rate of atrial flutter recurrence. Graphic 60090 Version 4.0 https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 15/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate Maintenance of sinus rhythm Therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation. Drugs are listed alphabetically and not in order of suggested use. The seriousness of heart disease progresses from left to right, and selection of therapy in patients with multiple conditions depends on the most serious condition present. LVH: left ventricular hypertrophy. Reproduced from: Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial brillation: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2011; 57:223. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 83173 Version 2.0 https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 16/17 7/6/23, 2:49 PM Atrial flutter: Maintenance of sinus rhythm - UpToDate Contributor Disclosures Jordan M Prutkin, MD, MHS, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-flutter-maintenance-of-sinus-rhythm/print 17/17

7/6/23, 2:48 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Basic principles and technique of external electrical cardioversion and defibrillation : Bradley P Knight, MD, FACC : Richard L Page, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 23, 2023. INTRODUCTION Electrical cardioversion and defibrillation have become routine procedures in the management of patients with cardiac arrhythmias. Cardioversion is the delivery of energy that is synchronized to the QRS complex, while defibrillation is the nonsynchronized delivery of a shock randomly during the cardiac cycle. In 1956, alternating current (AC) for transthoracic defibrillation was first used to treat ventricular fibrillation in humans [1]. Following this breakthrough, in 1962 direct current (DC) defibrillators were introduced into clinical practice [2]. Subsequent studies in the early 1960s demonstrated that electrical countershock or cardioversion across the closed chest could abolish other cardiac arrhythmias in addition to ventricular fibrillation [3-5]. This topic will review the basic principles and technique of electrical cardioversion and defibrillation. The clinical indications for these procedures, procedural sedation, potential side effects, and the use of the automated external defibrillator (AED) are discussed separately. (See "Cardioversion for specific arrhythmias" and "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications" and "Procedural sedation in children: Approach" and "Automated external defibrillators".) BACKGROUND INFORMATION ON DEFIBRILLATORS Most defibrillators are energy-based, meaning that the devices charge a capacitor to a selected voltage and then deliver a prespecified amount of energy in joules. The amount of energy that https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 1/25 7/6/23, 2:48 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate arrives at the myocardium is dependent upon the selected voltage and the transthoracic impedance (which varies by patient). Two other types of defibrillators are used less frequently in clinical practice: Impedance-based defibrillators allow selection of transthoracic current based upon the transthoracic impedance; the latter is assessed initially with a test pulse with the capacitor subsequently charged to the appropriate voltage [6]. Current-based defibrillation, in which a fixed dose of current is delivered, results in defibrillation thresholds that are independent of transthoracic impedance and are invariant for the individual [7,8]. Defibrillation success for a current-based method is independent of both transthoracic impedance and body weight [9]. Furthermore, this method achieves defibrillation with considerably less energy than does the conventional energy-based method. Defibrillators can also deliver energy in a variety of waveforms, broadly characterized as monophasic or biphasic ( figure 1). Initially defibrillators delivered only monophasic waveforms. Although monophasic defibrillation is highly effective, biphasic defibrillation terminates arrhythmias more consistently and at lower energy levels. Biphasic defibrillators have largely replaced monophasic defibrillators. (See 'Monophasic versus biphasic waveforms' below.) ELECTROPHYSIOLOGY OF DEFIBRILLATION AND CARDIOVERSION Cardioversion terminates arrhythmias by delivering a synchronized shock that depolarizes the tissue involved in a reentrant circuit ( figure 2 and figure 3). By depolarizing all excitable tissue of the circuit and making the tissue refractory, the circuit is no longer able to propagate or sustain reentry. As a result, cardioversion terminates those arrhythmias resulting from a single reentrant circuit, such as atrial flutter, atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, or monomorphic ventricular tachycardia. (See "Reentry and the development of cardiac arrhythmias".) Despite its widespread clinical use, controversy remains concerning the electrophysiologic mechanisms by which electrical cardioversion or defibrillation terminates atrial or ventricular fibrillation, arrhythmias which involve multiple microreentrant circuits. Fibrillation involves the entire atrial or ventricular myocardium and is considered to be a very persistent rhythm. (See "The electrocardiogram in atrial fibrillation" and "Pathophysiology and etiology of sudden cardiac arrest", section on 'Mechanism of ventricular fibrillation'.) https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 2/25 7/6/23, 2:48 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Most investigators agree that defibrillation occurs when a certain amount of current density reaches the myocardium. However, it is unclear what amount of current density is needed and what energy setting is necessary to achieve a homogeneous current density. At the cellular level, the delivered current flows around and through the myocardial cells, resulting in alteration of the transmembrane potentials [10]. At the organ level, the mechanisms responsible for termination of fibrillation are still controversial [11]. Two explanations have been proposed, which are not necessarily mutually exclusive: the critical mass hypothesis and the upper limit of vulnerability. Critical mass hypothesis There is general agreement that total elimination of fibrillatory activity can be achieved with relatively high defibrillation energy levels [12,13]. According to the critical mass hypothesis, a certain amount of myocardium must be available to sustain atrial or ventricular fibrillation and the entire myocardium must be uniformly depolarized in order to terminate the arrhythmia [14]. Electrophysiological evidence to support this theory has been obtained using a computerized mapping system that recorded simultaneous electrograms from 120 sites [12]. Defibrillation was successful only when fibrillatory activity was annihilated at all sites. Upper limit of vulnerability hypothesis According to the upper limit of vulnerability hypothesis, low-energy shocks can induce fibrillation up to a limit where further increases in energy do not induce fibrillation, and the largest shocks that do not induce fibrillation are slightly weaker than necessary for defibrillation [15]. Although shocks abolish small areas of localized reentry during ventricular fibrillation, shocks at strengths below the upper limit of vulnerability stimulate other regions of myocardium during their vulnerable period, giving rise to new areas of local reentry that reinitiate ventricular fibrillation [16-18]. To successfully defibrillate, therefore, the shock strength must be greater than the largest shock that reinitiates fibrillation (the upper limit of vulnerability). This hypothesis is supported by the observation that almost identical changes in the upper limit of vulnerability and the defibrillation threshold occur with changes in electrode polarity and waveform duration [19]. Transcardiac shocks of up to 30 joules were delivered to canine myocardial tissue at different times of the cardiac cycle [20]. A shock applied 10 milliseconds before the end of the refractory period extended the refractory period by 63 milliseconds, whereas the same shock given 40 milliseconds earlier produced only a 25-millisecond increase in the refractory period. In contrast, a five-joule shock applied at the same times during the cardiac cycle produced only a 36- and 10- millisecond increase in the refractory period, respectively. https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 3/25 7/6/23, 2:48 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Because the higher intensity shock selectively extends the refractory period of the myocardium, it may establish a zone of tissue in which repolarization is delayed. This zone is always immediately in front of the newly depolarized tissue, and the inability of the depolarizing impulse to propagate across these refractory zones may be the mechanism responsible for terminating fibrillation. The size of these zones and the duration of increased refractoriness both increase with increasing shock intensity; this may account for the relatively high shock energies required for defibrillation relative to the intensities required to directly depolarize the tissue. An electrical shock will also induce different degrees of action potential duration prolongation and dispersion of ventricular repolarization, depending upon shock strength and timing [21]. One study, performed during the post-implantation testing of implantable cardioverter- defibrillators, found that shocks delivered on the T wave generated variable degrees of action potential prolongation, depending upon myocardial repolarization [22]. The creation of high dispersion of repolarization facilitated reentry by creating functional blocks and subsequently favored the induction of ventricular fibrillation and the prevention of its termination by a shock. Defibrillation and cardioversion do not appear to cause significant myocardial necrosis [23]. (See "Cardioversion for specific arrhythmias", section on 'Myocardial necrosis'.) FACTORS AFFECTING DEFIBRILLATION AND CARDIOVERSION SUCCESS A variety of device-related and patient-related factors will influence the chances of successful cardioversion and/or defibrillation. The device-related variables include factors related to the electrodes (ie, position, size, hand-held versus adhesive patch) and factors related to the energy delivered (ie, number of joules, type of waveform), while the patient-related variables include the transthoracic impedance through which the energy much travel as well as the type and duration of arrhythmia. Device-related variables Electrodes A number of electrode characteristics can affect the outcome of cardioversion. These include electrode position, pad size, and hand-held versus patch electrodes. Electrode position The placement of defibrillation electrodes on the thorax determines the transthoracic current pathway for external defibrillation. There are two conventional positions for electrode placement ( figure 4): Anterolateral orientation Anteroposterior orientation https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 4/25 7/6/23, 2:48 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate In some patients, one (but not the other position) may be effective. As a result, if initial attempts are unsuccessful in terminating the arrhythmia, the electrodes should be relocated to the other position and attempts at defibrillation or cardioversion repeated. Several studies have suggested that less energy is required and the success rate is higher with the anteroposterior electrode position in patients cardioverted for atrial fibrillation [24-27]. As an example, in one study of 301 patients, sinus rhythm was restored in 87 percent using an anteroposterior position compared with 76 percent with an anterolateral orientation [25]. In the same study, the mean energy required for successful cardioversion was lower in patients with an anteroposterior electrode position (237 versus 287 joules) [25]. There is also evidence that anteroposterior pad position may be effective in treating refractory ventricular fibrillation [28]. The supporting study is described in detail separately. (See "Adult basic life support (BLS) for health care providers", section on 'Defibrillation'.) However, other reports have failed to confirm these findings and suggest that there is no clear advantage to either electrode configuration [29-31]. In a contemporary randomized trial of patients presenting to the emergency department with acute atrial fibrillation who underwent cardioversion, rates of successful cardioversion to sinus rhythm for at least 30 minutes were similar regardless of electrode position (94 percent with anterolateral placement versus 92 percent with anteroposterior placement) [32]. Pad size Electrode pad size is an important determinant of transthoracic current flow during external countershock [29,33-35]. One study analyzed the outcome of cardiac arrests in 105 patients using self-adhesive defibrillator pads of different sizes [35]. A single shock of 200 joules was successful in 31 percent of cardiac arrests using two small pads (each 8 cm in diameter), in 63 percent with one small and one large pad (8 and 12 cm in diameter), and in 82 percent when two large pads (each 12 cm in diameter) were used. A larger pad or paddle surface is associated with a decrease in resistance and increase in current and may cause less myocardial necrosis [36-38]. However, there appears to be an optimal electrode size (approximately 12.8 cm) above which any further increase in electrode area causes a decline in current density [39]. Hand-held versus patch The use of hand-held paddle electrodes may be more effective than self-adhesive patch electrodes. This was illustrated in a randomized trial of 201 patients referred for cardioversion of persistent atrial fibrillation [40]. Success rates were slightly higher for patients assigned to paddle electrodes (96 versus 88 percent with patch electrodes). Improved electrode-to-skin contact and reduced transthoracic impedance with hand-held electrodes may explain the benefit. https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 5/25 7/6/23, 2:48 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate However, there are no published data comparing hand-held paddle electrodes with self-adhesive patch electrodes for other arrhythmias requiring cardioversion (eg, atrioventricular nodal reentrant tachycardia, atrial flutter) or defibrillation (eg, ventricular fibrillation). Therefore, the decision to use hand-held or self-adhesive electrodes should be made based on the available equipment and the opinion of the operator regarding which electrodes are more likely to be effective for the patient at hand. Monophasic versus biphasic waveforms Defibrillators can deliver energy in a variety of waveforms that are broadly characterized as monophasic or biphasic. Defibrillators developed prior to 2000 deliver a monophasic wave of direct electrical current. Since then, "biphasic" devices, which reverse current polarity 5 to 10 milliseconds after discharge begins, have been developed ( figure 1). Biphasic waveforms defibrillate more effectively and at lower energies than monophasic waveforms. This benefit has been demonstrated in both animals and humans, and with both ventricular and atrial fibrillation [41-50]. However, monophasic defibrillation is still highly effective in most situations, and it is not clear that the superior efficacy of biphasic defibrillation results in important clinical advantages [51]. Ventricular fibrillation Several randomized trials have compared monophasic and biphasic waveforms in the treatment of ventricular fibrillation. In the Optimized Response to Cardiac Arrest (ORCA) trial, 115 patients with an out-of- hospital cardiac arrest due to ventricular fibrillation were randomly assigned to defibrillation using a 150 joule biphasic shock or traditional high-energy (200 to 360 joules) monophasic shocks [46]. Successful defibrillation was significantly more likely with biphasic waveforms compared with monophasic waveforms after one shock and total treatment under Emergency Medical Services care (96 versus 59, and 100 versus 84 percent respectively). In addition, the rate of return of spontaneous circulation was higher with biphasic shock therapy (76 versus 54 percent). However, there was no difference in the rate of survival to hospital discharge between the two therapies. Among patients who survived to discharge, those treated with a biphasic shock were more likely to have good cerebral performance (87 versus 53 percent). In the Out-of-hospital cardiac arrest rectilinear biphasic to monophasic damped sine defibrillation waveforms with advanced life support intervention trial (ORBIT) of 169 patient with out-of-hospital cardiac arrest, biphasic shocks (escalating 120, 150, or 200 joules) were more effective than monophasic shocks (escalating 200, 300, and 360 joules) as defined by conversion at 5 sec to an organized rhythm (52 versus 34 percent) [52]. However, there https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 6/25 7/6/23, 2:48 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate were no significant differences in return of spontaneous circulation (47 percent in both groups) or survival to discharge from hospital (9 versus 7 percent). In the Transthoracic Incremental Monophasic versus Biphasic defibrillation by Emergency Responders (TIMBER) trial, 168 patients with an out-of-hospital cardiac arrest due to ventricular fibrillation were randomly assigned to treatment with either monophasic or biphasic defibrillation [53]. Defibrillation was initially performed by Emergency Medical Service with an automated external defibrillator (AED), and if necessary, with a manual defibrillator by paramedics who arrived later. Patients were included only if all shocks were delivered with the same waveform. In contrast to the ORCA trial, in TIMBER the defibrillation energies were the same for both waveforms (200 followed by 200 and then 360 joules). There were no statistically significant differences between the treatment arms with regard to the success of initial shocks, the rate of survival, or neurologic outcomes. However, biphasic defibrillation did result in nonsignificant trends towards earlier return of spontaneous circulation and increased overall survival (41 versus 34 percent, compared with monophasic defibrillation). There is no clear explanation for the discrepant findings in these three trials. Due to the complexities and urgencies associated with resuscitation, in combination with the small sample sizes available for controlled studies, it is difficult to demonstrate or exclude important clinical benefits. Based upon the greater efficacy of biphasic defibrillation demonstrated in other settings, the lack of evidence of harm from biphasic defibrillation, and the trends towards outcome benefits suggested by clinical trials, we support the use of biphasic defibrillation for the treatment of ventricular arrhythmias. Atrial fibrillation The benefit of the biphasic waveform for the treatment of atrial fibrillation has been illustrated in two randomized trials: In one trial, 174 patients with AF were randomly assigned to cardioversion with a monophasic waveform, using sequential shocks of 100 to 360 joules, or biphasic waveform, with energies of 70 to 170 joules [48]. First shock efficacy was greater with a biphasic waveform (68 versus 21 percent), delivered energy was 50 percent less, and the overall cardioversion rate was higher (94 versus 79 percent). Similar benefits were noted in a comparable randomized trial of 210 patients [49]. Biphasic waveforms were associated with the following significant benefits: greater first shock efficacy (60 versus 22 percent); fewer total shocks (1.7 versus 2.8); less energy delivered (217 versus 548 joules), and a lower frequency of dermal injury (17 versus 41 percent). https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 7/25 7/6/23, 2:48 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate In a larger nonrandomized experience, 2546 patients with AF were cardioverted using a monophasic (1996 to 1999) or biphasic (1999 to 2001) defibrillator [50]. With the biphasic waveform, the overall success of cardioversion was greater (99.1 versus 92.4 percent) and the energy level required for cardioversion was lower (median 100 versus 200 joules). Similar findings have been reported for patients with atrial flutter, in whom cardioversion was successful more frequently and at lower energy levels when using biphasic waveforms [54,55]. Optimal biphasic defibrillation energies Because biphasic shocks are more effective at lower energies than monophasic shocks, initial protocols often suggested using lower-energy biphasic shocks during resuscitation (eg, 150 joules). The value of higher energy biphasic shocks was demonstrated in the BIPHASIC trial [56]. A series of 221 patients with out-of-hospital cardiac arrest were randomly assigned to either fixed lower energy defibrillation (150 joules, followed by up to two additional shocks at the same energy as necessary), or to escalating higher-energy shocks (200 joules, followed by 300 and 360 joule shocks as necessary). Shocks were administered by an AED. The following results were noted: The rate of successful defibrillation with the first shock was the same in both groups (37 versus 38 percent in the escalating higher and fixed lower treatment groups, respectively). Among patients requiring multiple shocks (n = 106), patients assigned to the escalating higher-energy protocol were significantly more likely to be successfully cardioverted (37 versus 25 percent, compared with patients assigned to the fixed lower-energy protocol). There were no significant differences between regimens in adverse events including cardiac enzyme elevation and left ventricular systolic dysfunction. There were no differences between regimens in survival outcomes, although this could be due in part to the relatively small sample size. Based upon the absence of adverse events and the greater efficacy in patients requiring multiple shocks, we agree with the use of escalating higher-energy shocks with biphasic defibrillators in the treatment of cardiac arrest due to a ventricular tachyarrhythmia that does not respond to an initial lower energy shock. Double sequential external defibrillation Double sequential external defibrillation (DSED) consists of rapid sequential shocks from two defibrillators; this has been shown to be effective at terminating refractory ventricular fibrillation [28]. The supporting study is described in detail separately. (See "Adult basic life support (BLS) for health care providers", section on 'Defibrillation'.) https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 8/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate If more studies are supportive of DSED for patients with refractory ventricular fibrillation, this could be a strategy employed in a hospital setting. Patient-related variables Transthoracic impedance To compensate for transthoracic impedance during transthoracic defibrillation, a considerably larger current must be delivered to the thorax than is required for internal defibrillation. Impedance results in the dissipation of energy due to shunting to the lungs, the thoracic cage, and other elements of the chest. In an animal study, 82 percent of the transthoracic current was shunted to the thoracic cage, 14 percent to the lungs, and only 4 percent passed through to the heart [57]. Transthoracic impedance is determined by multiple factors including: Energy level Electrode-to-skin interface Interelectrode distance Electrode pressure (with hand-held electrodes) Phase of ventilation Myocardial tissue and blood conductive properties In animals, repetitive shocks delivered at three minute intervals decrease the transthoracic impedance to a greater extent than repetitive shocks delivered at 15 or 60 second intervals [58,59]. Similar trends have been reported in humans, but the changes in impedance were not found to be clinically relevant [59,60]. With repeated shocks, impedance decreased by as much as 8 percent and the peak current increased by 4 percent [61]. Therefore, despite only a minimally larger amount of energy being delivered to the heart, an unsuccessful shock should be followed promptly by a higher energy shock. An animal study examined the mechanisms responsible for the decline in transthoracic impedance after direct current (DC) shocks [62]. After three 100-joule shocks, there was an 11 percent decline in transthoracic impedance which correlated with a tenfold increase in skeletal muscle blood flow. This observation suggests that tissue edema contributes to the DC shock- induced decline in transthoracic impedance. A second report evaluated the effect of prior sternotomy on transthoracic impedance [63]. Transthoracic impedance decreased after sternotomy and remained below preoperative measurements even after wound healing was complete, suggesting that the hyperemia, inflammation, tissue edema, and pleural effusion associated with sternotomy were the major contributors to the reduction in impedance. https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 9/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate The phase of ventilation is another factor that alters transthoracic impedance. Inspiration (and the increased volume of air within the lungs) is associated with a 13 percent higher transthoracic impedance than expiration [64]. The composition of the gel used during cardioversion also affects the transthoracic impedance. In a study comparing a non-salt-containing gel with a salt-containing gel, transthoracic impedance was 20 percent higher with the non-salt-containing gel [65]. Type of arrhythmia The type of arrhythmia and the patient's clinical condition are important determinants of defibrillation success [66-68]. As an example, patients with ventricular fibrillation as the primary event are easier to defibrillate than patients with secondary ventricular fibrillation resulting from uncompensated congestive heart failure and hypotension. The different energy requirements between organized and non-organized arrhythmias may be related to the electrophysiologic characteristics of the arrhythmia. Organized arrhythmias, such as sustained monomorphic ventricular tachycardia, arise from a discrete reentrant circuit which is easily depolarized by smaller amounts of current [69,70]. In contrast, in non-organized rhythms such as polymorphic ventricular tachycardia and ventricular fibrillation, the wavefronts are multiple and involve more myocardial mass, thereby requiring more energy for termination [18]. The electrical current and energy required to terminate ventricular tachyarrhythmias vary by arrhythmia. Ventricular tachycardia generally requires less energy than ventricular fibrillation. In one study of 203 patients who received 569 shocks for ventricular tachycardia or fibrillation, the heart rate and electrocardiographic degree of organization of the tachycardia were important determinants of transthoracic energy and the current requirements for cardioversion or defibrillation [71]. Transthoracic termination of monomorphic ventricular tachycardia required relatively low energy (70 to 100 joules) while polymorphic ventricular tachycardia required more energy (150 to 200 joules). The varying energy requirements for cardioversion for ventricular tachyarrhythmias are analogous to those of atrial tachyarrhythmias. Atrial flutter, a more organized rhythm than atrial fibrillation, generally terminates with lower electrical doses. Duration of arrhythmia An additional factor in the likelihood of a successful cardioversion or defibrillation, for both ventricular and atrial arrhythmias, is the amount of time an arrhythmia has been present. In ventricular fibrillation the duration of the arrhythmia is a determinant of the degree of organization of the electrical impulse. Even when using a biphasic waveform, the https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 10/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate effectiveness of defibrillation is reduced when the arrhythmia is of longer duration [72]. The more recent the onset of ventricular fibrillation, the coarser are the fibrillatory waves and the greater the success with defibrillation. As the arrhythmia persists (ie, more than 10 to 30 seconds), the fibrillatory waves become finer and the likelihood of successful termination decreases [73-75]. This relationship has also been demonstrated in a study of 22 patients with an implantable cardioverter-defibrillator [74]. Defibrillation was effective in 82 percent of patients when delivered after five seconds compared with 45 percent when delivered after 15 seconds. (See "Prognosis and outcomes following sudden cardiac arrest in adults".) In atrial fibrillation there is a similar relationship between duration of atrial fibrillation and the success of cardioversion, although longer time periods are usually involved. One study of 198 patients found that sinus rhythm was restored in 98 percent of patients when the duration of atrial fibrillation was less than 24 hours compared with a success rate of 62 percent when the duration was more than 24 hours [76]. The overall success rate for sinus rhythm restoration is approximately 90 percent when atrial fibrillation is of less than one year's duration compared with 50 percent when atrial fibrillation has been present for more than five years [77]. Use of antiarrhythmic drugs Antiarrhythmic drugs can increase or decrease the defibrillation energy requirements for ventricular fibrillation and the cardioversion energy requirements for atrial fibrillation. In general, sodium channel blockers increase the energy required for defibrillation, while potassium channel blockers and catecholamines decrease the energy needed. For example, lidocaine increases defibrillation energy requirements, and sotalol and ibutilide decrease the energy needed [78]. Epinephrine's effect on cycle length, synchronization, and dispersion of repolarization of fibrillatory waves may be the mechanisms by which it facilitates defibrillation [79]. These observations are relevant to external defibrillation success in the setting of a cardiac arrest, the ability to successfully defibrillate a patient with an implantable defibrillator during defibrillation threshold testing, and the use of ibutilide to facilitate restoration of sinus rhythm in patients undergoing elective cardioversion for atrial fibrillation [80]. Patients with an underlying cardiac implantable electronic device Patients with an underlying cardiac implantable electronic device (CIED) such as a permanent pacemaker or an implantable cardioverter-defibrillator require special attention to electrode placement. In such patients, we recommend placing the external electrode pads in the anteroposterior position and avoiding any contact with the skin overlying the CIED. Positioning of the electrode pads to avoid making contact with the skin overlying the CIED is critical to maximizing the efficacy of the https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 11/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate externally delivered shock and minimizing the likelihood of damage to the CIED from the externally delivered shock. ENERGY SELECTION FOR CARDIOVERSION AND DEFIBRILLATION The amount of energy selected for initial attempts of defibrillation has been controversial. The energy selected should be sufficient to accomplish prompt defibrillation because repeated failures expose the heart to damage from prolonged ischemia and multiple shocks. On the other hand, excessive energy should be avoided, since myocardial damage from high-energy shocks has been demonstrated in experimental studies, although the frequency with which this occurs in humans is not known. The choice of energy for initial attempts at cardioversion or defibrillation is discussed in detail separately. (See "Cardioversion for specific arrhythmias", section on 'Energy selection'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Basic and advanced cardiac life support in adults" and "Society guideline links: Cardiac arrest in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Cardioversion (Beyond the Basics)") https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 12/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate SUMMARY Electrical cardioversion and defibrillation have become routine procedures in the management of patients with cardiac arrhythmias. Cardioversion is the delivery of energy that is synchronized to the QRS complex, while defibrillation is the non-synchronized delivery of a shock during the cardiac cycle. (See 'Introduction' above.) Cardioversion terminates arrhythmias by delivering a synchronized shock that depolarizes the tissue involved in a reentrant circuit ( figure 2 and figure 3). By depolarizing all excitable tissue of the circuit and making the tissue refractory, the circuit is no longer able to propagate or sustain reentry. (See 'Electrophysiology of defibrillation and cardioversion' above.) Despite its widespread clinical use, controversy persists concerning the electrophysiologic mechanisms by which electrical cardioversion or defibrillation terminates atrial or ventricular fibrillation, arrhythmias which involve multiple microreentrant circuits. Most investigators agree that defibrillation occurs when a certain amount of current density reaches the myocardium. However, it is unclear what amount of current density is needed and what energy setting is necessary to achieve a homogeneous current density. (See 'Electrophysiology of defibrillation and cardioversion' above.) A variety of device-related factors will influence the chances of successful cardioversion and/or defibrillation, including electrode size and position, hand-held versus self-adhesive patch electrodes, and monophasic versus biphasic waveforms. (See 'Device-related variables' above.) A variety of patient-related factors also influence the chances of successful cardioversion and/or defibrillation, including transthoracic impedance, type of arrhythmia, use of antiarrhythmic drugs, and the duration of arrhythmia. (See 'Patient-related variables' above.) While the anteroposterior electrode position is suggested for most patients, for persons with an underlying cardiac implantable electronic device (CIED) such as a permanent pacemaker or an implantable cardioverter-defibrillator, we specifically recommend placing the external electrode pads in the anteroposterior position and avoiding any contact with the skin overlying the CIED. This placement should maximize the shock efficacy and minimize the likelihood of damage to the CIED. (See 'Electrode position' above and 'Patients with an underlying cardiac implantable electronic device' above.) https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 13/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. ZOLL PM, LINENTHAL AJ, GIBSON W, et al. Termination of ventricular fibrillation in man by externally applied electric countershock. N Engl J Med 1956; 254:727. 2. LOWN B, AMARASINGHAM R, NEUMAN J. New method for terminating cardiac arrhythmias. Use of synchronized capacitor discharge. JAMA 1962; 182:548. 3. ALEXANDER S, KLEIGER R, LOWN B. Use of external electric countershock in the treatment of ventricular tachycardia. JAMA 1961; 177:916. 4. Zoll PM, Linentha AJ. Termination of refractory tachycardia by external countershock. Circulation 1962; 25:596. 5. PAUL MH, MILLER RA. External electrical termination of supraventricular arrhythmias in congenital heart disease. Circulation 1962; 25:604. 6. Kerber RE, Martins JB, Kienzle MG, et al. Energy, current, and success in defibrillation and cardioversion: clinical studies using an automated impedance-based method of energy adjustment. Circulation 1988; 77:1038. 7. Lerman BB, Halperin HR, Tsitlik JE, et al. Relationship between canine transthoracic impedance and defibrillation threshold. Evidence for current-based defibrillation. J Clin Invest 1987; 80:797. 8. Kerber RE, Jensen SR, Gascho JA, et al. Determinants of defibrillation: prospective analysis of 183 patients. Am J Cardiol 1983; 52:739. 9. Lerman BB, DiMarco JP, Haines DE. Current-based versus energy-based ventricular defibrillation: a prospective study. J Am Coll Cardiol 1988; 12:1259. 10. Plonsey R, Barr RC. Effect of microscopic and macroscopic discontinuities on the response of cardiac tissue to defibrillating (stimulating) currents. Med Biol Eng Comput 1986; 24:130. 11. Mower MM, Mirowski M, Spear JF, Moore EN. Patterns of ventricular activity during catheter defibrillation. Circulation 1974; 49:858. 12. Witkowski FX, Penkoske PA, Plonsey R. Mechanism of cardiac defibrillation in open-chest dogs with unipolar DC-coupled simultaneous activation and shock potential recordings. Circulation 1990; 82:244.

underlying cardiac implantable electronic device (CIED) such as a permanent pacemaker or an implantable cardioverter-defibrillator require special attention to electrode placement. In such patients, we recommend placing the external electrode pads in the anteroposterior position and avoiding any contact with the skin overlying the CIED. Positioning of the electrode pads to avoid making contact with the skin overlying the CIED is critical to maximizing the efficacy of the https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 11/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate externally delivered shock and minimizing the likelihood of damage to the CIED from the externally delivered shock. ENERGY SELECTION FOR CARDIOVERSION AND DEFIBRILLATION The amount of energy selected for initial attempts of defibrillation has been controversial. The energy selected should be sufficient to accomplish prompt defibrillation because repeated failures expose the heart to damage from prolonged ischemia and multiple shocks. On the other hand, excessive energy should be avoided, since myocardial damage from high-energy shocks has been demonstrated in experimental studies, although the frequency with which this occurs in humans is not known. The choice of energy for initial attempts at cardioversion or defibrillation is discussed in detail separately. (See "Cardioversion for specific arrhythmias", section on 'Energy selection'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Basic and advanced cardiac life support in adults" and "Society guideline links: Cardiac arrest in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Cardioversion (Beyond the Basics)") https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 12/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate SUMMARY Electrical cardioversion and defibrillation have become routine procedures in the management of patients with cardiac arrhythmias. Cardioversion is the delivery of energy that is synchronized to the QRS complex, while defibrillation is the non-synchronized delivery of a shock during the cardiac cycle. (See 'Introduction' above.) Cardioversion terminates arrhythmias by delivering a synchronized shock that depolarizes the tissue involved in a reentrant circuit ( figure 2 and figure 3). By depolarizing all excitable tissue of the circuit and making the tissue refractory, the circuit is no longer able to propagate or sustain reentry. (See 'Electrophysiology of defibrillation and cardioversion' above.) Despite its widespread clinical use, controversy persists concerning the electrophysiologic mechanisms by which electrical cardioversion or defibrillation terminates atrial or ventricular fibrillation, arrhythmias which involve multiple microreentrant circuits. Most investigators agree that defibrillation occurs when a certain amount of current density reaches the myocardium. However, it is unclear what amount of current density is needed and what energy setting is necessary to achieve a homogeneous current density. (See 'Electrophysiology of defibrillation and cardioversion' above.) A variety of device-related factors will influence the chances of successful cardioversion and/or defibrillation, including electrode size and position, hand-held versus self-adhesive patch electrodes, and monophasic versus biphasic waveforms. (See 'Device-related variables' above.) A variety of patient-related factors also influence the chances of successful cardioversion and/or defibrillation, including transthoracic impedance, type of arrhythmia, use of antiarrhythmic drugs, and the duration of arrhythmia. (See 'Patient-related variables' above.) While the anteroposterior electrode position is suggested for most patients, for persons with an underlying cardiac implantable electronic device (CIED) such as a permanent pacemaker or an implantable cardioverter-defibrillator, we specifically recommend placing the external electrode pads in the anteroposterior position and avoiding any contact with the skin overlying the CIED. This placement should maximize the shock efficacy and minimize the likelihood of damage to the CIED. (See 'Electrode position' above and 'Patients with an underlying cardiac implantable electronic device' above.) https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 13/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. ZOLL PM, LINENTHAL AJ, GIBSON W, et al. Termination of ventricular fibrillation in man by externally applied electric countershock. N Engl J Med 1956; 254:727. 2. LOWN B, AMARASINGHAM R, NEUMAN J. New method for terminating cardiac arrhythmias. Use of synchronized capacitor discharge. JAMA 1962; 182:548. 3. ALEXANDER S, KLEIGER R, LOWN B. Use of external electric countershock in the treatment of ventricular tachycardia. JAMA 1961; 177:916. 4. Zoll PM, Linentha AJ. Termination of refractory tachycardia by external countershock. Circulation 1962; 25:596. 5. PAUL MH, MILLER RA. External electrical termination of supraventricular arrhythmias in congenital heart disease. Circulation 1962; 25:604. 6. Kerber RE, Martins JB, Kienzle MG, et al. Energy, current, and success in defibrillation and cardioversion: clinical studies using an automated impedance-based method of energy adjustment. Circulation 1988; 77:1038. 7. Lerman BB, Halperin HR, Tsitlik JE, et al. Relationship between canine transthoracic impedance and defibrillation threshold. Evidence for current-based defibrillation. J Clin Invest 1987; 80:797. 8. Kerber RE, Jensen SR, Gascho JA, et al. Determinants of defibrillation: prospective analysis of 183 patients. Am J Cardiol 1983; 52:739. 9. Lerman BB, DiMarco JP, Haines DE. Current-based versus energy-based ventricular defibrillation: a prospective study. J Am Coll Cardiol 1988; 12:1259. 10. Plonsey R, Barr RC. Effect of microscopic and macroscopic discontinuities on the response of cardiac tissue to defibrillating (stimulating) currents. Med Biol Eng Comput 1986; 24:130. 11. Mower MM, Mirowski M, Spear JF, Moore EN. Patterns of ventricular activity during catheter defibrillation. Circulation 1974; 49:858. 12. Witkowski FX, Penkoske PA, Plonsey R. Mechanism of cardiac defibrillation in open-chest dogs with unipolar DC-coupled simultaneous activation and shock potential recordings. Circulation 1990; 82:244. 13. Chen PS, Shibata N, Dixon EG, et al. Activation during ventricular defibrillation in open-chest dogs. Evidence of complete cessation and regeneration of ventricular fibrillation after unsuccessful shocks. J Clin Invest 1986; 77:810. https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 14/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate 14. Zipes DP, Fischer J, King RM, et al. Termination of ventricular fibrillation in dogs by depolarizing a critical amount of myocardium. Am J Cardiol 1975; 36:37. 15. Chen PS, Wolf PD, Ideker RE. Mechanism of cardiac defibrillation. A different point of view. Circulation 1991; 84:913. 16. Witkowski, FX, Kerber, RE . Currently known mechanisms underlying direct current external and internal cardiac defibrillation. J Cardiovasc Electrophysiol 1991; 2:562. 17. Chen PS, Shibata N, Dixon EG, et al. Comparison of the defibrillation threshold and the upper limit of ventricular vulnerability. Circulation 1986; 73:1022. 18. Chen PS, Wolf PD, Melnick SD, et al. Comparison of activation during ventricular fibrillation and following unsuccessful defibrillation shocks in open-chest dogs. Circ Res 1990; 66:1544. 19. Huang J, KenKnight BH, Walcott GP, et al. Effects of transvenous electrode polarity and waveform duration on the relationship between defibrillation threshold and upper limit of vulnerability. Circulation 1997; 96:1351. 20. Sweeney RJ, Gill RM, Steinberg MI, Reid PR. Ventricular refractory period extension caused by defibrillation shocks. Circulation 1990; 82:965. 21. Zhou XH, Knisley SB, Wolf PD, et al. Prolongation of repolarization time by electric field stimulation with monophasic and biphasic shocks in open-chest dogs. Circ Res 1991; 68:1761. 22. Moubarak JB, Karasik PE, Fletcher RD, Franz MR. High dispersion of ventricular repolarization after an implantable defibrillator shock predicts induction of ventricular fibrillation as well as unsuccessful defibrillation. J Am Coll Cardiol 2000; 35:422. 23. Goktekin O, Melek M, Gorenek B, et al. Cardiac troponin T and cardiac enzymes after external transthoracic cardioversion of ventricular arrhythmias in patients with coronary artery disease. Chest 2002; 122:2050. 24. Lown B, Kleiger R, Wolff G. THE TECHNIQUE OF CARDIOVERSION. Am Heart J 1964; 67:282. 25. Botto GL, Politi A, Bonini W, et al. External cardioversion of atrial fibrillation: role of paddle position on technical efficacy and energy requirements. Heart 1999; 82:726. 26. Kirchhof P, Eckardt L, Loh P, et al. Anterior-posterior versus anterior-lateral electrode positions for external cardioversion of atrial fibrillation: a randomised trial. Lancet 2002; 360:1275. 27. Myerburg RJ, Castellanos A. Electrode positioning for cardioversion of atrial fibrillation. Lancet 2002; 360:1263. 28. Cheskes S, Verbeek PR, Drennan IR, et al. Defibrillation Strategies for Refractory Ventricular Fibrillation. N Engl J Med 2022; 387:1947. https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 15/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate 29. Kerber RE, Jensen SR, Grayzel J, et al. Elective cardioversion: influence of paddle-electrode location and size on success rates and energy requirements. N Engl J Med 1981; 305:658. 30. Mathew TP, Moore A, McIntyre M, et al. Randomised comparison of electrode positions for cardioversion of atrial fibrillation. Heart 1999; 81:576. 31. Walsh SJ, McCarty D, McClelland AJ, et al. Impedance compensated biphasic waveforms for transthoracic cardioversion of atrial fibrillation: a multi-centre comparison of antero-apical and antero-posterior pad positions. Eur Heart J 2005; 26:1298. 32. Stiell IG, Sivilotti MLA, Taljaard M, et al. Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomised trial. Lancet 2020; 395:339. 33. Thomas ED, Ewy GA, Dahl CF, Ewy MD. Effectiveness of direct current defibrillation: role of paddle electrode size. Am Heart J 1977; 93:463. 34. Ewy GA, Horan WJ. Effectiveness of direct current defibrillation: role of paddle electrode size: II. Am Heart J 1977; 93:674. 35. Dalzell GW, Cunningham SR, Anderson J, Adgey AA. Electrode pad size, transthoracic impedance and success of external ventricular defibrillation. Am J Cardiol 1989; 64:741. 36. Kugelberg J. The interelectrode electrical resistance at defibrillation. Scand J Thorac Cardiovasc Surg 1972; 6:274. 37. Ewy GA, Taren D. Impedance to transthoracic direct current discharge: a model for testing interface material. Med Instrum 1978; 12:47. 38. Dahl CF, Ewy GA, Warner ED, Thomas ED. Myocardial necrosis from direct current countershock. Effect of paddle electrode size and time interval between discharges. Circulation 1974; 50:956. 39. Hoyt R, Grayzel J, Kerber RE. Determinants of intracardiac current in defibrillation. Experimental studies in dogs. Circulation 1981; 64:818. 40. Kirchhof P, M nnig G, Wasmer K, et al. A trial of self-adhesive patch electrodes and hand- held paddle electrodes for external cardioversion of atrial fibrillation (MOBIPAPA). Eur Heart J 2005; 26:1292. 41. Schuder JC, McDaniel WC, Stoeckle H. Defibrillation of 100 kg calves with asymmetrical, bidirectional, rectangular pulses. Cardiovasc Res 1984; 18:419. 42. Walcott GP, Melnick SB, Chapman FW, et al. Relative efficacy of monophasic and biphasic waveforms for transthoracic defibrillation after short and long durations of ventricular fibrillation. Circulation 1998; 98:2210. https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 16/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate 43. Leng CT, Paradis NA, Calkins H, et al. Resuscitation after prolonged ventricular fibrillation with use of monophasic and biphasic waveform pulses for external defibrillation. Circulation 2000; 101:2968. 44. Jones JL, Jones RE. Improved defibrillator waveform safety factor with biphasic waveforms. Am J Physiol 1983; 245:H60. 45. Niemann JT, Burian D, Garner D, Lewis RJ. Monophasic versus biphasic transthoracic countershock after prolonged ventricular fibrillation in a swine model. J Am Coll Cardiol 2000; 36:932. 46. Schneider T, Martens PR, Paschen H, et al. Multicenter, randomized, controlled trial of 150-J biphasic shocks compared with 200- to 360-J monophasic shocks in the resuscitation of out- of-hospital cardiac arrest victims. Optimized Response to Cardiac Arrest (ORCA) Investigators. Circulation 2000; 102:1780. 47. Mittal S, Ayati S, Stein KM, et al. Comparison of a novel rectilinear biphasic waveform with a damped sine wave monophasic waveform for transthoracic ventricular defibrillation. ZOLL Investigators. J Am Coll Cardiol 1999; 34:1595. 48. Mittal S, Ayati S, Stein KM, et al. Transthoracic cardioversion of atrial fibrillation: comparison of rectilinear biphasic versus damped sine wave monophasic shocks. Circulation 2000; 101:1282. 49. Page RL, Kerber RE, Russell JK, et al. Biphasic versus monophasic shock waveform for conversion of atrial fibrillation: the results of an international randomized, double-blind multicenter trial. J Am Coll Cardiol 2002; 39:1956. 50. Niebauer MJ, Brewer JE, Chung MK, Tchou PJ. Comparison of the rectilinear biphasic waveform with the monophasic damped sine waveform for external cardioversion of atrial fibrillation and flutter. Am J Cardiol 2004; 93:1495. 51. Faddy SC, Jennings PA. Biphasic versus monophasic waveforms for transthoracic defibrillation in out-of-hospital cardiac arrest. Cochrane Database Syst Rev 2016; 2:CD006762. 52. Morrison LJ, Dorian P, Long J, et al. Out-of-hospital cardiac arrest rectilinear biphasic to monophasic damped sine defibrillation waveforms with advanced life support intervention trial (ORBIT). Resuscitation 2005; 66:149. 53. Kudenchuk PJ, Cobb LA, Copass MK, et al. Transthoracic incremental monophasic versus biphasic defibrillation by emergency responders (TIMBER): a randomized comparison of monophasic with biphasic waveform ascending energy defibrillation for the resuscitation of out-of-hospital cardiac arrest due to ventricular fibrillation. Circulation 2006; 114:2010. https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 17/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate 54. Mortensen K, Risius T, Schwemer TF, et al. Biphasic versus monophasic shock for external cardioversion of atrial flutter: a prospective, randomized trial. Cardiology 2008; 111:57. 55. Niebauer MJ, Chung MK, Brewer JE, Tchou PJ. Reduced cardioversion thresholds for atrial fibrillation and flutter using the rectilinear biphasic waveform. J Interv Card Electrophysiol 2005; 13:145. 56. Stiell IG, Walker RG, Nesbitt LP, et al. BIPHASIC Trial: a randomized comparison of fixed lower versus escalating higher energy levels for defibrillation in out-of-hospital cardiac arrest. Circulation 2007; 115:1511. 57. Deale OC, Lerman BB. Intrathoracic current flow during transthoracic defibrillation in dogs. Transcardiac current fraction. Circ Res 1990; 67:1405. 58. Dahl CF, Ewy GA, Ewy MD, Thomas ED. Transthoracic impedance to direct current discharge: effect of repeated countershocks. Med Instrum 1976; 10:151. 59. Geddes LA, Tacker WA, Cabler P, et al. The decrease in transthoracic impedance during successive ventricular defibrillation trials. Med Instrum 1975; 9:179. 60. Kerber RE, Grayzel J, Hoyt R, et al. Transthoracic resistance in human defibrillation. Influence of body weight, chest size, serial shocks, paddle size and paddle contact pressure. Circulation 1981; 63:676. 61. Fumagalli S, Tarantini F, Caldi F, et al. Multiple shocks affect thoracic electrical impedance during external cardioversion of atrial fibrillation. Pacing Clin Electrophysiol 2009; 32:371. 62. Sirna SJ, Kieso RA, Fox-Eastham KJ, et al. Mechanisms responsible for decline in transthoracic impedance after DC shocks. Am J Physiol 1989; 257:H1180. 63. Kerber RE, Vance S, Schomer SJ, et al. Transthoracic defibrillation: effect of sternotomy on chest impedance. J Am Coll Cardiol 1992; 20:94. 64. Ewy GA, Hellman DA, McClung S, Taren D. Influence of ventilation phase on transthoracic impedance and defibrillation effectiveness. Crit Care Med 1980; 8:164. 65. Ewy GA, Taren D. Comparison of paddle electrode pastes used for defibrillation. Heart Lung 1977; 6:847. 66. Crampton R. Accepted, controversial, and speculative aspects of ventricular defibrillation. Prog Cardiovasc Dis 1980; 23:167. 67. Gascho JA, Crampton RS, Cherwek ML, et al. Determinants of ventricular defibrillation in adults. Circulation 1979; 60:231. 68. Link MS, Atkins DL, Passman RS, et al. Part 6: electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 18/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S706. 69. Winkle RA, Stinson EB, Bach SM Jr, et al. Measurement of cardioversion/defibrillation thresholds in man by a truncated exponential waveform and an apical patch-superior vena caval spring electrode configuration. Circulation 1984; 69:766. 70. Kienzle MG, Miller J, Falcone RA, et al. Intraoperative endocardial mapping during sinus rhythm: relationship to site of origin of ventricular tachycardia. Circulation 1984; 70:957. 71. Kerber RE, Kienzle MG, Olshansky B, et al. Ventricular tachycardia rate and morphology determine energy and current requirements for transthoracic cardioversion. Circulation 1992; 85:158. 72. Windecker S, Ideker RE, Plumb VJ, et al. The influence of ventricular fibrillation duration on defibrillation efficacy using biphasic waveforms in humans. J Am Coll Cardiol 1999; 33:33. 73. Dalzell GW, Adgey AA. Determinants of successful transthoracic defibrillation and outcome in ventricular fibrillation. Br Heart J 1991; 65:311. 74. Winkle RA, Mead RH, Ruder MA, et al. Effect of duration of ventricular fibrillation on defibrillation efficacy in humans. Circulation 1990; 81:1477. 75. Weaver WD, Cobb LA, Copass MK, Hallstrom AP. Ventricular defibrillation a comparative trial using 175-J and 320-J shocks. N Engl J Med 1982; 307:1101. 76. Ricard P, L vy S, Trigano J, et al. Prospective assessment of the minimum energy needed for external electrical cardioversion of atrial fibrillation. Am J Cardiol 1997; 79:815. 77. Lown B. Electrical reversion of cardiac arrhythmias. Br Heart J 1967; 29:469. 78. Echt DS, Black JN, Barbey JT, et al. Evaluation of antiarrhythmic drugs on defibrillation energy requirements in dogs. Sodium channel block and action potential prolongation. Circulation 1989; 79:1106. 79. Suddath WO, Deychak Y, Varghese PJ. Electrophysiologic basis by which epinephrine facilitates defibrillation after prolonged episodes of ventricular fibrillation. Ann Emerg Med 2001; 38:201. 80. Oral H, Souza JJ, Michaud GF, et al. Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment. N Engl J Med 1999; 340:1849. Topic 975 Version 30.0 https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 19/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate GRAPHICS Defibrillation waveforms in implantable cardioverter- defibrillators Figure A shows the monophasic, exponentially decaying pulse was the waveform used in the first generation of ICDs. Figure B shows the biphasic waveform, which is generated with a single capacitor by switching the output polarity during discharge. Each division is 2 milliseconds. ICD: implantable cardioverter-defibrillator. Graphic 51842 Version 3.0 https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 20/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Mechanisms of reentry in cardiac arrhythmias Schematic representation of possible reentrant circuits. The thick black arrow represents the circulating impulse; thin black lines represent advancing wavefronts in completely refractory tissue; speckled areas are partially refractory tissue; white areas are fully excitable tissue. A is the original model of circus movement around a fixed obstacle. There is a fully excitable gap, and the length and location of the circuit are fixed. B represents circus movement around 2 fixed anatomic obstacles. A fully excitable gap is present. C represents rapidly conducting bundles forming closed loops that serve as preferential circuits through which the impulse may travel. D is the leading circle type of reentry which does not require an anatomic obstacle. Instead, the impulse propagates around a functionally refractory core and among neighboring fibers that have different electrophysiologic properties. Since the refractoriness of the core is variable, the circuit size changes but will be the smallest possible circuit that can continue to propagate an impulse. Functional circuits tend to be small, rapid, and unstable. E represents reentry around a fixed anatomic obstacle, but a fully excitable gap is absent. F demonstrates an area of slowed conduction (hatched lines) between anatomic boundaries, while in G all areas of slowed conduction neighbor an anatomic obstacle. H represents anisotropic reentry. There are differences in the conduction of a single impulse in various fibers as a result of differences in their orientation. https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 21/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Courtesy of Philip J Podrid, MD, FACC. Graphic 52134 Version 5.0 https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 22/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Sites of reentry in supraventricular tachyarrhythmias Reentry may occur around a fixed anatomic obstacle or may be functional, developing in the absence of an anatomic obstacle and resulting from the intrinsic heterogeneity of electrophysiologic properties of the myocardial tissue. Reentrant circuits leading to a supraventricular tachyarrhythmia may develop in various parts of the heart: within and around the sinoatrial node (sinus node reentry); within the atrial myocardium (atrial tachycardia, atrial flutter, or atrial fibrillation); within the atrioventricular (AV) node due to the presence of a slow and fast pathway (atrioventricular nodal reentrant tachycardia); or involving the AV node and an accessory pathway (AP) (atrioventricular reentrant tachycardia). LAF: left anterior fascicle; LPF: left posterior fascicle. Graphic 82249 Version 4.0 https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 23/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Options for hands-free pacemaker/defibrillator pad positioning Positioning options for hands-free pacemaker/defibrillator pads showing anterior/lateral positioning (left) and anterior/posterior positioning (right). Graphic 103268 Version 2.0 https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 24/25 7/6/23, 2:49 PM Basic principles and technique of external electrical cardioversion and defibrillation - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Richard L Page, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/basic-principles-and-technique-of-external-electrical-cardioversion-and-defibrillation/print 25/25

7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Calcium channel blockers in the treatment of cardiac arrhythmias : Christopher Madias, MD : Mark S Link, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 06, 2021. INTRODUCTION Calcium channel blockers (CCBs) are useful antiarrhythmic agents in the management of certain arrhythmias, primarily supraventricular tachyarrhythmias [1-3]. They have diverse electrophysiologic properties and are therefore of variable antiarrhythmic efficacy. The primary settings in which they are useful can be best appreciated from an understanding of their mechanism of action. This topic will review the electrophysiological properties of CCBs and their clinical indications in a variety of arrhythmias. More detailed discussions of the use of CCBs in specific arrhythmias, CCBs for nonarrhythmic conditions, and other treatment options for arrhythmias are presented separately. (See "Calcium channel blockers in the management of chronic coronary syndrome".) (See "Calcium channel blockers in heart failure with reduced ejection fraction".) (See "Choice of drug therapy in primary (essential) hypertension".) (See "Atrioventricular nodal reentrant tachycardia".) (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome".) (See "Wide QRS complex tachycardias: Approach to management".) (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) (See "Control of ventricular rate in atrial flutter".) https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 1/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate ELECTROPHYSIOLOGIC PROPERTIES CCBs, considered class IV antiarrhythmic drugs ( table 1), preferentially affect myocardial tissue with a slow action potential that is mediated by calcium currents. The sinoatrial and atrioventricular nodes depend on calcium currents to generate slowly propagating action potentials. In contrast, fast response myocardial tissues (the atria, specialized infranodal conducting system, the ventricles, and accessory pathways) depend on sodium channel currents. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) CCBs block the slow calcium channel in a dose-dependent fashion, resulting in the following direct effects [3,4]: Slowing of phase 4 depolarization and the conduction velocity of the sinoatrial (SA) and atrioventricular (AV) nodes Lengthening the antegrade and retrograde refractory periods of the AV node Slowing of the sinus rate and increased PR interval on the electrocardiogram (ECG) via the slowing of conduction through the AV node Similar to sodium channel blockers, CCBs with antiarrhythmic activity (ie, verapamil and diltiazem) exhibit "use-dependence." This phenomenon is characterized by an increase in the extent of calcium channel blockade as the frequency of impulse generation and ventricular activation increases. CCBs can also cause significant peripheral vasodilation, an effect which can induce reflex activation of the sympathetic nervous system. As a result, the observed electropharmacologic and pharmacodynamic properties of CCBs represent a combination of direct effects and indirect sympathetic reflex actions. This is particularly important with dihydropyridines (ie, nifedipine), which are potent vasodilators and sympathetic activators. The serum concentration of dihydropyridine CCBs necessary to achieve electrophysiologic activity in humans is much higher than the concentration needed to induce potent vasodilation. Therefore, at prescribed doses, these agents do not exert measurable electrophysiologic effects and appear to be devoid of antiarrhythmic activity. In addition, the reflex activation of the sympathetic nervous system offsets any direct effect of the dihydropyridine CCBs on the sinoatrial and AV nodes. Among nondihydropyridine CCBs, the effect on vasodilation is more apparent with diltiazem than verapamil, which results in verapamil having a more pronounced effect on the SA and AV nodes as its action is not offset by vasodilatory activation of sympathetic activity. https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 2/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate CLINICAL USE Because verapamil and diltiazem primarily affect slow response tissues in the SA and AV nodes, these medications are primarily used for the management of supraventricular tachycardias dependent on conduction through the AV node (ie, atrioventricular nodal reentrant tachycardia and atrioventricular reentrant tachycardia) and for ventricular rate control in atrial fibrillation (AF), atrial flutter, and atrial tachycardia. They are largely ineffective for the direct prevention of most ventricular arrhythmias; however, there are some exceptions, such as the utility of verapamil for the treatment of idiopathic fascicular ventricular tachycardia. (See 'Ventricular arrhythmia' below.) The antiarrhythmic effect of verapamil appears to be similar in adults and children, although less experience is available in children [1,2,5]. Verapamil and to a lesser degree diltiazem may be harmful in patients with hypotension or impaired ventricular function (especially those with a history of heart failure [HF]), and in general should not be used in patients with these conditions. In addition, CCBs should be used cautiously in patients already taking a beta blocker because of the combined negative inotropic and chronotropic effects of both classes of medications [5]. A brief review of these issues is provided here; the use of CCBs in the treatment of specific arrhythmias is discussed in detail elsewhere. Supraventricular tachycardia Both diltiazem and verapamil are accepted as treatments of choice for the termination of supraventricular tachycardias (SVT), such as AV nodal reentrant tachycardia and atrioventricular reciprocating tachycardia due to an accessory pathway. An important exception to the first-line use of these agents occurs in unstable patients with hemodynamic compromise. In an unstable patient with SVT, the preferred treatment is direct electrical cardioversion or intravenous adenosine, a very short-acting AV nodal blocking agent that rarely produces additional hypotension. (See "Atrioventricular nodal reentrant tachycardia".) Another situation in which CCBs should be avoided or used with caution is in the presence of a wide QRS complex tachycardia. If there is no doubt that a wide QRS complex tachycardia is supraventricular in origin, therapy directed at the AV node and the SVT may be given. In such cases, management is similar to that described above for SVT with a normal QRS duration. However, with a wide QRS complex tachycardia that is potentially ventricular tachycardia, CCBs blockers should be avoided, as there is a risk for hemodynamic deterioration following the administration of these medications. (See "Wide QRS complex tachycardias: Approach to management".) https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 3/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate CCBs appear to be of limited value in other forms of reentrant and automatic SVT [2,3,5,6]. Limited data exist concerning their role in SA nodal reentrant tachycardia or in atrial tachycardia due to an ectopic focus or intraatrial reentry (except for rate control by AV nodal blockade). However, oral verapamil may convert paroxysmal atrial tachycardia with block to sinus rhythm under certain circumstances, such as digoxin toxicity. Multifocal atrial tachycardia Either a non-dihydropyridine calcium channel blocker (ie, verapamil and diltiazem) or a beta blocker is usually the treatment of choice for multifocal atrial tachycardia. These drugs impair AV nodal conduction and will therefore slow the ventricular rate in this disorder; they do not usually reverse or prevent this arrhythmia. (See "Multifocal atrial tachycardia".) Atrial fibrillation and flutter Verapamil and diltiazem are used both acutely (via the intravenous route) and chronically (via the oral route) to slow the ventricular response in AF and atrial flutter. Their efficacy for rate control is due to their direct action to slow conduction and prolonged refractoriness in the AV node. Verapamil and diltiazem reduce both the resting and the exercise-induced increases in heart rate, whereas the major effect of digoxin (which works on the AV node via enhancing vagal tone) is on the resting rate. Therefore, verapamil and diltiazem are generally preferred to digoxin as monotherapy (in the absence of underlying HF) [7]. However, for patients with inadequate ventricular rate control with monotherapy, the concurrent use of digoxin or a beta blocker with verapamil or diltiazem has an additive depressant effect on the AV node. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Control of ventricular rate in atrial flutter".) AV nodal blocking medications that are normally used to control the ventricular rate during AF (most importantly) or atrial flutter, including the CCBs verapamil and diltiazem, are contraindicated in patients with an accessory pathway and preexcitation. This is discussed in further detail in another topic. (See "Treatment of arrhythmias associated with the Wolff- Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.) CCBs also have a propensity to convert atrial flutter to fibrillation in a small number of patients, presumably due to a shortening of the atrial effective refractory period [8]. CCBs have been regarded as having little value in the termination and prevention of AF. However, verapamil may prevent the atrial electrical remodeling that occurs in AF, and the combination of verapamil with another agent has been shown to be effective in preventing AF recurrence [9]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Verapamil'.) https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 4/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Ventricular arrhythmia The role of CCBs in ventricular arrhythmias is less well defined [10- 15]. CCBs inadequately suppress ventricular premature beats in patients with structurally normal or abnormal hearts. They also have no significant effect on arrhythmia frequency or arrhythmic mortality in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, or mitral valve prolapse [1,2,16]. As a class, CCBs have a limited role in the treatment of ventricular tachycardia (VT) or ventricular fibrillation (VF) in the setting of organic heart disease. They do not suppress nonsustained VT, nor do they prevent the inducibility of VT/VF after programmed electrical stimulation. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management".) However, calcium blockers may have a role in the following clinical settings: They are often effective when ventricular tachycardia or fibrillation is due to transient coronary artery spasm [17]. (See "Vasospastic angina".) They may have a role for polymorphic VT in the structurally normal heart or in those with familial catecholaminergic polymorphic VT that is due to a RyR2 or calsequestrin gene mutation [18]. (See "Catecholaminergic polymorphic ventricular tachycardia".) Exercise-triggered VT (called repetitive monomorphic VT) having the morphologic pattern of left bundle branch block and an inferiorly directed axis deviation (right ventricular outflow tract tachycardia) or a pattern of right bundle branch block and rightward axis (left ventricular outflow tract tachycardia) may respond predictably and promptly to intravenous verapamil. Such an arrhythmia may occur in patients without identifiable cardiac disease [12,19,20]. (See "Ventricular tachycardia in the absence of apparent structural heart disease".) A relatively rare, sustained VT that occurs in patients without evidence of structural heart disease has the morphologic pattern of right bundle branch block with left axis deviation [21-23]. This arrhythmia, which is called an idiopathic fascicular ventricular tachycardia (primarily of the left posterior fascicle), verapamil sensitive tachycardia, or Belhassen tachycardia, appears to be a distinct clinical entity and, in most cases, responds to intravenous verapamil [21,24]. (See "Ventricular tachycardia in the absence of apparent structural heart disease".) Arrhythmia mortality after myocardial infarction Routine treatment of the post-MI patient with a calcium channel blocker is not justified. It is possible that CCBs might benefit selected https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 5/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate patients after MI, particularly those with a non-Q wave infarct, without HF, and who are unable to take a beta blocker [25-27]. However, the level of benefit, if present, is small. Additionally, there are subsets of patients in whom certain CCBs may increase mortality (see "Overview of the nonacute management of ST-elevation myocardial infarction" and "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Calcium channel blockers' and "Major side effects and safety of calcium channel blockers" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction", section on 'Calcium channel blockers'). CCBs reverse coronary vasospasm and attenuate myocardial ischemic damage following experimental coronary occlusion [28]. These observations led to clinical studies assessing if these drugs might increase survival in patients with acute myocardial infarction (MI). Numerous randomized controlled trials of CCBs (diltiazem, verapamil, and nifedipine) have been analyzed [29,30]. No agent was found to unequivocally and decisively decrease mortality; in fact, pooled data for five CCBs suggested an unfavorable trend in total mortality, particularly with the short-acting dihydropyridines ( figure 1). This is in contrast to the clear benefit associated with other drugs such as beta blockers, statins, aspirin, and angiotensin converting enzyme inhibitors. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS In addition to adenosine, the calcium channel blockers (CCBs) diltiazem and verapamil are treatments of choice for the termination of supraventricular tachycardia. (See 'Supraventricular tachycardia' above and "Atrioventricular nodal reentrant tachycardia".) Diltiazem and verapamil can be used both acutely (via the intravenous route) and chronically (via the oral route) to slow the ventricular response in atrial fibrillation (AF), atrial tachycardia, and atrial flutter. (See 'Atrial fibrillation and flutter' above.) https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 6/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate In patients with hypotension or impaired ventricular function, especially those with a history of heart failure, diltiazem and verapamil may be harmful, and are relatively contraindicated. (See 'Clinical use' above.) CCBs should be used cautiously in patients already taking a beta blocker because of the combined negative inotropic and chronotropic effects of both classes of medications. (See 'Clinical use' above.) In a patient with a wide QRS complex tachycardia that is potentially ventricular tachycardia, CCBs should be avoided, as there is a risk for hemodynamic deterioration following the administration of these medications. (See 'Supraventricular tachycardia' above and "Wide QRS complex tachycardias: Approach to management".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Haines DE, DiMarco JP. Current therapy for supraventricular tachycardia. Curr Probl Cardiol 1992; 17:411. 2. Singh BN, Ellrodt G, Peter CT. Verapamil: a review of its pharmacological properties and therapeutic use. Drugs 1978; 15:169. 3. Singh BN, Hecht HS, Nademanee K, Chew CY. Electrophysiologic and hemodynamic effects of slow-channel blocking drugs. Prog Cardiovasc Dis 1982; 25:103. 4. Cranefield PF, Aronson RS, Wit AL. Effect of verapamil on the noraml action potential and on a calcium-dependent slow response of canine cardiac Purkinje fibers. Circ Res 1974; 34:204. 5. Singh BN, Nademanee K, Baky SH. Calcium antagonists. Clinical use in the treatment of arrhythmias. Drugs 1983; 25:125. 6. Boriani G, Bertaglia E, Carboni A, et al. A controlled study on the effect of verapamil on atrial tachycaarrhythmias in patients with brady-tachy syndrome implanted with a DDDR pacemaker. Int J Cardiol 2005; 104:73. 7. Tsuneda T, Yamashita T, Fukunami M, et al. Rate control and quality of life in patients with permanent atrial fibrillation: the Quality of Life and Atrial Fibrillation (QOLAF) Study. Circ J 2006; 70:965. 8. Singh BN. Control of cardiac arrhythmias by modulation of the slow myocardial channel. In: Calcium channels, their properties, functions, regulation, and clinical relevance, Horowitz L, Partridge LD, Leach JK (Eds), CRC Press, Boca Raton 1991. p.327. https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 7/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate 9. De Simone A, De Pasquale M, De Matteis C, et al. VErapamil plus antiarrhythmic drugs reduce atrial fibrillation recurrences after an electrical cardioversion (VEPARAF Study). Eur Heart J 2003; 24:1425. 10. Belhassen B, Horowitz LN. Use of intravenous verapamil for ventricular tachycardia. Am J Cardiol 1984; 54:1131. 11. Wellens HJ, B r FW, Lie KI, et al. Effect of procainamide, propranolol and verapamil on mechanism of tachycardia in patients with chronic recurrent ventricular tachycardia. Am J Cardiol 1977; 40:579. 12. Gill JS, Blaszyk K, Ward DE, Camm AJ. Verapamil for the suppression of idiopathic ventricular tachycardia of left bundle branch block-like morphology. Am Heart J 1993; 126:1126. 13. Sung RJ, Shapiro WA, Shen EN, et al. Effects of verapamil on ventricular tachycardias possibly caused by reentry, automaticity, and triggered activity. J Clin Invest 1983; 72:350. 14. Sclarovsky S, Strasberg B, Fuchs J, et al. Multiform accelerated idioventricular rhythm in acute myocardial infarction: electrocardiographic characteristics and response to verapamil. Am J Cardiol 1983; 52:43. 15. Grenadier E, Alpan G, Maor N, et al. Polymorphous ventricular tachycardia in acute myocardial infarction. Am J Cardiol 1984; 53:1280. 16. McKenna, WJ, Harris, et al. Hypertrophic cardiomyopathy: Comparison of verapamil and amiodarone in the treatment of arrhythmia. Br Heart J 1980; 45:354. 17. Kimura E, Tanaka K, Mizuno K, et al. Suppression of repeatedly occurring ventricular fibrillation with nifedipine in variant form of angina pectoris. Jpn Heart J 1977; 18:736. 18. Swan H, Laitinen P, Kontula K, Toivonen L. Calcium channel antagonism reduces exercise- induced ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia patients with RyR2 mutations. J Cardiovasc Electrophysiol 2005; 16:162. 19. Palileo EV, Ashley WW, Swiryn S, et al. Exercise provocable right ventricular outflow tract tachycardia. Am Heart J 1982; 104:185. 20. Wu D, Kou HC, Hung JS. Exercise-triggered paroxysmal ventricular tachycardia. A repetitive rhythmic activity possibly related to afterdepolarization. Ann Intern Med 1981; 95:410. 21. Lin FC, Finley CD, Rahimtoola SH, Wu D. Idiopathic paroxysmal ventricular tachycardia with a QRS pattern of right bundle branch block and left axis deviation: a unique clinical entity with specific properties. Am J Cardiol 1983; 52:95. 22. German LD, Packer DL, Bardy GH, Gallagher JJ. Ventricular tachycardia induced by atrial stimulation in patients without symptomatic cardiac disease. Am J Cardiol 1983; 52:1202. https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 8/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate 23. Belhassen B, Shapira I, Pelleg A, et al. Idiopathic recurrent sustained ventricular tachycardia responsive to verapamil: an ECG-electrophysiologic entity. Am Heart J 1984; 108:1034. 24. Nogami A. Idiopathic left ventricular tachycardia: assessment and treatment. Card Electrophysiol Rev 2002; 6:448. 25. Verapamil in acute myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction. Eur Heart J 1984; 5:516. 26. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II DAVIT II). Am J Cardiol 1990; 66:779. 27. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988; 319:385. 28. Singh BN, Nayler WG. The role of calcium antagonists in acute myocardial infarction. In: Earl y interventions in acute myocardial infarction, Rapaport E (Ed), Kluwer Academic Publication s, Boston 1989. p.123. 29. Held PH, Yusuf S. Impact of calcium channel blockers on mortality. In: Cardiovascular pharm acology and therapeutics, Singh BN, Dzau VJ, Vanhoutte PM, Woosley RL (Eds), Churchill Livi ngtion, New York 1993. p.525. 30. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991; 67:1295. Topic 951 Version 26.0 https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 9/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 10/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 11/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Calcium channel blockers do not change mortality after acute myocardial infarction (MI) A meta-analysis of controlled trials of calcium channel blockers in post-myocardial infarction patients failed to show any effect on mortality. However, the agents that reduce heart rate, particularly verapamil, showed a trend toward an improved survival while nifedipine, which increases heart rate, showed a trend toward an increased mortality. Data from Held PH, Yusuf S. In: Cardiovascular Pharmacology and Therapeutics, Singh BN, Dzau V, Vanhoutte PM, Woosley RL (Eds), Churchill Livingstone, New York, 1993, p. 525. Graphic 74199 Version 3.0 https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 12/13 7/6/23, 2:48 PM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Contributor Disclosures Christopher Madias, MD No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 13/13

7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac implantable electronic devices: Patient follow-up : Bradley P Knight, MD, FACC : Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 24, 2023. INTRODUCTION As more people are living longer with more significant cardiac disease, permanent pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy st (CRT) devices are being implanted more frequently. Beginning early in the 21 century, there has also been an expansion in the indications for cardiac implantable electronic devices (CIEDs, a term which includes PPMs, ICDs, and CRT devices, as well as other devices such as insertable cardiac monitors [also sometimes referred to as implantable cardiac monitors or implantable loop recorders]), and device therapy has become more commonplace. Issues related to follow-up of patients with a CIED (PPM, ICD, or CRT devices only) will be reviewed here. The indications for PPM, ICD, and CRT use, as well as general issues related these devices, are discussed separately. (See "Permanent cardiac pacing: Overview of devices and indications" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Modes of cardiac pacing: Nomenclature and selection".) (See "Permanent cardiac pacing: Overview of devices and indications".) (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 1/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) (See "Modes of cardiac pacing: Nomenclature and selection".) METHODS AND FREQUENCY OF CIED FOLLOW-UP For several decades, follow-up evaluation of cardiac implantable electronic devices (CIEDs) required in-person assessment for device interrogation on a recurring basis. Subsequently, transtelephonic monitoring (TTM) became available for some types of permanent pacemakers (PPMs). Current technology, however, has evolved to enable comprehensive and safe remote monitoring for nearly all types of CIEDs [1-3]. Remote monitoring provides alerts in real-time (or on a daily basis), but is not as comprehensive as a complete device interrogation. A major difference between remote monitoring and an in-person interrogation is that a CIED cannot be adjusted or reprogrammed remotely. The equipment required for remote monitoring, which is proprietary and unique to each manufacturer just as the in-person programmers are, along with requirements (eg, internet connection) and instructions for use, should be discussed with the patient as part of the implantation process. Office-based versus remote follow-up For most patients, the majority of CIED follow-up device interrogations can be done either in person or remotely ( table 1) [3-5]. Following the immediate post-implant check, an initial in-person evaluation (IPE) should occur within weeks to three months post-implantation, and ideally one IPE annually for the duration of therapy with a CIED [6]. With the exception of these initial and annual IPEs, all other CIED follow-up assessments may be done either in person or remotely (if available) ( table 2), an approach consistent with the 2015 Heart Rhythm Society expert consensus statement on the remote device interrogation and monitoring [6]. Remote monitoring is strongly encouraged for patients. Multiple prospective randomized trials have demonstrated the feasibility and safety of remote CIED monitoring as well as identified a greater number of clinically significant issues and shortened the time to clinical action [7-15]. Multiple nonrandomized observational studies have suggested improved survival for patients with remote CIED monitoring; however, this has not been universally replicated in prospective randomized trials [16-18]. In a 2015 systematic review and meta-analysis of nine randomized trials involving 6469 ICD recipients who were randomized to either remote monitoring (3496 patients) or in-office follow-up (2973 patients), patients assigned to remote monitoring had nonsignificant reductions in total mortality (odds ratio [OR] 0.83; 95% CI 0.58-1.17), cardiovascular mortality (OR 0.66; 95% CI 0.41-1.09), and hospitalizations (OR 0.83; 95% CI 0.63- 1.10) along with significantly fewer inappropriate shocks (OR 0.55; 95% CI 0.38-0.80) [19]. Further evidence of improvements in mortality was seen in a 2017 analysis using patient-level data from https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 2/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate only three of the nine randomized trials included in the 2015 meta-analysis (IN-TIME, ECOST, and TRUST) [7,11,13], in which the absolute risk of overall mortality was reduced by 1.9 percent (95% CI 0.1-3.8 percent) [20]. In the 2019 RM-ALONE trial, which included 445 patients with CIEDs (151 ICDs and 294 PPMs including 54 percent pacemaker-dependent patients), participants were randomized to in-office device interrogation or remote device interrogation every six months; all patients in both groups were remotely monitored with daily transmission of alerts with unscheduled office visits at the provider's discretion following an alert [21]. Over a mean follow-up of 21 months, there was no significant difference between the two groups in major adverse cardiac events (20 percent in each group). More patients in the remote interrogation group had an unscheduled office visit (55 percent versus 45 percent of office interrogation patients); however, the remote interrogation group had 79 percent fewer total office visits (136 versus 653 in the office interrogation group). Overall, a strategy of remote-only device monitoring and interrogation appears to be as safe and efficacious as a strategy that includes twice yearly in-office visits. Important limitations include the relatively small sample size and the absence of CRT devices. Additional data from a multi-center randomized trial of remote-only versus periodic IPE, published after the RM-ALONE trial, suggest that remote-only follow-up for up to two years is safe and associated with significantly fewer office visits [22]. While most patients find remote follow-up more convenient, some may find in-office follow-up preferable for a variety of reasons (eg, the desire to be seen in-person more frequently for reassurance, social interaction, etc). With this in mind, the approach to CIED follow-up must be tailored to each individual patient. At present, standard practice continues to include at least an annual office visit, which is felt to be adequate for most patients. (See 'Frequency of CIED follow- up visits' below.) In some instances, an IPE may be associated with significant risks to patients and healthcare providers. For example, during the COVID-19 pandemic, when the risk of viral transmission was very high, it was recommended by experts to substitute IPEs with remote checks. In April of 2020, the Heart Rhythm Society COVID-19 Task Force recommended that every effort be made to perform CIED interrogation via remote monitoring rather than via IPE [23]. The recommendations stated that IPEs for CIEDs should be limited to potentially hazardous lead or generator issues not adequately assessed by remote monitoring, absolute need for reprogramming, or other issues per physician judgment. A creative response to the COVID-19 pandemic was the creation of drive-through pacing clinics [24]. Frequency of CIED follow-up visits The frequency of follow-up visits for patients with a CIED will vary according to the type of device, age of the device, and clinical status of the patient https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 3/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate ( table 2) [4,5]. In general, however, most patients with a CIED should have an annual IPE, with one or more additional follow-up assessments (either remotely or in-person) throughout the year. Patients who have received therapies (eg, ICD shocks or antitachycardia pacing), as well as those whose devices are approaching the end of battery life, may require more frequent follow- up. Furthermore, patients with advisory generators and/or leads may require more frequent follow-up, or additional testing (eg, lead fluoroscopy) during follow-up. Patients who have an ICD which was placed for primary prevention may require less frequent follow-up. In the REFORM trial of 155 patients receiving a primary prevention ICD based on MADIT II criteria, patients were randomized (following a routine 3-month post-implant visit in all patients) to either 3-month or 12-month follow-up intervals and followed for 24 months [25]. Patients in the 12-month interval group had significantly fewer in-office follow-up visits (1.6 versus 3.9 visits per year), with no significant differences in mortality or hospitalization. While these findings are encouraging regarding the potential for reduced frequency of follow-up in stable recipients of primary prevention ICDs, our recommendations for follow-up will remain unchanged until these data are replicated in other larger patient populations and/or until professional societies alter follow-up guidelines. (See 'Summary and recommendations' below.) FOLLOW-UP OF THE PATIENT WITH A PACEMAKER All patients with a permanent pacemaker (PPM) require routine follow-up on a periodic basis. Both office-based and remote follow-up strategies are available, safe, and effective for monitoring of PPM function ( table 1). For most stable patients with a PPM, follow-up should occur every three to four months ( table 2). However, the frequency of these follow-up visits may increase in certain clinical situations (eg, device nearing battery depletion or a suspected device infection). PPM evaluation Whether the system involves a single-chamber or dual-chamber pacemaker, the evaluation is similar. Device interrogation includes the evaluation of several aspects of device function (see "Pacing system malfunction: Evaluation and management"): Assessment of the presenting and underlying rhythms Programmed pacing parameters Pacing and sensing thresholds and lead impedance Evaluation of pacing capture Review of recorded episodes of arrhythmia detection, if the device is capable of storing these data Review of battery status and estimation of time until the pulse generator must be replaced https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 4/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate Review of all additional data collected Establish programmed parameters Interrogate the pacemaker so that the programmed parameters as well as measured data of lead and battery function are obtained. Evaluate capture To evaluate capture, the paced electrocardiogram (ECG) should be carefully examined. Contemporary pacemakers have automatic pacing threshold testing algorithms. The following points may be helpful when there is difficulty interpreting the auto- threshold tracings or when capture thresholds are determined manually. If the native rate is faster than the paced rate, thereby inhibiting the system, the rate and/or atrioventricular (AV) interval should be reprogrammed so that stimuli are visible. Capture is intact if there is a distinct change in the morphology of the QRS or P wave that follows each stimulus and if this morphology is stable and different from the native complexes. If this is not seen, there is noncapture, and the differential diagnosis for failure to capture should be considered. (See "Pacing system malfunction: Evaluation and management", section on 'Causes of loss of capture'.) If initial evaluation shows a pacing stimulus that is simultaneous with the native QRS complex, changing the rate and AV intervals will be helpful to distinguish capture from fusion. It may be necessary to assess the capture threshold by adjusting the output and demonstrating loss of capture before it is certain that capture was intact on the initial tracings. If there is loss of capture, one should also consider whether this is true failure to capture or functional loss of capture (ie, failure to sense a native QRS complex followed by the release of the pacing stimulus at a time when the myocardium is physiologically refractory and incapable of being stimulated). Evaluate sensing To evaluate sensing, intrinsic complexes must be present. Most contemporary pacemakers have automatic sensing threshold testing algorithms. Similar to capture determination, the following points may be helpful when there is difficulty interpreting the automatic sensing determination or when sensing thresholds are determined manually. If the rhythm is totally paced, the paced rate can be decreased, the AV delay increased, or the unit programmed to a non-tracking mode in order to evaluate ventricular sensing. If the system is then inhibited and the native rhythm appears, sensing is intact. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 5/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate To evaluate atrial sensing, it may be necessary to reduce the base pacing rate and shorten the AV interval. This will result in P wave tracking in the presence of in-tact atrial sensing. If sensing is not present or consistent, the etiology should be evaluated and appropriate corrective actions taken. Event markers Event markers are indicators of pacing and sensing reported directly by the pacemaker. However, the fact that the pacemaker released an output pulse does not mean that the pacing stimulus effectively captured the heart muscle and resulted in a depolarization. In addition, the fact that the system reports that it sensed an event does not mean that this was an appropriate complex to be sensed. Thus, the event markers need to be correlated with the surface ECG recordings and/or intracardiac electrogram, and are most valuable when the event markers are printed along with a simultaneously recorded surface ECG or intracardiac electrogram. A sense marker coinciding with a native P or R wave confirms proper sensing, unless there is a P marker over a native R wave or vice versa, in which case there may be a problem such as a dislodged atrial lead, inappropriate connection of the atrial and ventricular leads into the pulse generator, or far-field sensing. If the event markers indicated that the pacemaker is sensing an event that is not visible on the surface ECG, further evaluation is required. Electrogram assessment Endocardial electrograms can be particularly helpful in examining the morphology of the native complexes to determine capture as well as why a given signal may not have been sensed. It is also useful in examining the signals that are being sensed when these are not readily identified from the surface ECG. Electrogram telemetry will greatly facilitate the evaluation, allowing it to be completed more expeditiously and provide information that may not be easily acquired. FOLLOW-UP OF THE PATIENT WITH AN ICD All patients with an implantable cardioverter-defibrillator (ICD) require routine follow-up on a periodic basis as well as semi-urgent or urgent follow-up after receiving a shock from the ICD ( table 2). Both office-based and remote follow-up strategies are available, safe, and effective for monitoring of ICD function ( table 1) [6]. For most stable patients with an ICD who have not received a shock, follow-up should occur every three months. For most visits, follow-up may be in person or remote (if available) according to local protocol, but at least one follow-up per year should be an IPE. However, the frequency of these follow-up visits may increase in certain clinical situations https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 6/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate (eg, device nearing end of battery life or a CIED or lead that has been placed on a medical advisory). (See 'Routine ICD follow-up' below.) Patients with an ICD who have received a single ICD shock and who otherwise feel well should have follow-up within 24 to 48 hours. This follow-up may be done in person or remotely (if available). Patients who receive multiple ICD shocks within a short period of time (minutes to hours), or the patient who receives a single shock and feels unwell, require more urgent evaluation. (See 'Follow-up after ICD discharge' below.) Routine ICD follow-up Device interrogation and a detailed review of device function should be performed with each visit [26]. Monitoring for evidence of device complications should also be performed. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Pulse generator complications' and "Cardiac implantable electronic devices: Long-term complications".) Device interrogation includes the evaluation of several aspects of device function: Programmed detection criteria and programmed therapy for ventricular tachycardia and fibrillation (VT and VF). Pacing and sensing thresholds. Pacing and shocking lead impedance. Signal amplitudes and morphologies. Review of recorded episodes of arrhythmia detection and device activation, including pacing and shocks. Current devices include the date and time of each episode and store the electrograms from the event. In systems containing an atrial lead, review of diagnostic information regarding atrial arrhythmias. Review of battery status and estimation of time until the pulse generator must be replaced. Review of all additional data collected DFT testing as part of routine ICD follow-up In the past, many centers did defibrillation threshold (DFT) testing at the time of initial implant and at some periodic basis during follow-up. However, the induction and termination of a ventricular tachyarrhythmia has potential complications, is unpleasant for the patient, and adds additional cost, with a benefit to the patient that has not been proven. Although DFT testing at the time of the initial implant remains somewhat controversial, we do not recommend performing DFT testing as part of routine follow-up. The need for routine DFT testing has been assessed in large randomized clinical trials [27,28]. Both the SAFE-ICD and SIMPLE trials demonstrated that DFT testing does not improve shock https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 7/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate efficacy or reduce arrhythmic death. Follow-up after ICD discharge Patients who receive one or more shocks from their ICD require review of the episode and either remote or in-clinic follow-up depending on the clinical situation and the institutional guidelines. The timing and urgency of the follow-up varies according to the clinical scenario: Patients who receive a single ICD shock without loss of consciousness should have office- based or remote follow-up within 24 to 48 hours. If remote review of the data reveals a single appropriate ICD shock and the patient is feeling well, an IPE may not be required. However, if neither office-based nor remote follow-up is available for longer than 24 to 48 hours, the patient may need to be seen in the emergency department. For patients who receive a single ICD shock with loss of consciousness or near syncope, the decision as to whether the patient needs to be seen in clinic or in the emergency department will vary according to the clinical situation and the guidelines followed by a specific follow-up center. If a patient has a single appropriate shock as determined by review of remote data, or if the patient is feeling well and was not injured with loss of consciousness, some centers may not recommend a face-to-face visit. If the clinical situation is uncertain and/or if the patient is concerned or has been injured during the loss of consciousness, then the patient should be seen in the clinic or emergency department. Patients who receive multiple ICD shocks within a short period of time (minutes to hours) should have more urgent evaluation in the emergency department. Patients who are seen in the emergency department should all have a brief history and physical examination, 12- lead electrocardiogram (ECG), and additional laboratory testing as the clinical presentation dictates: Troponin level in a patient with suspected acute myocardial ischemia Potassium and magnesium in a patient with suspected electrolyte depletion Toxin screen in a patient with suspected intentional or inadvertent drug overdose Because ICDs are placed in patients felt to be at an increased risk of ventricular arrhythmias or sudden cardiac death, ICD discharge is an anticipated event during the long-term follow-up of such patients. Because a single ICD shock frequently represents the appropriate termination of a sustained ventricular tachyarrhythmia, patients who receive only a single ICD shock without loss of consciousness may have follow-up (either office-based or remotely) within 24 to 48 hours to ascertain that the device is functioning properly, to exclude other causes of the ICD shock (eg, supraventricular tachyarrhythmias, device malfunction) and to provide patient reassurance. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 8/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate Even though a single ICD shock often represents the appropriate termination of a sustained ventricular tachyarrhythmia, ICD discharges that are accompanied by loss of consciousness or near syncope should be promptly reviewed. These patients may need to have programming changes or, in the event of injury related to syncope, more immediate follow-up, usually in the clinic or the emergency department. Patients who receive multiple ICD shocks or clusters of shocks within minutes to hours require immediate evaluation in the emergency department to determine the cause. Such recurrent discharges may be either appropriate (due to recurrent VT and electrical storm) or inappropriate (due to a supraventricular tachycardia with a rapid rate, or to device malfunction). If frequent discharges are due to recurrent VT and electrical storm, additional therapy (such as an antiarrhythmic drug or catheter ablation) may be required. These therapies are discussed in detail elsewhere. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Other treatment options' and "Electrical storm and incessant ventricular tachycardia".) Prognosis following ICD shocks Several clinical trials have shown that patients who receive appropriate ICD therapy have a higher mortality than patients who do not. In the SCD-HeFT trial, both appropriate and inappropriate ICD therapy were associated with a higher mortality during follow-up [29]. The delivery of therapy by an ICD, therefore, should prompt clinicians to re- evaluate the patient's overall clinical status and therapeutic plan. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Driving following ICD shocks Guidelines for driving following ICD shocks have been developed by professional societies [30,31]. Legal restrictions on driving in such patients vary widely between municipalities, and each clinician and patient should be aware of his/her own local guidelines. A more extensive discussion of driving restrictions in patients with an ICD is presented separately. (See "Driving restrictions in patients with an implantable cardioverter-defibrillator".) FOLLOW-UP OF THE PATIENT WITH A CRT DEVICE Cardiac resynchronization therapy (CRT) is a device-based therapy which involves simultaneous pacing of both ventricles (biventricular or BiV pacing) or left ventricular pacing in an effort to optimize cardiac synchrony and function. CRT may involve pacing only (CRT-P) or may be combined with the typically therapeutic functions of an ICD (CRT-D). https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 9/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate All patients with a CRT device (either CRT-P or CRT-D) require routine follow-up on a periodic basis, and patients with a CRT-D device require semi-urgent or urgent follow-up after receiving one or more shocks from the ICD ( table 2). Both office-based and remote follow-up strategies are available, safe, and effective for monitoring of CRT function ( table 1). In general, the protocol for follow-up evaluation for CRT-P or CRT-D devices is similar to that for standard PPMs or ICDs. For most stable patients with a CRT-P (or CRT-D device with no ICD shocks), follow-up should occur every three to four months. For most visits, follow-up may be in person or remote (if available) according to local protocol, but at least one follow-up per year should be an IPE. However, the frequency of these follow-up visits may increase in certain clinical situations (eg, device nearing battery depletion or a suspected device infection). (See 'PPM evaluation' above and 'Routine ICD follow-up' above.) Patients with a CRT-D device who have received a single ICD shock should have follow-up within 24 to 48 hours. This follow-up may be done in person or remotely (if available). Patients who receive multiple ICD shocks within a short period of time (minutes to hours) require more urgent evaluation. (See 'Follow-up after ICD discharge' above.) The optimal approach to programming CRT devices is discussed in greater detail separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Concerns have been raised regarding the potential for cyber interference with CIEDs. Generally, this has not been shown to be a clinical concern. However, manufacturers are exploring ways to better protect devices from any hacking potential [32-34]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 10/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Sudden cardiac arrest (The Basics)") Beyond the Basics topic (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS The frequency of follow-up visits for patients with a cardiac implantable electronic device (CIED) will vary according to the type of device, age of the device, and clinical status of the patient ( table 2). Follow-up after pacemaker For most stable patients with a permanent pacemaker (PPM), follow-up should occur every three to four months. (See 'Follow-up of the patient with a pacemaker' above.) Follow-up after implantable cardioverter-defibrillator (ICD) For most stable patients with an ICD who have not received a shock, follow-up should occur every three months. (See 'Follow-up of the patient with an ICD' above.) Frequency of visits For stable patients with either a PPM or ICD, follow-up may be in person or remote (if available) according to local protocol, but at least one follow-up per year should be an in-person evaluation (IPE) ( table 1). The frequency of these follow-up visits may increase in certain clinical situations (eg, device nearing end of battery life or a suspected device infection). (See 'Follow-up of the patient with a pacemaker' above and 'Routine ICD follow-up' above.) Follow-up post-ICD shock Single shock Patients who receive a single ICD shock without loss of consciousness, and who otherwise feel well, should have office-based or remote follow-up within 24 to 48 hours. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 11/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate If remote review of the data reveals a single appropriate ICD shock and the patient is feeling well, an IPE may not be required. However, if neither office-based nor remote follow-up is available for longer than 24 to 48 hours, the patient may need to be seen in the emergency department. If the clinical situation is uncertain and/or if the patient is concerned or has been injured during the loss of consciousness, then the patient should be seen in the clinic or emergency department. Multiple shocks Patients who receive multiple ICD shocks within a short period of time (minutes to hours), or the patient who receives a single shock and feels unwell, should have more urgent evaluation in the emergency department. Patients who are seen in the emergency department should all have a brief history and physical examination, 12-lead electrocardiogram, and additional laboratory testing as the clinical presentation dictates. (See "Cardiac implantable electronic devices: Long-term complications".) ACKNOWLEDGMENT The UpToDate editorial staff thank David L. Hayes, MD, and Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. The author would like to thank Carrie Baumann-Matta, RN, for valuable input on this review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lampert R. Managing with pacemakers and implantable cardioverter defibrillators. Circulation 2013; 128:1576. 2. Al-Khatib SM, Friedman P, Ellenbogen KA. Defibrillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 3. Ploux S, Varma N, Strik M, et al. Optimizing implantable cardioverter-defibrillator remote monitoring: a practical guide. J Am Coll Cardiol EP 2017; 3:315. 4. Dubner S, Auricchio A, Steinberg JS, et al. ISHNE/EHRA expert consensus on remote monitoring of cardiovascular implantable electronic devices (CIEDs). Europace 2012; 14:278. 5. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 12/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate personnel, frequency and ethical considerations. Heart Rhythm 2008; 5:907. 6. Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015; 12:e69. 7. Gu don-Moreau L, Lacroix D, Sadoul N, et al. A randomized study of remote follow-up of implantable cardioverter defibrillators: safety and efficacy report of the ECOST trial. Eur Heart J 2013; 34:605. 8. Mabo P, Victor F, Bazin P, et al. A randomized trial of long-term remote monitoring of pacemaker recipients (the COMPAS trial). Eur Heart J 2012; 33:1105. 9. Crossley GH, Chen J, Choucair W, et al. Clinical benefits of remote versus transtelephonic monitoring of implanted pacemakers. J Am Coll Cardiol 2009; 54:2012. 10. Crossley GH, Boyle A, Vitense H, et al. The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial: the value of wireless remote monitoring with automatic clinician alerts. J Am Coll Cardiol 2011; 57:1181. 11. Varma N, Epstein AE, Irimpen A, et al. Efficacy and safety of automatic remote monitoring for implantable cardioverter-defibrillator follow-up: the Lumos-T Safely Reduces Routine Office Device Follow-up (TRUST) trial. Circulation 2010; 122:325. 12. Gu don-Moreau L, Kouakam C, Klug D, et al. Decreased delivery of inappropriate shocks achieved by remote monitoring of ICD: a substudy of the ECOST trial. J Cardiovasc Electrophysiol 2014; 25:763. 13. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014; 384:583. 14. Al-Khatib SM, Piccini JP, Knight D, et al. Remote monitoring of implantable cardioverter defibrillators versus quarterly device interrogations in clinic: results from a randomized pilot clinical trial. J Cardiovasc Electrophysiol 2010; 21:545. 15. Landolina M, Perego GB, Lunati M, et al. Remote monitoring reduces healthcare use and improves quality of care in heart failure patients with implantable defibrillators: the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study. Circulation 2012; 125:2985. 16. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010; 122:2359. 17. Akar JG, Bao H, Jones PW, et al. Use of Remote Monitoring Is Associated With Lower Risk of Adverse Outcomes Among Patients With Implanted Cardiac Defibrillators. Circ Arrhythm https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 13/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate Electrophysiol 2015; 8:1173. 18. Varma N, Piccini JP, Snell J, et al. The Relationship Between Level of Adherence to Automatic Wireless Remote Monitoring and Survival in Pacemaker and Defibrillator Patients. J Am Coll Cardiol 2015; 65:2601. 19. Parthiban N, Esterman A, Mahajan R, et al. Remote Monitoring of Implantable Cardioverter- Defibrillators: A Systematic Review and Meta-Analysis of Clinical Outcomes. J Am Coll Cardiol 2015; 65:2591. 20. Hindricks G, Varma N, Kacet S, et al. Daily remote monitoring of implantable cardioverter- defibrillators: insights from the pooled patient-level data from three randomized controlled trials (IN-TIME, ECOST, TRUST). Eur Heart J 2017; 38:1749. 21. Garc a-Fern ndez FJ, Osca Asensi J, Romero R, et al. Safety and efficiency of a common and simplified protocol for pacemaker and defibrillator surveillance based on remote monitoring only: a long-term randomized trial (RM-ALONE). Eur Heart J 2019; 40:1837. 22. Watanabe E, Yamazaki F, Goto T, et al. Remote Management of Pacemaker Patients With Biennial In-Clinic Evaluation: Continuous Home Monitoring in the Japanese At-Home Study: A Randomized Clinical Trial. Circ Arrhythm Electrophysiol 2020; 13:e007734. 23. Heart Rhythm Society COVID-19 Task Force Update. Management of cardiac implantable ele ctronic devices (CIED). 2020. https://www.hrsonline.org/COVID19-Challenges-Solutions/hrs-c ovid-19-task-force-update-april-15-2020 (Accessed on December 13, 2022). 24. Akhtar Z, Montalbano N, Leung LWM, et al. Drive-Through Pacing Clinic: A Popular Response to the COVID-19 Pandemic. JACC Clin Electrophysiol 2021; 7:128. 25. Hindricks G, Elsner C, Piorkowski C, et al. Quarterly vs. yearly clinical follow-up of remotely monitored recipients of prophylactic implantable cardioverter-defibrillators: results of the REFORM trial. Eur Heart J 2014; 35:98. 26. Winters SL, Packer DL, Marchlinski FE, et al. Consensus statement on indications, guidelines for use, and recommendations for follow-up of implantable cardioverter defibrillators. North American Society of Electrophysiology and Pacing. Pacing Clin Electrophysiol 2001; 24:262. 27. Brignole M, Occhetta E, Bongiorni MG, et al. Clinical evaluation of defibrillation testing in an unselected population of 2,120 consecutive patients undergoing first implantable cardioverter-defibrillator implant. J Am Coll Cardiol 2012; 60:981. 28. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015; 385:785. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 14/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate 29. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 30. Bleakley JF, Akiyama T, Canadian Cardiovascular Society, et al. Driving and arrhythmias: implications of new data. Card Electrophysiol Rev 2003; 7:77. 31. Task force members, Vijgen J, Botto G, et al. Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators. Europace 2009; 11:1097. 32. Ransford B, Kramer DB, Foo Kune D, et al. Cybersecurity and medical devices: A practical guide for cardiac electrophysiologists. Pacing Clin Electrophysiol 2017; 40:913. 33. Kramer DB, Fu K. Cybersecurity Concerns and Medical Devices: Lessons From a Pacemaker Advisory. JAMA 2017; 318:2077. 34. Pycroft L, Aziz TZ. Security of implantable medical devices with wireless connections: The dangers of cyber-attacks. Expert Rev Med Devices 2018; 15:403. Topic 1015 Version 39.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 15/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate GRAPHICS Remote monitoring recommendations for cardiac implantable electronic devices (CIEDs)

REFERENCES 1. Lampert R. Managing with pacemakers and implantable cardioverter defibrillators. Circulation 2013; 128:1576. 2. Al-Khatib SM, Friedman P, Ellenbogen KA. Defibrillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 3. Ploux S, Varma N, Strik M, et al. Optimizing implantable cardioverter-defibrillator remote monitoring: a practical guide. J Am Coll Cardiol EP 2017; 3:315. 4. Dubner S, Auricchio A, Steinberg JS, et al. ISHNE/EHRA expert consensus on remote monitoring of cardiovascular implantable electronic devices (CIEDs). Europace 2012; 14:278. 5. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 12/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate personnel, frequency and ethical considerations. Heart Rhythm 2008; 5:907. 6. Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015; 12:e69. 7. Gu don-Moreau L, Lacroix D, Sadoul N, et al. A randomized study of remote follow-up of implantable cardioverter defibrillators: safety and efficacy report of the ECOST trial. Eur Heart J 2013; 34:605. 8. Mabo P, Victor F, Bazin P, et al. A randomized trial of long-term remote monitoring of pacemaker recipients (the COMPAS trial). Eur Heart J 2012; 33:1105. 9. Crossley GH, Chen J, Choucair W, et al. Clinical benefits of remote versus transtelephonic monitoring of implanted pacemakers. J Am Coll Cardiol 2009; 54:2012. 10. Crossley GH, Boyle A, Vitense H, et al. The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial: the value of wireless remote monitoring with automatic clinician alerts. J Am Coll Cardiol 2011; 57:1181. 11. Varma N, Epstein AE, Irimpen A, et al. Efficacy and safety of automatic remote monitoring for implantable cardioverter-defibrillator follow-up: the Lumos-T Safely Reduces Routine Office Device Follow-up (TRUST) trial. Circulation 2010; 122:325. 12. Gu don-Moreau L, Kouakam C, Klug D, et al. Decreased delivery of inappropriate shocks achieved by remote monitoring of ICD: a substudy of the ECOST trial. J Cardiovasc Electrophysiol 2014; 25:763. 13. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014; 384:583. 14. Al-Khatib SM, Piccini JP, Knight D, et al. Remote monitoring of implantable cardioverter defibrillators versus quarterly device interrogations in clinic: results from a randomized pilot clinical trial. J Cardiovasc Electrophysiol 2010; 21:545. 15. Landolina M, Perego GB, Lunati M, et al. Remote monitoring reduces healthcare use and improves quality of care in heart failure patients with implantable defibrillators: the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study. Circulation 2012; 125:2985. 16. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010; 122:2359. 17. Akar JG, Bao H, Jones PW, et al. Use of Remote Monitoring Is Associated With Lower Risk of Adverse Outcomes Among Patients With Implanted Cardiac Defibrillators. Circ Arrhythm https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 13/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate Electrophysiol 2015; 8:1173. 18. Varma N, Piccini JP, Snell J, et al. The Relationship Between Level of Adherence to Automatic Wireless Remote Monitoring and Survival in Pacemaker and Defibrillator Patients. J Am Coll Cardiol 2015; 65:2601. 19. Parthiban N, Esterman A, Mahajan R, et al. Remote Monitoring of Implantable Cardioverter- Defibrillators: A Systematic Review and Meta-Analysis of Clinical Outcomes. J Am Coll Cardiol 2015; 65:2591. 20. Hindricks G, Varma N, Kacet S, et al. Daily remote monitoring of implantable cardioverter- defibrillators: insights from the pooled patient-level data from three randomized controlled trials (IN-TIME, ECOST, TRUST). Eur Heart J 2017; 38:1749. 21. Garc a-Fern ndez FJ, Osca Asensi J, Romero R, et al. Safety and efficiency of a common and simplified protocol for pacemaker and defibrillator surveillance based on remote monitoring only: a long-term randomized trial (RM-ALONE). Eur Heart J 2019; 40:1837. 22. Watanabe E, Yamazaki F, Goto T, et al. Remote Management of Pacemaker Patients With Biennial In-Clinic Evaluation: Continuous Home Monitoring in the Japanese At-Home Study: A Randomized Clinical Trial. Circ Arrhythm Electrophysiol 2020; 13:e007734. 23. Heart Rhythm Society COVID-19 Task Force Update. Management of cardiac implantable ele ctronic devices (CIED). 2020. https://www.hrsonline.org/COVID19-Challenges-Solutions/hrs-c ovid-19-task-force-update-april-15-2020 (Accessed on December 13, 2022). 24. Akhtar Z, Montalbano N, Leung LWM, et al. Drive-Through Pacing Clinic: A Popular Response to the COVID-19 Pandemic. JACC Clin Electrophysiol 2021; 7:128. 25. Hindricks G, Elsner C, Piorkowski C, et al. Quarterly vs. yearly clinical follow-up of remotely monitored recipients of prophylactic implantable cardioverter-defibrillators: results of the REFORM trial. Eur Heart J 2014; 35:98. 26. Winters SL, Packer DL, Marchlinski FE, et al. Consensus statement on indications, guidelines for use, and recommendations for follow-up of implantable cardioverter defibrillators. North American Society of Electrophysiology and Pacing. Pacing Clin Electrophysiol 2001; 24:262. 27. Brignole M, Occhetta E, Bongiorni MG, et al. Clinical evaluation of defibrillation testing in an unselected population of 2,120 consecutive patients undergoing first implantable cardioverter-defibrillator implant. J Am Coll Cardiol 2012; 60:981. 28. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015; 385:785. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 14/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate 29. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 30. Bleakley JF, Akiyama T, Canadian Cardiovascular Society, et al. Driving and arrhythmias: implications of new data. Card Electrophysiol Rev 2003; 7:77. 31. Task force members, Vijgen J, Botto G, et al. Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators. Europace 2009; 11:1097. 32. Ransford B, Kramer DB, Foo Kune D, et al. Cybersecurity and medical devices: A practical guide for cardiac electrophysiologists. Pacing Clin Electrophysiol 2017; 40:913. 33. Kramer DB, Fu K. Cybersecurity Concerns and Medical Devices: Lessons From a Pacemaker Advisory. JAMA 2017; 318:2077. 34. Pycroft L, Aziz TZ. Security of implantable medical devices with wireless connections: The dangers of cyber-attacks. Expert Rev Med Devices 2018; 15:403. Topic 1015 Version 39.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 15/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate GRAPHICS Remote monitoring recommendations for cardiac implantable electronic devices (CIEDs) Class of recommendation Level of evidence Device follow-up paradigm A strategy of remote CIED monitoring and interrogation, combined with at least annual in-person examination, is recommended over a calendar-based schedule of in-person CIED evaluation alone (when technically feasible). I A All patients with CIEDs should be offered RM as part of the standard follow-up management strategy. I A Before implementing RM, it is recommended that each patient be educated about the nature of RM, their responsibilities and expectations, potential benefits, and limitations. The I E occurrence of this discussion should be documented in the medical record. It is recommended that all CIEDs be checked through direct patient contact 2 to 12 weeks postimplantation. I E It may be beneficial to initiate RM within the two weeks of CIED implantation. IIa C All patients with an implantable loop recorder with wireless data transfer capability should be enrolled in an RM program, given the daily availability of diagnostic data. I E It is recommended that allied health care professionals responsible for interpreting RM transmissions and who are involved in subsequent patient management decisions have the same qualifications as those performing in-clinic I E assessments and should ideally possess IBHRE certification for device follow-up or equivalent experience. It is recommended that RM programs develop and document appropriate policies and procedures to govern program operations, the roles and responsibilities of those involved in the program, and the expected timelines for providing service. I E CIED: cardiac implantable electronic device; HRS: Heart Rhythm Society; IBHRE: International Board of Heart Rhythm Examiners; RM: remote monitoring. Reproduced from: Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015; 12:e69. Illustration used with the https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 16/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate permission of Elsevier Inc. All rights reserved. Graphic 108755 Version 1.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 17/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate Minimum frequency of cardiac implantable electronic device (CIED) follow- up Type Frequency Delivery method Immediate post-implant check Within 72 hours In person Early post-implant check 2 to 12 weeks In person Routine PPM/CRT-PPM check Every 3 to 12 months In person or remote Routine ICD/CRT-D Every 3 to 6 months In person or remote Following one ICD/CRT-D shock Within 24 to 48 hours In person or remote Following >1 ICD/CRT-D shocks Immediately In person Any CIED until signs of battery depletion Annually In person Any CIED following signs of battery depletion Every 1 to 3 months In person or remote CIED: cardiac implantable electronic device; CRT: cardiac resynchronization therapy; ICD: implantable cardioverter-defibrillator; PPM: permanent pacemaker. Adapted from: Wilko BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, personnel, frequency and ethical considerations. Heart Rhythm 2008; 5:907. Graphic 91502 Version 3.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 18/19 7/6/23, 2:48 PM Cardiac implantable electronic devices: Patient follow-up - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 19/19

7/6/23, 2:49 PM Cardioversion for specific arrhythmias - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardioversion for specific arrhythmias : Bradley P Knight, MD, FACC : Richard L Page, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2022. INTRODUCTION Electrical cardioversion and defibrillation are commonly used procedures in the management of patients with cardiac arrhythmias. Elective outpatient cardioversions are routinely performed on patients with persistent atrial fibrillation (AF) to restore sinus rhythm. Cardioversion is the delivery of energy that is synchronized to the QRS complex, while defibrillation is asynchronous delivery of a shock randomly during the cardiac cycle. This topic will review the clinical settings in which electrical cardioversion and defibrillation are used, along with a brief discussion of the complications that can occur independent of the arrhythmia that is being treated. The basic principles and technique of electrical cardioversion and defibrillation, the specific indications for external cardioversion and defibrillation, and the use of the automated external defibrillator are presented separately. (See "Basic principles and technique of external electrical cardioversion and defibrillation" and "Automated external defibrillators".) EXTERNAL CARDIOVERSION/DEFIBRILLATION Preparation and personnel Nonemergency electrical cardioversion should ideally be performed in a controlled environment with monitoring capabilities and the nearby availability of emergency equipment should complications arise. The following are considered part of the routine preparation and monitoring involved in electrical cardioversion: https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 1/36 7/6/23, 2:49 PM Cardioversion for specific arrhythmias - UpToDate Standard cardiorespiratory monitoring, including blood pressure, pulse, oxygen saturation, end-tidal CO monitoring, and cardiac telemetry. 2 Intravenous access for administration of sedation and for management of any rhythm- related complications (ie, ventricular fibrillation, sinus bradycardia, etc). Available supplemental oxygen, suction device, and intubation equipment for management of respiratory complications (though supplemental oxygen should be removed prior to delivery of the electrical shock) (see 'Supplemental oxygen' below). Available code cart with medications used in advanced cardiac life support in the event of life-threatening arrhythmias (see "Advanced cardiac life support (ACLS) in adults"). There is considerable activation of thoracic skeletal muscles during a transthoracic shock that causes patients and their arms to move during a shock. For this reason, and because these patients are anticoagulated, padding or cushioning should be placed between the patient's extremities and any hard bed railings to avoid injury during cardioversion. While many cardiologists are trained in the administration of moderate sedation, sedation may also be administered by an anesthesiologist who can immediately assist in the management of respiratory complications should any develop. An advantage of having an anesthesiologist routinely administer sedation for elective cardioversions is that at many hospitals, the use of ultra-short acting sedatives such as propofol is restricted to anesthesiologists. The tradeoff for such involvement is often added costs and scheduling complexity. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications", section on 'Anticipating and mitigating Complications'.) Elective cardioversions for AF and atrial flutter can also be safely performed autonomously by a midlevel provider. With appropriate training and a protocol that includes a guideline-directed procedural checklist ( table 1), physician supervision, and sedation administered by an anesthesiologist, an advanced practice nurse can safely perform cardioversions autonomously with outcomes and patient satisfaction similar to those for cardioversions performed by a physician [1]. Supplemental oxygen Supplemental oxygen is a fire hazard in the event of electrical arcing during external cardioversion or defibrillation. Because of this, supplemental oxygen flow should be stopped, or the oxygen delivery device (eg, nasal cannula, face mask, etc) removed from the patient, prior to the delivery of an external shock. Oxygen flow can be restarted after the shock has been delivered. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 2/36 7/6/23, 2:49 PM Cardioversion for specific arrhythmias - UpToDate Paddle/pad placement For electrical cardioversion of atrial tachyarrhythmias, particularly AF, an anterior-posterior pad position is preferred to anterior-lateral placement ( figure 1) based on evidence from several randomized trials that have shown higher success rates and lower energy requirements for successful cardioversion with the anterior-posterior configuration [2,3]. The historical rationale for the superiority of the anterior-posterior position is a more favorable shock vector through the atria as well as reduced transthoracic impedance. Moreover, there is some evidence that applying external force to self-adhesive electrodes may decrease transthoracic impedance further [4]. However, pad placement may not significantly affect outcomes of cardioversion with contemporary defibrillator devices that employ impedance compensated biphasic waveforms [5]. For urgent cardioversion/defibrillation of unstable rhythms, an anterior-lateral pad configuration may be preferred for ease of application, and device manufacturer recommendations should be followed in all cases. (See "Basic principles and technique of external electrical cardioversion and defibrillation", section on 'Electrodes'.) Energy selection The amount of energy selected for initial attempts of cardioversion or defibrillation has been controversial. The energy selected should be sufficient to accomplish prompt cardioversion or defibrillation because repeated failures expose the heart to damage from prolonged ischemia and multiple shocks. On the other hand, excessive energy should be avoided, since myocardial damage from high-energy shocks has been demonstrated in experimental studies, although the frequency with which this occurs in humans is not known [6,7]. Early defibrillators delivered energy in a monophasic waveform, meaning that electrons flowed in a single direction. The newer defibrillators deliver a biphasic waveform, meaning that during the shock, polarity and electron flow reverse. In addition to reversing polarity, biphasic defibrillators also deliver a more consistent magnitude of current ( figure 2). In general, biphasic defibrillators successfully terminate arrhythmias at lower energies than monophasic defibrillators. The relative efficacy of biphasic and monophasic defibrillators has been compared in a number of settings and is discussed in detail separately. (See "Basic principles and technique of external electrical cardioversion and defibrillation", section on 'Monophasic versus biphasic waveforms'.) While nearly all available external defibrillators now use a biphasic waveform, it is still important to fully understand the type of waveform that is delivered when using an external defibrillator. For example, the Zoll brand of external defibrillators uses a truncated waveform that results in the delivery of more current to the heart compared to defibrillators made by other manufacturers that use a standard biphasic waveform, when set to deliver the same amount of energy in joules. Unlike most defibrillators that deliver a maximum energy of 360 joules, the Zoll defibrillators have a maximum energy setting of 200 joules but deliver similar current to the https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 3/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate heart with comparable defibrillation efficacy. The energy selection recommendations in this topic are in joules and are for defibrillators that use a standard biphasic waveform. Lower energies can be used with defibrillators that use a truncated biphasic waveform. In 2010, the American Heart Association issued guidelines for cardiopulmonary resuscitation and emergency cardiovascular care that discussed detailed starting energy levels for treatment of various types of arrhythmias [8]. In the 2014 AHA/ACC/HRS guidelines on the management of AF, no specific energy levels for cardioversion or defibrillation are discussed, but some broad concepts are presented. We agree with the suggested initial energy selection for specific arrhythmias as addressed in the society guidelines, with the following suggested initial energy requirements for monophasic and biphasic waveforms [8]: When available, a biphasic defibrillator is preferred due to greater efficacy. For AF, 120 to 200 joules ( algorithm 1). For atrial flutter, 50 to 100 joules. For ventricular tachycardia with a pulse, 100 joules. For ventricular fibrillation or pulseless ventricular tachycardia, 200 to 360 joules ( algorithm 2). To increase the likelihood of initial shock success and reduce the duration of sedation, a higher initial energy may be considered, particularly in obese patients or in patients known to be difficult to cardiovert. When an external defibrillator is being prepared to deliver a rescue shock in the event that an implantable defibrillator fails to convert a patient during defibrillation threshold testing, the energy should be set to the maximum output and in the asynchronous mode. Cardioversion with higher energy levels may be effective when prior cardioversion attempts using a maximal energy of 360 joules have failed to restore sinus rhythm. In one study, 55 patients who did not have sinus rhythm restored after at least two attempts of external cardioversion with 360 joules underwent cardioversion with 720 joules, which was performed by using two external cardioverters, each connected to its own pair of patches [9]. Sinus rhythm was restored in 84 percent of these patients with no major complications, hemodynamic compromise, or strokes occurring after the procedure. As another option besides high-energy cardioversion, pretreatment with an antiarrhythmic drug can facilitate cardioversion at lower energy levels. Pretreatment with ibutilide prior to electrical https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 4/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate cardioversion has been shown to significantly improve the rate of successful cardioversion to sinus rhythm and was also associated with the use of significantly lower energy levels to achieve cardioversion [10]. Amiodarone, sotalol, quinidine, and procainamide have also been shown to increase the likelihood of successful cardioversion or lower the energy threshold required for cardioversion [11]. When an antiarrhythmic drug is chosen, however, the potential side effects must be carefully considered. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol".) Efficacy External cardioversion and defibrillation have been used in the treatment of a variety of arrhythmias, with variable results depending on the chronicity of the arrhythmia, triggers for the arrhythmia, and the patient s overall clinical condition. For example, electrical cardioversion success rates approach 100 percent in patients with atrial flutter or AF of short duration and no structural heart disease, while the success rates are much lower in patients with chronic AF and concomitant mitral valve disease. The term "failed cardioversion" can indicate failure to restore sinus rhythm at all, or an immediate recurrence of the arrhythmia. It is important to differentiate these two failure mechanisms because different approaches can be used to address each type of failure. While antiarrhythmic medications can sometimes result in restoration of sinus rhythm without electrical cardioversion, they are primarily used in an effort to maintain sinus rhythm following successful electrical cardioversion. However, many antiarrhythmic drugs can alter the defibrillation threshold, ie, the minimal amount of energy necessary for reversion of an arrhythmia ( table 2). Amiodarone, quinidine, flecainide, and phenytoin may cause a significant rise in defibrillation thresholds [12-15]. (See "Amiodarone: Clinical uses" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Atrial fibrillation AF is the most frequent arrhythmia treated with electrical cardioversion ( movie 1). Cardioversion is part of the overall treatment approach to AF, which also includes rate control and anticoagulation. To reduce the risk of thromboembolism following cardioversion, therapeutic anticoagulation is generally recommended for at least three to four weeks before and after cardioversion. Alternatively, the presence of existing intracardiac thrombus should be excluded using transesophageal echocardiography prior to cardioversion if therapeutic anticoagulation has not been achieved for an adequate duration. However, a negative TEE does not preclude the need for anticoagulation at the time of the cardioversion or afterwards. Detailed discussions regarding the decision to perform cardioversion versus rate control, as well as the optimal approach to anticoagulation, are provided elsewhere. (See "Atrial fibrillation: Cardioversion" and "Management of atrial fibrillation: Rhythm control versus rate control" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 5/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Role of echocardiography in atrial fibrillation", section on 'Transesophageal echocardiography'.) The energy requirement for successful cardioversion of AF varies according to the type of electrical waveform and chronicity of AF ( algorithm 1) [8]. (See "Basic principles and technique of external electrical cardioversion and defibrillation", section on 'Energy selection for cardioversion and defibrillation'.) Most currently available defibrillators deliver biphasic waveforms. When biphasic waveforms are used, the efficacy is higher [16,17]. In a study of 912 patients with AF or atrial flutter, restoration of sinus rhythm was higher with the use of biphasic waveforms (94 versus 84 percent for monophasic waveforms) and the cumulative energy was lower (199 J versus 554 J) [16]. The use of biphasic waveforms may be of particular benefit in patients who fail to revert with the use of monophasic waveforms [18]. Although it had been hoped that cardioversion to and maintenance of sinus rhythm would improve the prognosis of and reduce embolic risk in patients with AF, this concept was not confirmed in the two largest randomized trials comparing rate control plus anticoagulation versus rhythm control for AF (the AFFIRM and RACE trials) [19,20]. Both studies showed a trend toward a lower incidence of the primary endpoint with rate control and anticoagulation (hazard ratio 0.87 for mortality in AFFIRM and 0.73 for a composite endpoint in RACE). In addition, embolization occurred with equal frequency regardless of whether a rhythm control or a rate control strategy was adopted. In both groups, embolization primarily occurred after warfarin had been stopped or when the INR was subtherapeutic. (See "Management of atrial fibrillation: Rhythm control versus rate control".) Atrial flutter Electrical cardioversion is highly successful in the treatment of typical (type I) atrial flutter, which arises from a single reentrant circuit in the right atrium ( waveform 1 and figure 3). The energy requirement for successful cardioversion of typical (type I) atrial flutter is usually lower than that required for AF ( algorithm 1) [8]. Many patients with type I atrial flutter can be cardioverted with 50 to 100 joules or less [21-24]. In a review including 985 cardioversions in 840 patients with atrial flutter, the median energy level for successful cardioversion was 50 joules with a biphasic defibrillator [22]. (See "Restoration of sinus rhythm in atrial flutter" and "Electrocardiographic and electrophysiologic features of atrial flutter" and "Basic principles and technique of external electrical cardioversion and defibrillation", section on 'Energy selection for cardioversion and defibrillation'.) In contrast to typical (type I) atrial flutter, atypical (type II) atrial flutter may result from reentrant circuits in various locations and tends to require higher energy levels for cardioversion, but in https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 6/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate most cases sinus rhythm can be successfully restored. While starting at 50 to 100 joules may be effective for cardioversion of atypical (type II) atrial flutter, particularly with biphasic defibrillators, this approach has the potential adverse effect of requiring additional shocks [21]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) The role of anticoagulation during and after cardioversion is similar to that with AF and is discussed in detail elsewhere. (See "Embolic risk and the role of anticoagulation in atrial flutter".) Supraventricular tachycardia The most common mechanisms for supraventricular tachycardia are atrioventricular (AV) nodal reentry, AV reentrant tachycardia, and atrial tachycardia. These arrhythmias often terminate with vagal maneuvers or intravenous antiarrhythmic therapy with adenosine or verapamil when they are AV nodal dependent; as such, electrical cardioversion is usually not required. However, if these arrhythmias persist and electrical cardioversion is attempted, cardioversion is usually successful but may require relatively high energy levels, probably due to the deep location of the reentrant pathway. If sinus rhythm is not restored following an initial 50 to 100 joule shock, subsequent shocks should be at higher energy levels ( algorithm 1). (See "Atrioventricular nodal reentrant tachycardia".) Ventricular tachycardia Electrical cardioversion is usually successful in the acute treatment of ventricular tachycardia (VT), which typically arises from a reentrant circuit in the ventricle. If a distinct QRS and T wave are identified, allowing the delivery of energy to be synchronized to the QRS complex, monomorphic VT can often be terminated with a low-energy shock. Despite the potential for terminating VT with very low-energy shocks, one must consider the seriousness of the arrhythmia and the desire to avoid repeated shocks. As a result, the initial synchronized shock in these circumstances is recommended to be 100 joules ( algorithm 1) [8]. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis" and "Basic principles and technique of external electrical cardioversion and defibrillation", section on 'Energy selection for cardioversion and defibrillation'.) In contrast, synchronized cardioversion may be impossible or hazardous if the VT is rapid and distinct QRS complexes are not identified, if the QRS complexes are wide and bizarre, or if the VT is polymorphic. In these settings, there is a potential for delivery of a discharge on the T wave, possibly provoking ventricular fibrillation. Under these circumstances, nonsynchronized defibrillation should be performed starting with 200 joules for a biphasic device. (See "Catecholaminergic polymorphic ventricular tachycardia".) Ventricular fibrillation The only definitive treatment for ventricular fibrillation (VF) is defibrillation. When defibrillation is performed promptly, the success rate for terminating https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 7/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate ventricular fibrillation can be as high as 95 percent [25-28]. However, the success rate falls substantially as the duration of ventricular fibrillation increases, probably due to myocardial ischemia, acidosis, and other metabolic changes. These cellular changes are associated with an electrophysiologic deterioration of ventricular fibrillation, leading to an increase in fibrillation cycle length and prolonged diastolic duration between fibrillation action potentials [29]. For these reasons, defibrillation as soon as possible has been considered to be the standard of care for VF ( algorithm 2). Some studies suggest that when VF has been present for longer than four to five minutes, outcomes are better if cardiopulmonary resuscitation is performed prior to defibrillation [30,31]. The recommended starting energy to effectively defibrillate VF is 200 joules with biphasic waveforms ( algorithm 1) [8]. There is no reported benefit to using more than 360 joules, and there may be harm since high-energy shocks may be associated with myocardial damage and the risk for developing new arrhythmias. (See "Supportive data for advanced cardiac life support in adults with sudden cardiac arrest", section on 'Defibrillation' and "Advanced cardiac life support (ACLS) in adults", section on 'Pulseless ventricular tachycardia and ventricular fibrillation' and "Basic principles and technique of external electrical cardioversion and defibrillation", section on 'Energy selection for cardioversion and defibrillation' and 'Complications' below.) Special populations Cardioversion during pregnancy Cardioversion can be performed during pregnancy without affecting the rhythm of the fetus [32,33]. It is recommended, however, that the fetal heart rate be monitored during the procedure using standard fetal monitoring techniques. (See "Nonstress test and contraction stress test".) Cardioversion in patients with permanent pacemakers/ICDs Several precautions are necessary when attempting external electrical cardioversion or defibrillation in a patient with a permanent pacemaker or an implantable cardioverter-defibrillator (ICD). Defibrillation in these patients can damage the pulse generator, the lead system, or the myocardial tissue, resulting in device dysfunction [34]. The electrode paddle (or patch) should be at least 12 cm from the pulse generator and an anteroposterior paddle position is recommended [35,36]. Elective cardioversion should be initiated with the lowest indicated energy (which will vary depending on the arrhythmia) in order to avoid damage to the device circuitry and the electrode-myocardial interface. After cardioversion, the pacemaker should be interrogated and evaluated to ensure normal pacemaker function. When these precautions have been used, cardioversion with either monophasic or biphasic shocks is safe and effective in patients with an implantable device [37]. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 8/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Alternatively, in patients with an ICD, internal cardioversion can be attempted by an electrophysiologist using the device programmer to deliver the shock. (See 'Internal cardioversion/defibrillation' below.) Cardioversion in patients with digitalis toxicity Patients with digitalis overdose or intoxication can present with almost any type of arrhythmia, including tachyarrhythmias and bradyarrhythmias. In particular, ventricular arrhythmias (including VF) are more likely to occur in patients who have digitalis toxicity, especially if the patient is also hypokalemic. There is a relative contraindication to cardioversion in the setting of digitalis toxicity since digitalis sensitizes the heart to the electrical stimulus and, hence, cardioversion could trigger additional arrhythmias, most importantly ventricular fibrillation. Supraventricular arrhythmias Cardioversion should be deferred until digitalis levels have returned to a normal range and clinical toxicity has resolved. If urgent restoration of sinus rhythm is necessary for a hemodynamically unstable supraventricular arrhythmia, the lowest energy that is likely to be successful should be used. In addition, rapid atrial pacing may be successful for certain arrhythmias (eg, atrial flutter) and is probably the safest method. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion' and "Restoration of sinus rhythm in atrial flutter", section on 'Atrial overdrive pacing'.) Ventricular arrhythmias If cardioversion must be performed for a life-threatening ventricular arrhythmia, prophylactic lidocaine (1 mg/kg up to a maximum dose of 100 mg IV push) should be given and the lowest indicated energy levels used. When time permits, hypokalemia should be corrected prior to cardioversion. (See "Digitalis (cardiac glycoside) poisoning".) Complications While electrical cardioversion and defibrillation are generally well tolerated, complications may occur. Most complications are self-limiting (eg, changes in the electrocardiogram, hypotension related to sedation and/or vasodilation) or relatively benign (eg, skin irritation). However, providers should be aware of potential life-threatening complications such as postcardioversion arrhythmias and the possibility of thromboembolism. ST segment and T wave changes Electrocardiographic (ECG) changes can occur immediately after cardioversion, usually consisting of ST segment and T wave changes [38-42]. ECG changes, including ST segment elevation, are nonspecific findings and should not be used as the sole criteria for identifying an acute ischemic event as the cause for the ventricular tachyarrhythmia [42]. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 9/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate In one study of 56 patients with ventricular arrhythmias treated with monophasic shocks, ST segment and T wave changes were common immediately after cardioversion but usually resolved within five minutes [38]. The ECG changes included ST segment elevation in 15 percent, ST segment depression in 35 percent, or an increase in T wave amplitude. Transient ST elevation has also been reported in a series of patients undergoing cardioversion with monophasic waveforms for atrial arrhythmias [39]. These changes were noted primarily in the precordial leads, and normalized within 1.5 minutes. The occurrence of ST segment elevation was associated with a lower conversion rate and lower rate of long-term maintenance of sinus rhythm. The pathogenesis of ST elevation is uncertain, since elevations in cardiac enzymes (ie, CK-MB and troponin) are uncommon and, when they occur, are usually minimal [43-45]. However, both the incidence and the extent of ST segment changes appear to be lower with the use of biphasic waveforms [46,47]. Arrhythmia and conduction abnormalities Arrhythmias are frequently observed after cardioversion [38,48-51]. In many cases these arrhythmias are benign (eg, sinus tachycardia, nonsustained ventricular tachycardia [VT]), but in other cases the arrhythmias can be clinically and/or hemodynamically significant (eg, ventricular fibrillation [VF], sustained VT). Ventricular arrhythmias Runs of nonsustained ventricular tachycardia (VT) are seen in up to five percent of patients, and can occur in patients with or without structural heart disease [38]. On the other hand, a sustained ventricular arrhythmia generally occurs only in patients with clinically documented VT or long-lasting VF [38,49]. Cardioversion can also induce VF, usually but not always after the administration of an asynchronous shock [49]. The occurrence of ventricular arrhythmias does not appear to be related to the number of shocks and cannot be prevented by antiarrhythmic therapy. Conversely, antiarrhythmic drugs may contribute to the development of new arrhythmias [52]. Atrial arrhythmias Atrial arrhythmias can also occur following cardioversion. Approximately 30 percent of patients have a supraventricular tachycardia, primarily sinus tachycardia. However, AV nodal reentrant tachycardia and atrial flutter have been observed following cardioversion attempts for chronic AF [50]. Bradyarrhythmias and conduction abnormalities Bradyarrhythmias following electrical cardioversion are relatively rare. In a retrospective multicenter cohort study of 6906 electrical cardioversions in 2868 patients with AF and less than 48 hours of symptoms, bradyarrhythmias were identified following 63 cardioversions (0.9 percent) in 54 patients [53]. Pre-procedure use of digoxin, beta blocker, or antiarrhythmic drug did not impact the https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 10/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate development of bradyarrhythmias post-cardioversion. Nevertheless, it is reasonable to anticipate clinically significant bradycardia in patients undergoing cardioversion who have been in AF for over a year, have very slow ventricular rates during AF, or in whom amiodarone loading was recently administered. A transient left bundle branch block is occasionally seen after cardioversion, but high-degree atrioventricular block is more common. In one study of 75 patients who underwent 112 shocks, sinus bradycardia occurred in 18 patients and high-degree AV block in 11 [48]. Temporary pacing was necessary in 10 patients. The likelihood of requiring either external or transvenous cardiac pacing immediately after a cardioversion is much lower in clinical practice than this study suggests. The incidence appears to be less than 1 percent. Patients receiving antiarrhythmic drugs are more prone to develop bradycardia and asystole and an external pacemaker should be readily available in such patients [48,49]. (See "Temporary cardiac pacing".) Thromboembolism Cardioversion may be associated with pulmonary or systemic thromboembolism. Thromboembolism after the return of synchronous atrial contraction can occur because of dislodgement of left atrial thrombi present at the time of cardioversion or a thrombus that forms after cardioversion due to transient post conversion left atrial mechanical dysfunction. This complication is more likely to occur in patients with AF who have not been anticoagulated prior to cardioversion. Patients with a previous embolism do not have an increased risk of embolization if anticoagulation of adequate intensity and length are administered [54]. The estimated incidence of thromboembolism varies, but in a large nonrandomized series that included 437 patients, thromboembolism occurred in 5.3 percent of patients who were not anticoagulated compared with 0.8 percent of those who were receiving anticoagulation [55]. For patients with AF of at least 48 hours duration, the current recommendation is to anticoagulate patients for several weeks prior to and following cardioversion. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Myocardial necrosis Minimal myocardial necrosis, particularly of the epicardium, may occur as a result of high-energy shocks. This is typically asymptomatic and is manifested by small rises in serum CK-MB and troponin levels. In contrast, substantial elevations of either CK-MB or troponin following electrical cardioversion, or the development of chest pain suggestive of angina, suggests the presence of myocardial injury from causes unrelated to the procedure. As such, we do not routinely monitor cardiac enzymes following electrical cardioversion in asymptomatic patients. Although the cause is unknown, it has been suggested that myocardial necrosis may be due to the sustained depolarization of a critical mass of myocardial cells [40]. The risk of myocardial https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 11/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate necrosis appears related to the amount of energy delivered with each shock rather than to the number of shocks, although many repeated shocks may lead to myocardial damage and scarring. In one study of 30 patients who underwent cardioversion, an increase in serum CK-MB was seen in only two patients, despite substantial release of CK from skeletal muscle [56]. Furthermore, the small release of CK-MB in this report cannot be considered diagnostic for myocardial damage since the total CK from skeletal muscle includes approximately 1 percent CK-MB [57]. (See "Troponin testing: Clinical use".) The desire for improved specificity in the diagnosis of myocardial injury has led to measurement of the serum troponin levels. Among 38 patients undergoing elective cardioversion, only three patients had minimal elevations of troponin I (0.8 to 1.5 mcg/L), suggesting subtle myocardial injury [44]. Two other studies, however, reported no elevations in troponin T following cardioversion [45,58]. Myocardial dysfunction Global left ventricular dysfunction due to myocardial stunning may be seen in patients with cardiac arrest who have undergone successful cardiopulmonary resuscitation. This is related in part to defibrillation, but is also a result of the arrhythmia itself and due to the absence of cardiac output and coronary blood flow during the period of arrest with resultant ischemia. Myocardial dysfunction due to stunning may reverse within the first 24 to 48 hours after cardiac arrest. It is routine to image the heart and evaluate ventricular function shortly after a patient suffers a cardiac arrest to determine if there is evidence of structural heart disease. This evaluation should not be delayed. However, it is important to recognize that ventricular dysfunction may be transient and that imaging should be repeated within a few days if ventricular dysfunction is present immediately after the arrest [59]. In animals, the severity of postresuscitation myocardial dysfunction is related, in part, to the energy used for defibrillation [60]. Further support for this observation comes from another animal study comparing biphasic and monophasic waveforms for reversion of ventricular fibrillation [61]. Although lower-energy biphasic waveforms were as effective as higher-energy monophasic waveforms for restoration of sinus rhythm, there was less myocardial dysfunction after defibrillation with the use of biphasic waveforms. The process of electrical cardioversion may transiently injure or "stun" the atria as well [62,63]. Pulmonary edema Pulmonary edema is a rare complication of cardioversion, which is probably due to transient left atrial standstill or left ventricular dysfunction. It is unrelated to the amount of energy used. Pulmonary edema may be more common in patients with AF associated with valvular heart disease or left ventricular dysfunction. In this setting, the return of atrial https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 12/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate systole after cardioversion can result in a significant elevation in left atrial pressure and pulmonary edema [64]. Transient hypotension Transient hypotension can occur for several hours after cardioversion. Most patients require no therapy; if necessary, the fall in blood pressure usually responds to fluid replacement [65]. Although the mechanism is not certain, the hypotension may be related to vasodilation or the use of sedation during the procedure. Cutaneous burns Following cardioversion or defibrillation, skin burns occur in 20 to 25 percent of patients and are more likely with improper technique and placement of electrodes [66]. The risk of burns is less with the use of biphasic waveforms and the use of gel-based pads [67]. The use of steroid cream, silver sulfadiazine cream, or topical ibuprofen reduces the pain and inflammation [68,69]. INTERNAL CARDIOVERSION/DEFIBRILLATION Technique and efficacy Internal or intracardiac cardioversion is an effective technique for patients in whom external cardioversion has failed to restore sinus rhythm. However, the need for internal cardioversion has been greatly diminished due to the efficacy of biphasic waveform defibrillators and the availability of ibutilide in restoring sinus rhythm. In addition, given the invasive nature of the procedure, specialized training is required to perform internal cardioversion. An ACC/AHA task force on clinical competency has published recommendations for technical and cognitive skills needed to perform internal direct current cardioversion ( table 3A-B) [70]. Internal cardioversion can be performed in various ways: Using a preexisting ICD to deliver a clinician-directed shock. Using epicardial wires placed during surgery or internal paddles applied directly to the epicardium in a patient with a sternotomy [71]. Two defibrillation electrodes are placed in the right atrium and coronary sinus or in the right atrium and left pulmonary artery, respectively, and then intracardiac shocks are delivered by an external defibrillator. Internal cardioversion complications Although internal cardioversion is an effective approach for restoring sinus rhythms in patients with AF refractory to pharmacologic or external electrical cardioversion, one study reported that complications occurred in 19 percent of patients, including low cardiac output from ventricular stunning, pericardial effusion, and a brief https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 13/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate period of ventricular asystole requiring ventricular pacing [72]. Another report of 25 patients found that 36 percent developed transient bradycardia, related to sinus and atrioventricular nodal depression, requiring temporary ventricular pacing [73]. Shocks of up to 20 joules did not affect the function of permanent pacemakers. Implantable cardioverter-defibrillators ICDs are in widespread use in patients with a history of sustained ventricular tachycardia or ventricular fibrillation and also for primary prevention in selected patients. In patients with an ICD, internal cardioversion can be attempted by a cardiologist using the device programmer to deliver the shock. The advantage of using the ICD is that it avoids the risk of a skin irritation from an external shock and the small chance of damage to the ICD system from the shock. The disadvantage of using the ICD is that it consumes some of the battery in the device and does not always work for cardioversion of atrial arrhythmias. Indications for and efficacy of ICDs are discussed in detail elsewhere. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)

atrial fibrillation".) Myocardial necrosis Minimal myocardial necrosis, particularly of the epicardium, may occur as a result of high-energy shocks. This is typically asymptomatic and is manifested by small rises in serum CK-MB and troponin levels. In contrast, substantial elevations of either CK-MB or troponin following electrical cardioversion, or the development of chest pain suggestive of angina, suggests the presence of myocardial injury from causes unrelated to the procedure. As such, we do not routinely monitor cardiac enzymes following electrical cardioversion in asymptomatic patients. Although the cause is unknown, it has been suggested that myocardial necrosis may be due to the sustained depolarization of a critical mass of myocardial cells [40]. The risk of myocardial https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 11/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate necrosis appears related to the amount of energy delivered with each shock rather than to the number of shocks, although many repeated shocks may lead to myocardial damage and scarring. In one study of 30 patients who underwent cardioversion, an increase in serum CK-MB was seen in only two patients, despite substantial release of CK from skeletal muscle [56]. Furthermore, the small release of CK-MB in this report cannot be considered diagnostic for myocardial damage since the total CK from skeletal muscle includes approximately 1 percent CK-MB [57]. (See "Troponin testing: Clinical use".) The desire for improved specificity in the diagnosis of myocardial injury has led to measurement of the serum troponin levels. Among 38 patients undergoing elective cardioversion, only three patients had minimal elevations of troponin I (0.8 to 1.5 mcg/L), suggesting subtle myocardial injury [44]. Two other studies, however, reported no elevations in troponin T following cardioversion [45,58]. Myocardial dysfunction Global left ventricular dysfunction due to myocardial stunning may be seen in patients with cardiac arrest who have undergone successful cardiopulmonary resuscitation. This is related in part to defibrillation, but is also a result of the arrhythmia itself and due to the absence of cardiac output and coronary blood flow during the period of arrest with resultant ischemia. Myocardial dysfunction due to stunning may reverse within the first 24 to 48 hours after cardiac arrest. It is routine to image the heart and evaluate ventricular function shortly after a patient suffers a cardiac arrest to determine if there is evidence of structural heart disease. This evaluation should not be delayed. However, it is important to recognize that ventricular dysfunction may be transient and that imaging should be repeated within a few days if ventricular dysfunction is present immediately after the arrest [59]. In animals, the severity of postresuscitation myocardial dysfunction is related, in part, to the energy used for defibrillation [60]. Further support for this observation comes from another animal study comparing biphasic and monophasic waveforms for reversion of ventricular fibrillation [61]. Although lower-energy biphasic waveforms were as effective as higher-energy monophasic waveforms for restoration of sinus rhythm, there was less myocardial dysfunction after defibrillation with the use of biphasic waveforms. The process of electrical cardioversion may transiently injure or "stun" the atria as well [62,63]. Pulmonary edema Pulmonary edema is a rare complication of cardioversion, which is probably due to transient left atrial standstill or left ventricular dysfunction. It is unrelated to the amount of energy used. Pulmonary edema may be more common in patients with AF associated with valvular heart disease or left ventricular dysfunction. In this setting, the return of atrial https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 12/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate systole after cardioversion can result in a significant elevation in left atrial pressure and pulmonary edema [64]. Transient hypotension Transient hypotension can occur for several hours after cardioversion. Most patients require no therapy; if necessary, the fall in blood pressure usually responds to fluid replacement [65]. Although the mechanism is not certain, the hypotension may be related to vasodilation or the use of sedation during the procedure. Cutaneous burns Following cardioversion or defibrillation, skin burns occur in 20 to 25 percent of patients and are more likely with improper technique and placement of electrodes [66]. The risk of burns is less with the use of biphasic waveforms and the use of gel-based pads [67]. The use of steroid cream, silver sulfadiazine cream, or topical ibuprofen reduces the pain and inflammation [68,69]. INTERNAL CARDIOVERSION/DEFIBRILLATION Technique and efficacy Internal or intracardiac cardioversion is an effective technique for patients in whom external cardioversion has failed to restore sinus rhythm. However, the need for internal cardioversion has been greatly diminished due to the efficacy of biphasic waveform defibrillators and the availability of ibutilide in restoring sinus rhythm. In addition, given the invasive nature of the procedure, specialized training is required to perform internal cardioversion. An ACC/AHA task force on clinical competency has published recommendations for technical and cognitive skills needed to perform internal direct current cardioversion ( table 3A-B) [70]. Internal cardioversion can be performed in various ways: Using a preexisting ICD to deliver a clinician-directed shock. Using epicardial wires placed during surgery or internal paddles applied directly to the epicardium in a patient with a sternotomy [71]. Two defibrillation electrodes are placed in the right atrium and coronary sinus or in the right atrium and left pulmonary artery, respectively, and then intracardiac shocks are delivered by an external defibrillator. Internal cardioversion complications Although internal cardioversion is an effective approach for restoring sinus rhythms in patients with AF refractory to pharmacologic or external electrical cardioversion, one study reported that complications occurred in 19 percent of patients, including low cardiac output from ventricular stunning, pericardial effusion, and a brief https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 13/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate period of ventricular asystole requiring ventricular pacing [72]. Another report of 25 patients found that 36 percent developed transient bradycardia, related to sinus and atrioventricular nodal depression, requiring temporary ventricular pacing [73]. Shocks of up to 20 joules did not affect the function of permanent pacemakers. Implantable cardioverter-defibrillators ICDs are in widespread use in patients with a history of sustained ventricular tachycardia or ventricular fibrillation and also for primary prevention in selected patients. In patients with an ICD, internal cardioversion can be attempted by a cardiologist using the device programmer to deliver the shock. The advantage of using the ICD is that it avoids the risk of a skin irritation from an external shock and the small chance of damage to the ICD system from the shock. The disadvantage of using the ICD is that it consumes some of the battery in the device and does not always work for cardioversion of atrial arrhythmias. Indications for and efficacy of ICDs are discussed in detail elsewhere. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Supraventricular arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 14/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Heart failure and atrial fibrillation (The Basics)") Beyond the Basics topics (see "Patient education: Cardioversion (Beyond the Basics)" and "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Definitions Electrical cardioversion and defibrillation are commonly performed procedures in the management of patients with cardiac arrhythmias. Elective outpatient cardioversions are routinely performed on patients with persistent atrial fibrillation (AF) to restore sinus rhythm ( movie 1). Cardioversion is the delivery of energy that is synchronized to the QRS complex, while defibrillation is asynchronous delivery of a shock randomly during the cardiac cycle. (See 'Introduction' above.) Energy selection When available, a biphasic defibrillator is preferred due to greater efficacy. Nearly all available external defibrillators now use a biphasic waveform. However, it is still important to fully understand the type of waveform that is delivered when using an external defibrillator. The energy selection recommendations in this topic are in joules and are for defibrillators that use a standard biphasic waveform. Lower energies can be used with defibrillators that use a truncated biphasic waveform. (See 'Energy selection' above.) Once an arrhythmia has been identified, the most important factor in the likelihood of a successful cardioversion or defibrillation is the choice of the initial energy level to be delivered to the patient. To increase the likelihood of initial shock success and reduce the duration of sedation, a higher initial energy may be considered. The following are suggested initial energy requirements for monophasic and biphasic waveforms (see "Basic principles and technique of external electrical cardioversion and defibrillation", section on 'Energy selection for cardioversion and defibrillation'): For AF, 120 to 200 joules ( algorithm 1) For atrial flutter, 50 to 100 joules For ventricular tachycardia with a pulse, 100 joules For ventricular fibrillation or pulseless ventricular tachycardia, 200 to 360 joules ( algorithm 2) Efficacy External cardioversion and defibrillation have been used in the treatment of a variety of arrhythmias, with variable results depending on the chronicity of the arrhythmia, https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 15/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate triggers for the arrhythmia, and the patient s overall clinical condition. The term "failed cardioversion" can indicate failure to restore sinus rhythm at all, or an immediate recurrence of the arrhythmia. It is important to differentiate these two failure mechanisms because different approaches can be used to address each type of failure. (See 'Efficacy' above.) Atrial fibrillation or atrial flutter Electrical cardioversion success rates approach 100 percent in patients with atrial flutter or AF of short duration and no structural heart disease, while the success rates are much lower in patients with chronic AF and concomitant mitral valve disease. (See 'Atrial fibrillation' above and 'Atrial flutter' above.) Ventricular tachycardia Electrical cardioversion is usually successful in the acute treatment of ventricular tachycardia. If a distinct QRS and T wave are identified, synchronized cardioversion can be attempted. In contrast, synchronized cardioversion may be impossible or hazardous if distinct QRS complexes are not identified. As such, under these circumstances, asynchronous defibrillation should be used. (See 'Ventricular tachycardia' above.) Ventricular fibrillation Defibrillation is the only definitive treatment for ventricular fibrillation (VF), with high success rates when performed promptly. However, the success rate falls substantially as the duration of ventricular fibrillation increases, probably due to myocardial ischemia, acidosis, and other metabolic changes. For these reasons, defibrillation as soon as possible has been considered to be the standard of care for VF ( algorithm 2). (See 'Ventricular fibrillation' above.) Complications While electrical cardioversion and defibrillation are generally well tolerated, complications may occur. Most complications are self-limited (eg, changes in the electrocardiogram, hypotension related to sedation and/or vasodilation) or relatively benign (eg, skin irritation). However, providers should be aware of potential life- threatening complications such as post-cardioversion arrhythmias and thromboembolism. (See 'Complications' above.) Internal cardioversion Internal or intracardiac cardioversion is an effective technique for patients in whom external cardioversion has failed to restore sinus rhythm. The need for internal cardioversion has been greatly diminished due to the efficacy of biphasic waveform defibrillators in restoring sinus rhythm. Given the invasive nature of the procedure, specialized training is required to perform internal cardioversion. (See 'Internal cardioversion/defibrillation' above.) https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 16/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Ramsey Wehbe, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Strzelczyk TA, Kaplan RM, Medler M, Knight BP. Outcomes Associated With Electrical Cardioversion for Atrial Fibrillation When Performed Autonomously by an Advanced Practice Provider. JACC Clin Electrophysiol 2017; 3:1447. 2. Kirchhof P, Eckardt L, Loh P, et al. Anterior-posterior versus anterior-lateral electrode positions for external cardioversion of atrial fibrillation: a randomised trial. Lancet 2002; 360:1275. 3. Botto GL, Politi A, Bonini W, et al. External cardioversion of atrial fibrillation: role of paddle position on technical efficacy and energy requirements. Heart 1999; 82:726. 4. Ramirez FD, Fiset SL, Cleland MJ, et al. Effect of Applying Force to Self-Adhesive Electrodes on Transthoracic Impedance: Implications for Electrical Cardioversion. Pacing Clin Electrophysiol 2016; 39:1141. 5. Walsh SJ, McCarty D, McClelland AJ, et al. Impedance compensated biphasic waveforms for transthoracic cardioversion of atrial fibrillation: a multi-centre comparison of antero-apical and antero-posterior pad positions. Eur Heart J 2005; 26:1298. 6. Dahl CF, Ewy GA, Warner ED, Thomas ED. Myocardial necrosis from direct current countershock. Effect of paddle electrode size and time interval between discharges. Circulation 1974; 50:956. 7. Warner ED, Dahl C, Ewy GA. Myocardial injury from transthoracic defibrillator countershock. Arch Pathol 1975; 99:55. 8. Link MS, Atkins DL, Passman RS, et al. Part 6: electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S706. 9. Saliba W, Juratli N, Chung MK, et al. Higher energy synchronized external direct current cardioversion for refractory atrial fibrillation. J Am Coll Cardiol 1999; 34:2031. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 17/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate 10. Oral H, Souza JJ, Michaud GF, et al. Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment. N Engl J Med 1999; 340:1849. 11. Sung RJ. Facilitating electrical cardioversion of persistant atrial fibrillation by antiarrhythmic drugs: update on clinical trial results. Card Electrophysiol Rev 2003; 7:300. 12. Babbs CF, Yim GK, Whistler SJ, et al. Elevation of ventricular defibrillation threshold in dogs by antiarrhythmic drugs. Am Heart J 1979; 98:345. 13. Troup PJ, Chapman PD, Olinger GN, Kleinman LH. The implanted defibrillator: relation of defibrillating lead configuration and clinical variables to defibrillation threshold. J Am Coll Cardiol 1985; 6:1315. 14. Tacker WA Jr, Niebauer MJ, Babbs CF, et al. The effect of newer antiarrhythmic drugs on defibrillation threshold. Crit Care Med 1980; 8:177. 15. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Effects of flecainide on the atrial defibrillation threshold. Am J Cardiol 1989; 63:112. 16. Gurevitz OT, Ammash NM, Malouf JF, et al. Comparative efficacy of monophasic and biphasic waveforms for transthoracic cardioversion of atrial fibrillation and atrial flutter. Am Heart J 2005; 149:316. 17. Page RL, Kerber RE, Russell JK, et al. Biphasic versus monophasic shock waveform for conversion of atrial fibrillation: the results of an international randomized, double-blind multicenter trial. J Am Coll Cardiol 2002; 39:1956. 18. Khaykin Y, Newman D, Kowalewski M, et al. Biphasic versus monophasic cardioversion in shock-resistant atrial fibrillation:. J Cardiovasc Electrophysiol 2003; 14:868. 19. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 20. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 21. Fuster V, Ryd n LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006; 114:e257. 22. Niebauer MJ, Brewer JE, Chung MK, Tchou PJ. Comparison of the rectilinear biphasic waveform with the monophasic damped sine waveform for external cardioversion of atrial https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 18/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate fibrillation and flutter. Am J Cardiol 2004; 93:1495. 23. Gallagher MM, Guo XH, Poloniecki JD, et al. Initial energy setting, outcome and efficiency in direct current cardioversion of atrial fibrillation and flutter. J Am Coll Cardiol 2001; 38:1498. 24. Mortensen K, Risius T, Schwemer TF, et al. Biphasic versus monophasic shock for external cardioversion of atrial flutter: a prospective, randomized trial. Cardiology 2008; 111:57. 25. Faddy SC, Powell J, Craig JC. Biphasic and monophasic shocks for transthoracic defibrillation: a meta analysis of randomised controlled trials. Resuscitation 2003; 58:9. 26. Morrison LJ, Dorian P, Long J, et al. Out-of-hospital cardiac arrest rectilinear biphasic to monophasic damped sine defibrillation waveforms with advanced life support intervention trial (ORBIT). Resuscitation 2005; 66:149. 27. Martens PR, Russell JK, Wolcke B, et al. Optimal Response to Cardiac Arrest study: defibrillation waveform effects. Resuscitation 2001; 49:233. 28. Stothert JC, Hatcher TS, Gupton CL, et al. Rectilinear biphasic waveform defibrillation of out- of-hospital cardiac arrest. Prehosp Emerg Care 2004; 8:388. 29. Tovar OH, Jones JL. Electrophysiological deterioration during long-duration ventricular fibrillation. Circulation 2000; 102:2886. 30. Cobb LA, Fahrenbruch CE, Walsh TR, et al. Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation. JAMA 1999; 281:1182. 31. Wik L, Hansen TB, Fylling F, et al. Delaying defibrillation to give basic cardiopulmonary resuscitation to patients with out-of-hospital ventricular fibrillation: a randomized trial. JAMA 2003; 289:1389. 32. VOGEL JH, PRYOR R, BLOUNT SG Jr. DIRECT-CURRENT DEFIBRILLATION DURING PREGNANCY. JAMA 1965; 193:970. 33. Schroeder JS, Harrison DC. Repeated cardioversion during pregnancy. Treatment of refractory paroxysmal atrial tachycardia during 3 successive pregnancies. Am J Cardiol 1971; 27:445. 34. Waller C, Callies F, Langenfeld H. Adverse effects of direct current cardioversion on cardiac pacemakers and electrodes Is external cardioversion contraindicated in patients with permanent pacing systems? Europace 2004; 6:165. 35. Gould L, Patel S, Gomes GI, Chokshi AB. Pacemaker failure following external defibrillation. Pacing Clin Electrophysiol 1981; 4:575. 36. Levine PA, Barold SS, Fletcher RD, Talbot P. Adverse acute and chronic effects of electrical defibrillation and cardioversion on implanted unipolar cardiac pacing systems. J Am Coll Cardiol 1983; 1:1413. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 19/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate 37. Manegold JC, Israel CW, Ehrlich JR, et al. External cardioversion of atrial fibrillation in patients with implanted pacemaker or cardioverter-defibrillator systems: a randomized comparison of monophasic and biphasic shock energy application. Eur Heart J 2007; 28:1731. 38. Eysmann SB, Marchlinski FE, Buxton AE, Josephson ME. Electrocardiographic changes after cardioversion of ventricular arrhythmias. Circulation 1986; 73:73. 39. Van Gelder IC, Crijns HJ, Van der Laarse A, et al. Incidence and clinical significance of ST segment elevation after electrical cardioversion of atrial fibrillation and atrial flutter. Am Heart J 1991; 121:51. 40. Chun PK, Davia JE, Donohue DJ. ST-segment elevation with elective DC cardioversion. Circulation 1981; 63:220. 41. Zelinger AB, Falk RH, Hood WB Jr. Electrical-induced sustained myocardial depolarization as a possible cause for transient ST elevation post-DC elective cardioversion. Am Heart J 1982; 103:1073. 42. Kok LC, Mitchell MA, Haines DE, et al. Transient ST elevation after transthoracic cardioversion in patients with hemodynamically unstable ventricular tachyarrhythmia. Am J Cardiol 2000; 85:878. 43. Reiffel JA, Gambino SR, McCarthy DM, Leahey EB Jr. Direct current cardioversion. Effect on creatine kinase, lactic dehydrogenase and myocardial isoenzymes. JAMA 1978; 239:122. 44. Allan JJ, Feld RD, Russell AA, et al. Cardiac troponin I levels are normal or minimally elevated after transthoracic cardioversion. J Am Coll Cardiol 1997; 30:1052. 45. Neumayr G, Hagn C, G nzer H, et al. Plasma levels of troponin T after electrical cardioversion of atrial fibrillation and flutter. Am J Cardiol 1997; 80:1367. 46. Reddy RK, Gleva MJ, Gliner BE, et al. Biphasic transthoracic defibrillation causes fewer ECG ST-segment changes after shock. Ann Emerg Med 1997; 30:127. 47. Ambler JJ, Deakin CD. A randomized controlled trial of efficacy and ST change following use of the Welch-Allyn MRL PIC biphasic waveform versus damped sine monophasic waveform for external DC cardioversion. Resuscitation 2006; 71:146. 48. Waldecker B, Brugada P, Zehender M, et al. Dysrhythmias after direct-current cardioversion. Am J Cardiol 1986; 57:120. 49. DeSilva RA, Graboys TB, Podrid PJ, Lown B. Cardioversion and defibrillation. Am Heart J 1980; 100:881. 50. LEMBERG L, CASTELLANOS A Jr, SWENSON J, GOSSELIN A. ARRHYTHMIAS RELATED TO CARDIOVERSION. Circulation 1964; 30:163. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 20/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate 51. PELESKA B. CARDIAC ARRHYTHMIAS FOLLOWING CONDENSER DISCHARGES AND THEIR DEPENDENCE UPON STRENGTH OF CURRENT AND PHASE OF CARDIAC CYCLE. Circ Res 1963; 13:21. 52. Cohen TJ, Scheinman MM, Pullen BT, et al. Emergency intracardiac defibrillation for refractory ventricular fibrillation during routine electrophysiologic study. J Am Coll Cardiol 1991; 18:1280. 53. Gr nberg T, Nuotio I, Nikkinen M, et al. Arrhythmic complications after electrical cardioversion of acute atrial fibrillation: the FinCV study. Europace 2013; 15:1432. 54. Elhendy A, Gentile F, Khandheria BK, et al. Safety of electrical cardioversion in patients with previous embolic events. Mayo Clin Proc 2001; 76:364. 55. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969; 23:208. 56. Ehsani A, Ewy GA, Sobel BE. Effects of electrical countershock on serum creatine phosphokinase (CPK) isoenzyme activity. Am J Cardiol 1976; 37:12. 57. Lindberg K, Lundin A, Nordlander R, et al. Detection of acute myocardial infarction by a new, sensitive and rapid method for determination of creatine kinase B-subunit activity. Eur Heart J 1980; 1:327. 58. Goktekin O, Melek M, Gorenek B, et al. Cardiac troponin T and cardiac enzymes after external transthoracic cardioversion of ventricular arrhythmias in patients with coronary artery disease. Chest 2002; 122:2050. 59. Kern KB, Hilwig RW, Rhee KH, Berg RA. Myocardial dysfunction after resuscitation from cardiac arrest: an example of global myocardial stunning. J Am Coll Cardiol 1996; 28:232. 60. Xie J, Weil MH, Sun S, et al. High-energy defibrillation increases the severity of postresuscitation myocardial dysfunction. Circulation 1997; 96:683. 61. Sun S, Klouche K, Tang W, Weil MH. The effects of biphasic and conventional monophasic defibrillation on postresuscitation myocardial function. J Am Coll Cardiol 2001; 37:1753. 62. Grimm RA, Stewart WJ, Maloney JD, et al. Impact of electrical cardioversion for atrial fibrillation on left atrial appendage function and spontaneous echo contrast: characterization by simultaneous transesophageal echocardiography. J Am Coll Cardiol 1993; 22:1359. 63. Omran H, Jung W, Rabahieh R, et al. Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study. J Am Coll Cardiol 1997; 29:131. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 21/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate 64. Gowda RM, Misra D, Khan IA, Schweitzer P. Acute pulmonary edema after cardioversion of cardiac arrhythmias. Int J Cardiol 2003; 92:271. 65. Resnekov L. High-energy electrical current and myocardial damage. Med Instrum 1978; 12:24. 66. Ambler JJ, Sado DM, Zideman DA, Deakin CD. The incidence and severity of cutaneous burns following external DC cardioversion. Resuscitation 2004; 61:281. 67. Ambler JJ, Deakin CD. A randomised controlled trial of the effect of biphasic or monophasic waveform on the incidence and severity of cutaneous burns following external direct current cardioversion. Resuscitation 2006; 71:293. 68. Ambler JJ, Zideman DA, Deakin CD. The effect of prophylactic topical steroid cream on the incidence and severity of cutaneous burns following external DC cardioversion. Resuscitation 2005; 65:179. 69. Ambler JJ, Zideman DA, Deakin CD. The effect of topical non-steroidal anti-inflammatory cream on the incidence and severity of cutaneous burns following external DC cardioversion. Resuscitation 2005; 65:173. 70. Tracy CM, Akhtar M, DiMarco JP, et al. American College of Cardiology/American Heart Association Clinical Competence Statement on invasive electrophysiology studies, catheter ablation, and cardioversion: A report of the American College of Cardiology/American Heart Association/American College of Physicians-American Society of Internal Medicine Task Force on Clinical Competence. Circulation 2000; 102:2309. 71. Liebold A, Wahba A, Birnbaum DE. Low-energy cardioversion with epicardial wire electrodes: new treatment of atrial fibrillation after open heart surgery. Circulation 1998; 98:883. 72. Mansourati J, Larlet JM, Salaun G, et al. Safety of high energy internal cardioversion for atrial fibrillation. Pacing Clin Electrophysiol 1997; 20:1919. 73. Prakash A, Saksena S, Mathew P, Krol RB. Internal atrial defibrillation: effect on sinus and atrioventricular nodal function and implanted cardiac pacemakers. Pacing Clin Electrophysiol 1997; 20:2434. Topic 983 Version 47.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 22/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate GRAPHICS Protocol for direct current cardioversion (CV) for atrial fibrillation (AF) when performed autonomously by a mid-level provider and when sedation is administered by anesthesiologist Pre-procedure 1. Obtain medical history that includes the indication for CV and review records. 2. Document that NPO status is at least 6 hours prior to procedure. 3. Confirm appropriate anticoagulation unless onset of AF is <24 to 48 hours: For warfarin, document therapeutic INRs (>2.0) for last 4 weeks. For non-warfarin oral anticoagulants, confirm no doses missed for last 4 weeks. Document therapeutic INR and/or NOAC dose within 12 hrs. Perform TEE if OAC has not been therapeutic for at least 4 weeks prior to procedure or if there is a history of prior atrial thrombus. 4. Complete ECG to confirm presence of AF or flutter. 5. Obtain consent: review indications, discuss risks and benefits, including potential skin irritation, stroke, abnormal rhythms, and inform patient of the role of each care team member. 6. Interrogate any CIED before CV. 7. Review case with supervising physician. Procedure 1. Apply cardioversion skin pads using anterior-posterior or base-apex placement. 2. Connect the pads to a synchronized biphasic defibrillator. 3. Complete a Time-Out procedure pursuant to hospital policy. 4. Anesthesia team provides deep sedation. 5. Select initial shock energy: AF begin at 200 to 360 joules. Atrial flutter begin at 50 to 100 joules. Atrial tachycardia begin at 50 joules. 6. If sinus rhythm was restored but there is an IRAF: Resynchronize defibrillator and repeat CV at same energy. If IRAF continues, contact supervising physician. Consider ibutilide 1 mg IV over 10 minutes with repeat CV after 10 additional minutes. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 23/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Post procedure 1. Perform ECG. 2. Interrogation of any CIED post procedure. 3. Document post procedure note including appropriate discharge medications. 4. Continue anticoagulation for a minimum of 4 weeks. 5. Update family or friends accompanying patient. 6. Ensure follow-up is arranged. NPO: nothing by mouth; INR: internal normalized ratio; NOAC: non-vitamin K oral anticoagulants; TEE: transesophageal echocardiography; OAC: oral anticoagulant; ECG: electrocardiogram; CIED: cardiac implantable electronic device; IRAF: immediate reoccurrence of atrial fibrillation; IV: intravenous. Original gure modi ed for this publication. From: Strzelczyk TA, Kaplan RM, Medler M, Knight BP. Outcomes Associated With Electrical Cardioversion for Atrial Fibrillation When Performed Autonomously by an Advanced Practice Provider. J Am Coll Cardiol 2017; 3:1447. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 121196 Version 1.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 24/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Options for hands-free pacemaker/defibrillator pad positioning Positioning options for hands-free pacemaker/defibrillator pads showing anterior/lateral positioning (left) and anterior/posterior positioning (right). Graphic 103268 Version 2.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 25/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Defibrillation waveforms in implantable cardioverter- defibrillators Figure A shows the monophasic, exponentially decaying pulse was the waveform used in the first generation of ICDs. Figure B shows the biphasic waveform, which is generated with a single capacitor by switching the output polarity during discharge. Each division is 2 milliseconds. ICD: implantable cardioverter-defibrillator. Graphic 51842 Version 3.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 26/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Adult tachycardia with a pulse algorithm 2020 update Reprinted with permission. ACLS Provider Manual. Copyright 2020 American Heart Association, Inc. Graphic 130747 Version 10.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 27/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Adult cardiac arrest algorithm https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 28/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 29/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Reprinted with permission. Highlights of the 2020 American Heart Association Guidelines for CPR and ECC. Copyright 2020 American Association, Inc. Graphic 129983 Version 9.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 30/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate The effect of antiarrhythmic agents on cardioversion energy requirements Antiarrhythmic agent Energy requirement Lidocane Increased or no change Quinidine Increased Phenytoin Increased Amiodarone Increased Flecainide Increased Ibutilide Decreased Graphic 81781 Version 3.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 31/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate 12 lead ECG of atrial flutter The 12 lead electrocardiogram (ECG) of atrial flutter shows a regular rhythm with a narrow QRS complex. Flutter waves are present, best seen in leads II, III, and aVF (*). In this ECG, the flutter waves are negative in leads II, III, and aVF, and positive in lead V1. One flutter wave is obvious between the QRS complexes, while the second one is superimposed on the terminal portion of the QRS complex; hence there is 2:1 atrioventricular nodal block, which is the most common presentation for atrial flutter. Reproduced with permission by Samuel Levy, MD. Graphic 75931 Version 3.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 32/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Reentrant circuit of typical atrial flutter within the right atrium Schematic representation of reentrant circuit (red arrow) of typical (type 1) atrial flutter. The reentrant impulse rotates in a counterclockwise direction around the tricuspid annulus. The crista terminalis (CT) and eustacian ridge (ER) serve as lines of block, preventing the impulse from short-circuiting the annulus. Ablation is performed in the isthmus between the IVC and TA, which is an obligatory part of the circuit. SVC: superior vena cava; CS: coronary sinus; IVC: inferior vena cava; FO: foramen ovale Graphic 52904 Version 5.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 33/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Cognitive skills necessary to perform internal DC cardioversion Physicians should have knowledge of the following: Cognitive and technical skills for performing intracardiac electrophysiologic study Principles of intracavitary cardioversion with catheter technology, catheters, chest electrodes, or whatever variant the operator plans to use Indications and complications associated with transvenous catheterization and with the intracavitary delivery of DC shock The safe delivery of DC shock and the limit of energy that can be delivered via electrode catheters The use of conscious sedation or, when appropriate, anesthesia The use of intravenous antiarrhythmic medications Cognitive skills necessary for external DC cardioversion Data from Tracy CM, Akhtar M, DiMarco JP, et al. Circulation 2000; 102:2309. Graphic 57223 Version 2.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 34/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Technical skills necessary to perform internal DC cardioversion Competency in performing diagnostic cardiac electrophysiology studies Ability to place electrode catheters in appropriate locations for intracardiac synchronization and DC cardioversion Familiarity with the catheter characteristics, synchronization, and DC cardioversion equipment Ability to confirm the timing and energy of the shock for safe shock delivery Adequate electrocardiographic and rhythm monitoring equipment Ability to handle complications, including the use of temporary pacing and defibrillation Proficiency in the appropriate use of sedation during procedures, including airway management Data from Tracy CM, Akhtar M, DiMarco JP, et al. Circulation 2000; 102:2309. Graphic 65048 Version 2.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 35/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Contributor Disclosures

6. Interrogate any CIED before CV. 7. Review case with supervising physician. Procedure 1. Apply cardioversion skin pads using anterior-posterior or base-apex placement. 2. Connect the pads to a synchronized biphasic defibrillator. 3. Complete a Time-Out procedure pursuant to hospital policy. 4. Anesthesia team provides deep sedation. 5. Select initial shock energy: AF begin at 200 to 360 joules. Atrial flutter begin at 50 to 100 joules. Atrial tachycardia begin at 50 joules. 6. If sinus rhythm was restored but there is an IRAF: Resynchronize defibrillator and repeat CV at same energy. If IRAF continues, contact supervising physician. Consider ibutilide 1 mg IV over 10 minutes with repeat CV after 10 additional minutes. https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 23/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Post procedure 1. Perform ECG. 2. Interrogation of any CIED post procedure. 3. Document post procedure note including appropriate discharge medications. 4. Continue anticoagulation for a minimum of 4 weeks. 5. Update family or friends accompanying patient. 6. Ensure follow-up is arranged. NPO: nothing by mouth; INR: internal normalized ratio; NOAC: non-vitamin K oral anticoagulants; TEE: transesophageal echocardiography; OAC: oral anticoagulant; ECG: electrocardiogram; CIED: cardiac implantable electronic device; IRAF: immediate reoccurrence of atrial fibrillation; IV: intravenous. Original gure modi ed for this publication. From: Strzelczyk TA, Kaplan RM, Medler M, Knight BP. Outcomes Associated With Electrical Cardioversion for Atrial Fibrillation When Performed Autonomously by an Advanced Practice Provider. J Am Coll Cardiol 2017; 3:1447. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 121196 Version 1.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 24/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Options for hands-free pacemaker/defibrillator pad positioning Positioning options for hands-free pacemaker/defibrillator pads showing anterior/lateral positioning (left) and anterior/posterior positioning (right). Graphic 103268 Version 2.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 25/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Defibrillation waveforms in implantable cardioverter- defibrillators Figure A shows the monophasic, exponentially decaying pulse was the waveform used in the first generation of ICDs. Figure B shows the biphasic waveform, which is generated with a single capacitor by switching the output polarity during discharge. Each division is 2 milliseconds. ICD: implantable cardioverter-defibrillator. Graphic 51842 Version 3.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 26/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Adult tachycardia with a pulse algorithm 2020 update Reprinted with permission. ACLS Provider Manual. Copyright 2020 American Heart Association, Inc. Graphic 130747 Version 10.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 27/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Adult cardiac arrest algorithm https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 28/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 29/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Reprinted with permission. Highlights of the 2020 American Heart Association Guidelines for CPR and ECC. Copyright 2020 American Association, Inc. Graphic 129983 Version 9.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 30/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate The effect of antiarrhythmic agents on cardioversion energy requirements Antiarrhythmic agent Energy requirement Lidocane Increased or no change Quinidine Increased Phenytoin Increased Amiodarone Increased Flecainide Increased Ibutilide Decreased Graphic 81781 Version 3.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 31/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate 12 lead ECG of atrial flutter The 12 lead electrocardiogram (ECG) of atrial flutter shows a regular rhythm with a narrow QRS complex. Flutter waves are present, best seen in leads II, III, and aVF (*). In this ECG, the flutter waves are negative in leads II, III, and aVF, and positive in lead V1. One flutter wave is obvious between the QRS complexes, while the second one is superimposed on the terminal portion of the QRS complex; hence there is 2:1 atrioventricular nodal block, which is the most common presentation for atrial flutter. Reproduced with permission by Samuel Levy, MD. Graphic 75931 Version 3.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 32/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Reentrant circuit of typical atrial flutter within the right atrium Schematic representation of reentrant circuit (red arrow) of typical (type 1) atrial flutter. The reentrant impulse rotates in a counterclockwise direction around the tricuspid annulus. The crista terminalis (CT) and eustacian ridge (ER) serve as lines of block, preventing the impulse from short-circuiting the annulus. Ablation is performed in the isthmus between the IVC and TA, which is an obligatory part of the circuit. SVC: superior vena cava; CS: coronary sinus; IVC: inferior vena cava; FO: foramen ovale Graphic 52904 Version 5.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 33/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Cognitive skills necessary to perform internal DC cardioversion Physicians should have knowledge of the following: Cognitive and technical skills for performing intracardiac electrophysiologic study Principles of intracavitary cardioversion with catheter technology, catheters, chest electrodes, or whatever variant the operator plans to use Indications and complications associated with transvenous catheterization and with the intracavitary delivery of DC shock The safe delivery of DC shock and the limit of energy that can be delivered via electrode catheters The use of conscious sedation or, when appropriate, anesthesia The use of intravenous antiarrhythmic medications Cognitive skills necessary for external DC cardioversion Data from Tracy CM, Akhtar M, DiMarco JP, et al. Circulation 2000; 102:2309. Graphic 57223 Version 2.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 34/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Technical skills necessary to perform internal DC cardioversion Competency in performing diagnostic cardiac electrophysiology studies Ability to place electrode catheters in appropriate locations for intracardiac synchronization and DC cardioversion Familiarity with the catheter characteristics, synchronization, and DC cardioversion equipment Ability to confirm the timing and energy of the shock for safe shock delivery Adequate electrocardiographic and rhythm monitoring equipment Ability to handle complications, including the use of temporary pacing and defibrillation Proficiency in the appropriate use of sedation during procedures, including airway management Data from Tracy CM, Akhtar M, DiMarco JP, et al. Circulation 2000; 102:2309. Graphic 65048 Version 2.0 https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 35/36 7/6/23, 2:50 PM Cardioversion for specific arrhythmias - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Richard L Page, MD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardioversion-for-specific-arrhythmias/print 36/36

7/6/23, 2:48 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 13, 2022. INTRODUCTION The primary trigger for most episodes of atrial fibrillation (AF) is an electrical discharge(s) within one of the four pulmonary veins (see "Mechanisms of atrial fibrillation", section on 'Triggers of AF'). The cornerstone of any procedure aimed at reducing AF burden is the electrical isolation of the pulmonary veins so that these discharges do not trigger the initiation of AF. In those with persistent and longstanding persistent AF, and in some patients with paroxysmal AF, additional areas, often in one or both of the atria or surrounding structures, are targeted for ablation, as they may also serve as a source of AF triggers or maintenance. Catheter ablation (CA) is the procedure that is used to prevent the initiation of AF by electrically isolating these triggers from the rest of the atrial chamber tissue. This topic is intended to be viewed primarily by non-electrophysiologists. Electrophysiologists may be more interested in other topics: (See "Overview of catheter ablation of cardiac arrhythmias".) (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) (See "Atrial fibrillation: Catheter ablation".) (See "Invasive diagnostic cardiac electrophysiology studies".) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 1/27 7/6/23, 2:48 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) PATIENT SELECTION A major clinical goal of CA is a reduction in AF-related symptoms. CA is superior to medical therapy at improving quality of life. Therefore, it is generally reserved for individuals with symptoms attributable to the arrhythmia, which most often include palpitations, shortness of breath, or generalized fatigue [1,2]. Even if they have no AF-related symptoms, older individuals with early AF (duration <1 year) and additional cardiovascular conditions also benefit from therapies aimed at maintaining sinus rhythm; these therapies include CA [3]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Recommendations of others'.) Patients should be considered for ablation for AF after the history and physical exam have been reviewed and there is documentation of symptomatic correlation with AF on electrocardiogram (ECG) or other forms of monitoring. Modifiable risk factors including obesity, excessive alcohol intake, and sleep apnea should be addressed, as they are important components of AF treatment and impact the success of any rhythm control intervention [4-8]. AF CA may be appropriate in the following groups: Patients with paroxysmal or persistent AF who have tried a class I or III antiarrhythmic drug ablation can be considered if such medications are either unsuccessful or are not tolerated. Some individuals may choose ablation as first-line therapy. For patients with long-standing persistent AF, a trial of one or more class I or III antiarrhythmic drugs is recommended. Ablation as first-line therapy can be considered in those with contraindications to drugs. Asymptomatic younger individuals and patients with heart failure due to reduced ejection fraction may also benefit from ablation [9,10]. We do not perform CA in: Individuals who are too frail to safely undergo the procedure. Patients with a left atrial appendage thrombus. Individuals with bleeding diathesis who cannot receive intra- and postprocedural anticoagulation. PREPROCEDURAL PREPARATION https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 2/27 7/6/23, 2:48 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Once a patient has been selected for AF ablation, the clinician performing the procedure or their designee should obtain informed consent from the patient. This involves shared decision- making after discussing the indications, benefits, risks, and alternatives of the planned procedure. Sedation options include general anesthesia that requires an endotracheal tube or monitored anesthesia care with sedation but not requiring intubation. Most procedures are performed under general anesthesia. Medication management Most physicians performing ablation will discontinue antiarrhythmic drugs prior to the ablation with the rationale that it may help to identify the triggers of the AF at the time of the procedure. We acknowledge that many other electrophysiologists will continue them. There are no well-performed studies to guide practice. With regard to oral anticoagulation, randomized trials have demonstrated superior efficacy and safety of uninterrupted anticoagulation throughout the ablation procedure compared with temporary discontinuation of anticoagulation and bridging with low molecular weight heparin. Most operators, including the authors, perform the procedure on uninterrupted or minimally interrupted direct-acting oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) such as warfarin. A meta-analysis of 17,434 patients from 12 observational trials and one randomized trial compared uninterrupted warfarin with interrupted warfarin and heparin bridging at the time of AF ablation. Uninterrupted warfarin was associated with significant reductions in stroke and major and minor bleeding [11]. Studies have shown that patients on uninterrupted DOACs have either lower (dabigatran, edoxaban [12,13]) or similar (rivaroxaban, apixaban) [14,15] bleeding risks compared with those on uninterrupted VKA. Studies of DOACS with lower bleeding risks compared with VKA: The RE-CIRCUIT trial randomized 704 patients undergoing AF ablation to uninterrupted dabigatran or VKA. The incidence of major bleeding events during and up to eight weeks after ablation was lower with dabigatran than with warfarin (1.6 versus 6.9 percent) [12]. In a trial of 614 patients undergoing CA, participants were randomly assigned to uninterrupted edoxaban or VKA. Major bleeds were nonsignificantly lower in persons assigned to edoxaban compared with VKA (0.2 versus 2 percent; hazard ratio 0.16; 95% CI 0.02-1.73) [13]. Studies of DOACS with similar bleeding risks compared with VKA: https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 3/27 7/6/23, 2:48 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate In a trial of rivaroxaban or VKA in people undergoing AF ablation, bleeding events were similar in the two study arms [14]. In a trial that compared uninterrupted apixaban with placebo, the rates of clinically significant and major bleeding were also similar for both groups (10.6 versus 9.8 percent) [15]. Imaging All patients with AF, not just those being considered for CA, should undergo transthoracic echocardiography (TTE) to evaluate for factors that may affect treatment including the presence and extent of valvular disease, chamber size, and ventricular function. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Echocardiogram'.) Transesophageal echocardiography (TEE), which is superior to TTE for finding atrial thrombus, is often performed within 24 hours prior to ablation since the presence of thrombus in the left atrium or left atrial appendage is a contraindication to AF ablation. Some operators may choose to forego TEE in patients with a low risk of stroke (ie, CHA DS -VASc 1) who are expected to be 2 2 in sinus rhythm at the time of the procedure and who have been and will be maintained on uninterrupted anticoagulation throughout the periprocedural timeframe. Some operators will individualize the need for preprocedure TEE and tend to only perform it in higher-risk patients. Risk factors for left atrial appendage thrombus prior to ablation include hypertrophic cardiomyopathy, ejection fraction <30 percent, persistent or longstanding persistent AF, and elevated CHA DS -VASc score [16]. In a study of 1058 preprocedure TEEs, the rate of detection of 2 2 left atrial thrombus or prethrombus was 1 percent in patients with paroxysmal AF in sinus rhythm and 2 percent for patients with paroxysmal AF who were in AF at the time of the procedure. The risk increased with increasing CHADS score [17]. 2 Computed tomography (CT) or cardiac magnetic resonance imaging (cMRI) may be performed preablation to define the left atrial anatomy, specifically the number, size, and location of the pulmonary veins ( figure 1). Data are emerging to suggest that these imaging techniques are also highly sensitive for left atrial thrombus, and many operators use CT or cMRI to evaluate for left atrial thrombus instead of TEE in low-risk individuals. A comparison of cMRI with TEE to evaluate preablation left atrial appendage thrombus demonstrated 100 percent sensitivity and 99.2 percent specificity for equilibrium phase delayed enhancement CMR with a long inversion time [18]. New high-dimensional mapping catheters used during the procedure can create high- definition structural geometry, and for many operators has obviated the need for preprocedure imaging. PROCEDURAL ISSUES https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 4/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Ablation for AF is among the most complicated procedures performed by electrophysiologists. The procedure should be performed in centers with experience with complex electrophysiologic procedures and capabilities in managing acute complications. Advancements in procedural technologies and techniques have significantly shortened the duration of ablation procedures for AF. Total procedure time typically ranges from 1.5 to 4 hours [19]. The ablation is performed using uni- or bilateral femoral venous access and transseptal puncture for accessing the left atrium. Anesthesia Ablation for AF is performed in the fasting state with general anesthesia or monitored anesthesia care (MAC) using sedation. In a retrospective cohort study of CA performed under either general anesthesia or conscious sedation, conscious sedation had shorter total procedure times and equivalent success rates compared with general anesthesia [20]. In a retrospective cohort study of CA performed under either general anesthesia or MAC, MAC had shorter total procedure times and equivalent success rates with general anesthesia [19]. Agents typically used for conscious sedation include short-acting benzodiazepines (eg, midazolam) and opioids (eg, fentanyl) in divided doses [21]. The type of anesthesia used for AF ablation procedures is dependent on several variables including the expected complexity and duration of the procedure, energy source being utilized, patient comorbidities, patient preference, and availability of anesthesia support. Patient immobility is important to optimize catheter contact and reduce movement error in the anatomic mapping systems. Paralytics should not be used when testing for phrenic nerve capture during ablation. High frequency ventilation, also called jet ventilation, which utilizes a respiratory rate greater than four times the normal value. (>150 [Vf] breaths per minute) and very small tidal volumes, is used in some centers to aid catheter stability and has been associated with improved outcomes [22]. Intraprocedural medications In addition to anesthetic agents, intravenous heparin is administered throughout the AF ablation procedure to reduce the risk of thrombus formation on the catheters, sheaths, left atrium and left atrial appendage, and at ablation sites. Heparin is administered prior to or immediately after transseptal access has been achieved with a targeted activated clotting time (ACT) of >300 seconds. Target ACT may be reached faster and with lower loading doses in patients undergoing ablation on uninterrupted vitamin K antagonists (VKA) compared with non-vitamin K antagonist oral anticoagulants (NOACs; also referred to as direct acting oral anticoagulants [DOAC]) [23]. Additionally, time to target ACT varies amongst the NOACs, with average time in minutes required to achieve a target ACT of >300 seconds https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 5/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate significantly longer in those receiving uninterrupted dabigatran or apixaban compared with those receiving rivaroxaban [24]. Protamine can be used to reverse anticoagulation at the time of sheath removal post-procedure. Esophageal imaging and temperature monitoring The proximity of the esophagus to the posterior left atrium makes it susceptible to thermal injury (see 'Complications' below). Atrioesophageal fistula, typically occurring one to four weeks post-ablation, is a potentially lethal consequence of AF ablation, with a reported incidence of 0.02 to 0.11 percent. To minimize risk, operators will limit energy delivery in the posterior wall in areas adjacent to the esophagus. As the esophagus can have a highly variable position that can vary throughout the procedure, visualization of the esophagus can be performed using electroanatomic mapping, intracardiac ultrasound (ICE), or barium paste. Many operators use an esophageal temperature probe to assess the effects of ablation on intraluminal temperature, though this practice has not yet been shown to reduce the risk of fistula formation given the low incidence of these events. Given the very low overall incidence of fistula, there have been no randomized data to demonstrate superiority of one esophageal monitoring strategy over another. Consequently, minimization of power delivery to the atrial tissue adjacent to the esophagus or minimization of temperature elevation remain surrogates for procedural safety Vascular ultrasound CA for AF requires multiple sheaths with large diameters in one or both femoral veins in patients receiving oral and intravenous anticoagulation. These issues make vascular complications the most common complications of AF ablation. Access can be obtained through the modified Seldinger approach. Vascular ultrasound has been used for venipuncture guidance and postprocedural evaluation. In a cohort study of 1435 patients undergoing cryoballoon ablation for AF, major clinical events occurred in 1.7 percent of those patients who had their procedure performed without ultrasound guidance versus 0 percent in those that did have ultrasound guidance [25]. In a multicenter, randomized trial, 320 patients were randomized to ultrasound guided versus conventional venipuncture. Major complications were low and not significantly different between groups. Puncture time, inadvertent arterial puncture, and need for extra puncture attempts were all significantly reduced in the ultrasound arm [26]. Intracardiac ultrasound Intracardiac ultrasound allows for real-time imaging of cardiac anatomy. The probe is placed in the right atrium via the inferior vena cava. Common uses of ICE include the identification of intra- and extracardiac anatomic structures such as the esophagus, facilitation of transseptal puncture, guidance of catheter placement, and recognition of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 6/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate complications including thrombus formation on sheaths and catheters and early recognition of pericardial effusion. Fluoroscopy Mapping and ablation of AF requires precise navigation of catheters within the left atrium and localization of intra- and extracardiac structures. Fluoroscopy is used to assess catheter placement, to visualize catheter movement, and to assess proximity to adjacent structures such as the esophagus when marked by an intraluminal catheter or barium paste. Patient and physician exposure to ionizing radiation during AF ablation are highly variable, and radiation injury to the patient is reported in <0.1 percent of cases. Efforts to reduce patient and physician exposure to ionizing radiation have successfully relied on alternative imaging modalities, including ICE and electroanatomic mapping. (See "Radiation-related risks of imaging".) Electroanatomic mapping Electroanatomic mapping systems combine real-time, detailed information of the anatomy and electrical properties of the cardiac structures under evaluation. These systems (Carto [Biosense Webster], NAVX [Abbott], and Rhythmia [Boston Scientific]) use diagnostic and ablation catheters and navigation patches on the patient's skin to create a three- dimensional anatomical map used to help localize critical sites for ablation. ABLATION TECHNIQUES AND TARGETS Energy sources There are three US Food and Drug Administration (FDA)-approved energy sources for AF ablation: radiofrequency energy, cryothermal energy in the form of cryoballoon, and laser balloon. This issue is discussed in detail elsewhere. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Energy sources used for ablation'.) The commonly used and approved energy sources for CA are radiofrequency and cryothermal. The efficacy and safety associated with these two energy sources have been found to be similar in multiple studies. This issue is discussed elsewhere. (See "Atrial fibrillation: Catheter ablation", section on 'Comparison of radiofrequency and cryothermal ablation'.) Pulmonary vein isolation Complete electrical isolation of all PVs using circumferential, wide area pulmonary vein isolation (PVI) is the goal of most procedures. The following explains the rationale. The initiation of AF requires a trigger either within or near the atrium (eg, PVs, crista terminalis, superior vena cava), and substrate within the atrium to maintain AF [9] (see "Mechanisms of atrial fibrillation", section on 'Basic atrial electrophysiology'). The anatomic significance of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 7/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate triggers and substrate differs somewhat, depending upon whether the AF is paroxysmal, persistent, or permanent (see "Paroxysmal atrial fibrillation", section on 'Introduction'). In patients with paroxysmal AF, PV triggers are the primary stimulus in most cases. As AF becomes more persistent, non-PV sources become more important [27]. The following important observations regarding triggers came from early studies of patients with paroxysmal AF and have guided the development of successful ablation techniques for AF [28-30]. AF is commonly triggered by ectopic beats from muscle fibers (fascicles) extending from the left atrium into the PVs ( figure 1). Ectopic foci are localized to the PVs in approximately 90 percent of patients with predominantly structurally normal hearts [31]. Most patients have multiple foci that can act as triggers. Most (94 percent) of the foci are 2 to 4 cm inside the PVs, with the left superior vein being the most common site [28]. The remaining foci are usually in the right or left atrium. The superior vena cava is a much less common site of triggering ectopic beats [28]. Because of these observations, early attempts at ablation targeted these focal ectopic beats within the PV [28]. This approach was limited by: Inconsistent ability to identify the triggering beats during electrophysiology study. Difficulties with precise localization of appropriate ablation sites. The risk of PV stenosis, which can occur following ablation within the PVs. (See "Atrial fibrillation: Catheter ablation".) These limitations lead to the adoption of ablative techniques focused on the complete electrical isolation of all PVs using circumferential wide area PVI. The majority of ablations performed use radiofrequency energy or cryothermy (cryoballoon ablation). Infrared laser received FDA approval in 2018. Circumferential PVI involves the creation of confluent ablation lesions that encircle the ostia of all four PVs, usually in two pairs (ie, a left- and right-sided circles) [32-34]. The goal is to electrically isolate the PVs from the left atrium. For ablation using radiofrequency energy, power, duration, and the catheter contact force determine the size and the depth of the lesion created. It is generally felt that some lesions create edema but not scars, leading to temporary but not permanent ablation, and this ultimately leads to electrical reconnection of the left atrium to the https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 8/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate PVs. Greater power, longer duration, and greater contact force improve the efficacy of the procedure but lead to an increase in complications such as cardiac perforation [35,36]. The efficacy and safety of high-power, short-duration ablation, which creates larger, shallower, and more homogeneous lesions, is under evaluation [37]. Circumferential PVI results in extensive ablation across a wider area of the left atrium. Because of the more extensive ablation, this technique may provide additional methods for preventing AF, including autonomic denervation, elimination of triggering foci outside the PVs, and alteration of the left atrial substrate necessary for perpetuating AF. However, more extensive ablation, particularly in the posterior left atrium, may increase the rate of complications, including the development of left atrial tachycardias or flutters months or years after the ablation. The relative efficacy and safety of these methods are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) Use of a contact force-sensing catheter We use a contact force-sensing catheter in all patients with AF undergoing radiofrequency CA (RFA). The TOCCASTAR study found that patients who underwent CA with this catheter and who received a higher force ( 10 grams) had significantly lower rates of AF recurrence at one year. Use of adenosine-guided pulmonary vein isolation The administration of intravenous adenosine can be used to unmask dormant conduction at the time of CA. Reconnection rates are high in RFA, with three large studies finding rates of 21 (ADVICE), 27 (UNDER-ATP), and 34 percent [38-40]. The use of adenosine to guide additional CA has been shown to improve arrhythmia-free survival in some studies using RFA. Some technical aspects of the procedure are discussed separately. (See 'Ablation techniques and targets' above.) In the ADVICE study, 534 patients with paroxysmal AF who had failed drug therapy underwent a standard PV isolation procedure using radiofrequency energy [38]. Patients were observed for spontaneous recovery of conduction over 20 minutes to allow for reconnected PVs to be reisolated before adenosine administration. Intravenous adenosine was then given to all patients. The 284 patients in whom dormant conduction (evidence of persistent PV conduction) was unmasked by adenosine were randomly assigned to additional adenosine-guided ablation to abolish dormant conduction or to no additional ablation. Among the 250 patients without dormant conduction, 117 were enrolled in a registry. The primary endpoint of the time to first recurrence of symptomatic electrocardiographically documented atrial tachyarrhythmia was between 91 and 365 days. The following findings were noted: Dormant PV conduction was present in 284 (53 percent) of patients. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 9/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Freedom from symptomatic atrial tachycardia occurred more often with adenosine-guided further ablation (69.4 versus 42.3 percent; hazard ratio [HR] 0.44, 95% CI 0.31-0.64). Among patients in the registry, approximately 56 percent remained free from symptomatic atrial tachyarrhythmia. The rate of serious adverse events was similar in both groups. Limitations of this study include lack of generalizability (does not apply to patients undergoing cryoablation), lack of use of force-sensing catheters, which are used by many of our experts, and the use of "dormant connection" as an endpoint rather than AF recurrence. In the UNDER-ATP trial, 2113 patients with paroxysmal, persistent, or long-lasting AF were randomly assigned to either adenosine-guided PV isolation (1112 patients) or conventional PV isolation (1001 patients) [39]. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 seconds or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at one year with the blanking period of 90 days post-ablation. Among patients assigned to adenosine-guided PV isolation, adenosine provoked dormant PV conduction in 307 patients (27.6 percent). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4 percent). At one year, 68.7 percent of patients in the adenosine-guided PV isolation group and 67.1 percent of patients in the conventional PV isolation group were free from the primary endpoint, with no significant difference (adjusted HR 0.89; 95% CI 0.74-1.09; p = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the one-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; p = 0.16). Based on these studies, the use an adenosine in patients undergoing CA with radiofrequency energy is at the discretion of the operator. Confirmation of complete isolation Unlike many other cardiac ablation procedures, AF does not need to be present or induced at the time of the ablation procedure nor is termination of AF or inability to reinduce the arrhythmia a required endpoint of the procedure. For PVI, acute procedural success is defined as electrical isolation of all PVs [41]. This is defined by entry block or the inability to electrically capture PV myocardial tissue distal to the area of ablation when pacing is performed proximal to the ablation line. To do this, a circular catheter is positioned just distal to the PV ostium for the purpose of recording electrograms within the PVs. Confirmation is attempted after a 30-minute waiting period after isolation. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 10/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Some operators also test for exit block, defined by the inability to capture atrial myocardium when pacing is performed within the PV distal to the ablation line. There is a high correlation between AF recurrences and the demonstration of persistent or recurrent conduction between the PVs and left atrium (see "Atrial fibrillation: Catheter ablation", section on 'Efficacy'). Recurrent PV conduction explains most cases of recurrence; it is thought to be due to recovery of function of tissue that has been acutely injured (ie, edema and inflammation) but not permanently scarred. Administration of adenosine has been shown to identify PVs with dormant conduction by transiently restoring excitability and conduction across circumferential ablation lines at risk of reconnection [38]. However, improvements in ablation tools and techniques have significantly reduced the routine use of adenosine. It is used at the discretion of the operator. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) Ablation targets in persistent atrial fibrillation In contrast to patients with paroxysmal AF, patients with persistent AF (and in particular longstanding persistent AF) often have multiple triggers distributed throughout the atria in addition to triggers within the PV [42]. It is thought that mechanisms that maintain rather than trigger the arrhythmia are more important in these individuals. These observations may explain the reduced efficacy of CA procedures that are limited to PVI in patients with longstanding persistent AF seen in most studies. In these patients, additional lesions are often needed to prevent recurrence of AF. These lesions are often placed anatomically in the left atrial posterior wall and roof, in the left atrial appendage, coronary sinus, or in the right atrium. Additional targets include sites of complex fractionated electrograms and rotors [43,44] (see "Mechanisms of atrial fibrillation", section on 'Mechanisms of atrial fibrillation: triggers and substrates'). Though the goal of additional lesion sets are to modify the AF substrate, these approaches may also result in proarrhythmia through the creation of new reentrant circuits. Data supporting the benefits and optimal approach for the treatment of persistent AF are inconclusive and are often individualized by patient and operator. Additional ablation targets/techniques outside the PVs include: Non-PV triggers (eg, coronary sinus, posterior left atrium, crista terminalis) Complex fractionated electrograms (CFAEs) Linear ablation (LA roof, mitral isthmus) Other thoracic veins (superior vena cava, coronary sinus) Posterior wall isolation Left atrial appendage isolation Ablation of cardiac autonomic nerves (ganglionic plexi) Focal impulse and rotor modulation (FIRM) phase mapping-guided ablation Stepwise approach (PVI, CFAE, linear, coronary sinus) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 11/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate POSTPROCEDURAL ISSUES After the procedure, patients usually remain supine for a fixed period (usually two to four hours) following sheath removal to promote hemostasis at the venous puncture sites. Vascular closure devices allow for more rapid hemostasis and shorter time to ambulation. Most centers keep patients overnight following the procedure. Same-day discharge has become increasingly common given the shorter procedure times and use of venous closure techniques [45,46]. Post-discharge medications Oral anticoagulation is usually continued [47] for at least two months to ensure that the increased risk of embolization associated with the procedure has returned to a baseline risk, regardless of CHADS VA Sc score. This also allows for adequate time 2 2 to document an absence of recurrence of AF for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [48]. Importantly, there are no randomized data on the safety of discontinuing anticoagulation post-ablation for patients who have presumably maintained sinus rhythm. The risk of AF recurrence, the recognized proportional increase in the burden of asymptomatic AF, and the uncertainty surrounding the causal association between the arrhythmia itself and stroke all support the recommendation to risk stratify patients for oral anticoagulation use based on CHA DS -VASc no differently than if an 2 2 ablation had not been performed. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Postprocedural anticoagulation'.) Antiarrhythmic medications may or may not be continued after the procedure. Our preference is to stop them after the procedure. Patients in whom consideration should be given to continuing them include patients with long-standing persistent AF or patients with debilitating AF symptoms. Post-discharge follow-up At the time of discharge, patients are given instructions on activity and what potential complications to look for. They should refrain from heavy physical activity, including exercise and weight lifting, for the week post-procedure to allow for complete healing of the vascular access sites. Baths should also be avoided for one week to reduce infection risk. In patients without identified post-procedural complications such as vascular access site problems, we wait three months to reevaluate the patient [9] (see 'Complications' below). Patients with potential complications should be seen immediately. Patients who develop symptoms should contact either their primary care physician, general cardiologist, or electrophysiologist to discuss the need for early evaluation. Yearly follow-up with a physician thereafter is also recommended. These ongoing interactions with the medical profession allow the patient's clinical status to be evaluated, including an https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 12/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate assessment of the presence or absence of AF, as well as their stroke risk profile and anticoagulation needs. These interactions also provide an opportunity to focus on the treatment of associated diseases and lifestyle modifications [9]. Routine ECG should be performed at the time of follow-up visits, and more intense monitoring may be performed as dictated by patient symptoms and the clinical impact of AF detection [41]. Evaluation for recurrent atrial fibrillation The primary purpose of the first follow-up visit around the three-month mark is to determine the success of the procedure. Screening for post- procedure AF is discussed separately. (See "Atrial fibrillation: Catheter ablation", section on 'Follow-up'.) In general, we do not evaluate the patient for the presence of AF prior to three months, as early episodes do not necessarily predict the long-term success or failure of the procedure. They can often be managed with antiarrhythmic drugs or cardioversion. Repeat ablation during this time is rarely necessary. During this three-month healing phase, there is resolution of inflammation and consolidation of lesion formation. This time period is referred to in clinical research trials as the "post-procedure blanking period." Anticoagulants are continued throughout this period regardless of the patient's CHA DS -VASc score ( table 1). Antiarrhythmic drugs and/or electrical cardioversion 2 2 are used during this blanking period at the discretion of the treating physician and usually reserved for those with debilitating symptoms or recurrent persistent AF. Success rates The success rate of AF ablation is dependent on multiple factors including patient selection, technique, definition of success, and the intensity and duration of rhythm monitoring post-ablation. For research purposes, the primary endpoint of AF ablation trials is freedom from recurrent AF/ atrial tachycardia (AT) defined as the absence of any recurrent AF/AT >30 seconds without antiarrhythmic drugs. Using this strict definition, the one-year success rate for paroxysmal AF is approximately 70 to 80 percent and 60 to 70 percent for persistent AF at most experienced centers. However, a greater proportion of patients will derive an improvement in AF-related symptoms from ablation, and studies using implantable cardiac monitors or other devices that can record all episodes of AF have shown an AF burden reduction of over 98 percent [49]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients with prior antiarrhythmic drug treatment'.) Complications Complications are discussed in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 13/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Pulmonary vein origin of atrial fibrillation (AF) The primary trigger for most episodes

11/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate POSTPROCEDURAL ISSUES After the procedure, patients usually remain supine for a fixed period (usually two to four hours) following sheath removal to promote hemostasis at the venous puncture sites. Vascular closure devices allow for more rapid hemostasis and shorter time to ambulation. Most centers keep patients overnight following the procedure. Same-day discharge has become increasingly common given the shorter procedure times and use of venous closure techniques [45,46]. Post-discharge medications Oral anticoagulation is usually continued [47] for at least two months to ensure that the increased risk of embolization associated with the procedure has returned to a baseline risk, regardless of CHADS VA Sc score. This also allows for adequate time 2 2 to document an absence of recurrence of AF for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [48]. Importantly, there are no randomized data on the safety of discontinuing anticoagulation post-ablation for patients who have presumably maintained sinus rhythm. The risk of AF recurrence, the recognized proportional increase in the burden of asymptomatic AF, and the uncertainty surrounding the causal association between the arrhythmia itself and stroke all support the recommendation to risk stratify patients for oral anticoagulation use based on CHA DS -VASc no differently than if an 2 2 ablation had not been performed. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Postprocedural anticoagulation'.) Antiarrhythmic medications may or may not be continued after the procedure. Our preference is to stop them after the procedure. Patients in whom consideration should be given to continuing them include patients with long-standing persistent AF or patients with debilitating AF symptoms. Post-discharge follow-up At the time of discharge, patients are given instructions on activity and what potential complications to look for. They should refrain from heavy physical activity, including exercise and weight lifting, for the week post-procedure to allow for complete healing of the vascular access sites. Baths should also be avoided for one week to reduce infection risk. In patients without identified post-procedural complications such as vascular access site problems, we wait three months to reevaluate the patient [9] (see 'Complications' below). Patients with potential complications should be seen immediately. Patients who develop symptoms should contact either their primary care physician, general cardiologist, or electrophysiologist to discuss the need for early evaluation. Yearly follow-up with a physician thereafter is also recommended. These ongoing interactions with the medical profession allow the patient's clinical status to be evaluated, including an https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 12/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate assessment of the presence or absence of AF, as well as their stroke risk profile and anticoagulation needs. These interactions also provide an opportunity to focus on the treatment of associated diseases and lifestyle modifications [9]. Routine ECG should be performed at the time of follow-up visits, and more intense monitoring may be performed as dictated by patient symptoms and the clinical impact of AF detection [41]. Evaluation for recurrent atrial fibrillation The primary purpose of the first follow-up visit around the three-month mark is to determine the success of the procedure. Screening for post- procedure AF is discussed separately. (See "Atrial fibrillation: Catheter ablation", section on 'Follow-up'.) In general, we do not evaluate the patient for the presence of AF prior to three months, as early episodes do not necessarily predict the long-term success or failure of the procedure. They can often be managed with antiarrhythmic drugs or cardioversion. Repeat ablation during this time is rarely necessary. During this three-month healing phase, there is resolution of inflammation and consolidation of lesion formation. This time period is referred to in clinical research trials as the "post-procedure blanking period." Anticoagulants are continued throughout this period regardless of the patient's CHA DS -VASc score ( table 1). Antiarrhythmic drugs and/or electrical cardioversion 2 2 are used during this blanking period at the discretion of the treating physician and usually reserved for those with debilitating symptoms or recurrent persistent AF. Success rates The success rate of AF ablation is dependent on multiple factors including patient selection, technique, definition of success, and the intensity and duration of rhythm monitoring post-ablation. For research purposes, the primary endpoint of AF ablation trials is freedom from recurrent AF/ atrial tachycardia (AT) defined as the absence of any recurrent AF/AT >30 seconds without antiarrhythmic drugs. Using this strict definition, the one-year success rate for paroxysmal AF is approximately 70 to 80 percent and 60 to 70 percent for persistent AF at most experienced centers. However, a greater proportion of patients will derive an improvement in AF-related symptoms from ablation, and studies using implantable cardiac monitors or other devices that can record all episodes of AF have shown an AF burden reduction of over 98 percent [49]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients with prior antiarrhythmic drug treatment'.) Complications Complications are discussed in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 13/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Pulmonary vein origin of atrial fibrillation (AF) The primary trigger for most episodes of AF involves electrical discharges within one or more pulmonary veins (PVs) ( figure 1). A principal goal of any procedure is to reduce the frequency of AF and electrically isolate the PVs so that these discharges do not activate atrial tissue. (See 'Introduction' above.) Clinical goal of catheter ablation (CA) The major clinical goal of CA is a reduction in AF- related symptoms. CA is superior to medical therapy at improving a patient's quality of life. Therefore, it is generally reserved for individuals with symptoms attributable to the arrhythmia, which most often include palpitations, shortness of breath, or generalized fatigue. Even if they have no AF-related symptoms, older individuals with early AF (duration <1 year) and additional cardiovascular conditions also benefit from therapies aimed at maintaining sinus rhythm; these therapies include CA. (See 'Patient selection' above.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 14/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Role of shared decision-making AF ablation is a complicated procedure with defined risks. Shared decision-making among the patient, primary care physician, general cardiologist, and electrophysiologist is essential. Ablation techniques Radiofrequency, cryothermal, and laser energy are the approved energy sources for CA of AF. (See 'Energy sources' above.) Various methods of CA have been used, and most focus on isolating the triggers in the PVs from the vulnerable substrate in the left atrium. The most common technique is circumferential PV isolation. (See 'Pulmonary vein isolation' above.) Complications Treating physicians should be aware of three serious complications that can occur postprocedurally: pericardial effusion causing cardiac tamponade, an atrial esophageal fistula, and PV stenosis ( table 2 and table 3). (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Mark DB, Anstrom KJ, Sheng S, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1275. 2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Heart Rhythm 2017; 14:e445. 3. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1305. 4. Larsson SC, Drca N, Wolk A. Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis. J Am Coll Cardiol 2014; 64:281. 5. Congrete S, Bintvihok M, Thongprayoon C, et al. Effect of obstructive sleep apnea and its treatment of atrial fibrillation recurrence after radiofrequency catheter ablation: A meta- analysis. J Evid Based Med 2018; 11:145. 6. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014; 64:2222. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 15/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 7. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 8. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 9. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 10. Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med 2018; 378:417. 11. Nairooz R, Sardar P, Payne J, et al. Meta-analysis of major bleeding with uninterrupted warfarin compared to interrupted warfarin and heparin bridging in ablation of atrial fibrillation. Int J Cardiol 2015; 187:426. 12. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med 2017; 376:1627. 13. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019; 40:3013. 14. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36:1805. 15. Reynolds MR, Allison JS, Natale A, et al. A Prospective Randomized Trial of Apixaban Dosing During Atrial Fibrillation Ablation: The AEIOU Trial. JACC Clin Electrophysiol 2018; 4:580. 16. Gunawardene MA, Dickow J, Schaeffer BN, et al. Risk stratification of patients with left atrial appendage thrombus prior to catheter ablation of atrial fibrillation: An approach towards an individualized use of transesophageal echocardiography. J Cardiovasc Electrophysiol 2017; 28:1127. 17. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 16/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 18. Kitkungvan D, Nabi F, Ghosn MG, et al. Detection of LA and LAA Thrombus by CMR in Patients Referred for Pulmonary Vein Isolation. JACC Cardiovasc Imaging 2016; 9:809. 19. Kuck KH, Brugada J, F rnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016; 374:2235. 20. Wasserlauf J, Knight BP, Li Z, et al. Moderate Sedation Reduces Lab Time Compared to General Anesthesia during Cryoballoon Ablation for AF Without Compromising Safety or Long-Term Efficacy. Pacing Clin Electrophysiol 2016; 39:1359. 21. Di Biase L, Conti S, Mohanty P, et al. General anesthesia reduces the prevalence of pulmonary vein reconnection during repeat ablation when compared with conscious sedation: results from a randomized study. Heart Rhythm 2011; 8:368. 22. Sivasambu B, Hakim JB, Barodka V, et al. Initiation of a High-Frequency Jet Ventilation Strategy for Catheter Ablation for Atrial Fibrillation: Safety and Outcomes Data. JACC Clin Electrophysiol 2018; 4:1519. 23. Briceno DF, Villablanca PA, Lupercio F, et al. Clinical Impact of Heparin Kinetics During Catheter Ablation of Atrial Fibrillation: Meta-Analysis and Meta-Regression. J Cardiovasc Electrophysiol 2016; 27:683. 24. Nagao T, Inden Y, Yanagisawa S, et al. Differences in activated clotting time among uninterrupted anticoagulants during the periprocedural period of atrial fibrillation ablation. Heart Rhythm 2015; 12:1972. 25. Str ker E, de Asmundis C, Kupics K, et al. Value of ultrasound for access guidance and detection of subclinical vascular complications in the setting of atrial fibrillation cryoballoon ablation. Europace 2019; 21:434. 26. Yamagata K, Wichterle D, Roub cek T, et al. Ultrasound-guided versus conventional femoral venipuncture for catheter ablation of atrial fibrillation: a multicentre randomized efficacy and safety trial (ULTRA-FAST trial). Europace 2018; 20:1107. 27. Kurotobi T, Iwakura K, Inoue K, et al. Multiple arrhythmogenic foci associated with the development of perpetuation of atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3:39. 28. Ha ssaguerre M, Ja s P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339:659. 29. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999; 100:1879. 30. Tsai CF, Tai CT, Hsieh MH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 17/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate radiofrequency ablation. Circulation 2000; 102:67. 31. Lee G, Spence S, Teh A, et al. High-density epicardial mapping of the pulmonary vein-left atrial junction in humans: insights into mechanisms of pulmonary vein arrhythmogenesis. Heart Rhythm 2012; 9:258. 32. Pappone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation. Circulation 2000; 102:2619. 33. Pappone C, Santinelli V. The who, what, why, and how-to guide for circumferential pulmonary vein ablation. J Cardiovasc Electrophysiol 2004; 15:1226. 34. Oral H, Knight BP, Tada H, et al. Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. Circulation 2002; 105:1077. 35. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. Heart Rhythm 2012; 9:1789. 36. Neuzil P, Reddy VY, Kautzner J, et al. Electrical reconnection after pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I study. Circ Arrhythm Electrophysiol 2013; 6:327. 37. Bourier F, Duchateau J, Vlachos K, et al. High-power short-duration versus standard radiofrequency ablation: Insights on lesion metrics. J Cardiovasc Electrophysiol 2018; 29:1570. 38. Macle L, Khairy P, Weerasooriya R, et al. Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial. Lancet 2015; 386:672. 39. Kobori A, Shizuta S, Inoue K, et al. Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial. Eur Heart J 2015; 36:3276. 40. Ghanbari H, Jani R, Hussain-Amin A, et al. Role of adenosine after antral pulmonary vein isolation of paroxysmal atrial fibrillation: A randomized controlled trial. Heart Rhythm 2016; 13:407. 41. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012; 14:528. 42. Lin JL, Lai LP, Tseng YZ, et al. Global distribution of atrial ectopic foci triggering recurrence of atrial tachyarrhythmia after electrical cardioversion of long-standing atrial fibrillation: a bi- https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 18/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate atrial basket mapping study. J Am Coll Cardiol 2001; 37:904. 43. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004; 43:2044. 44. Narayan SM, Patel J, Mulpuru S, Krummen DE. Focal impulse and rotor modulation ablation of sustaining rotors abruptly terminates persistent atrial fibrillation to sinus rhythm with elimination on follow-up: a video case study. Heart Rhythm 2012; 9:1436. 45. Bartoletti S, Mann M, Gupta A, et al. Same-day discharge in selected patients undergoing atrial fibrillation ablation. Pacing Clin Electrophysiol 2019; 42:1448. 46. Natale A, Mohanty S, Liu PY, et al. Venous Vascular Closure System Versus Manual Compression Following Multiple Access Electrophysiology Procedures: The AMBULATE Trial. JACC Clin Electrophysiol 2020; 6:111. 47. Eitel C, Koch J, Sommer P, et al. Novel oral anticoagulants in a real-world cohort of patients undergoing catheter ablation of atrial fibrillation. Europace 2013; 15:1587. 48. Karasoy D, Gislason GH, Hansen J, et al. Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long- term follow-up in nationwide cohort of Denmark. Eur Heart J 2015; 36:307. 49. Lohrmann G, Kaplan R, Ziegler PD, et al. Atrial fibrillation ablation success defined by duration of recurrence on cardiac implantable electronic devices. J Cardiovasc Electrophysiol 2020; 31:3124. Topic 95704 Version 21.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 19/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate GRAPHICS Junction of left atrium and pulmonary veins The common pattern of the superficial myocardial fibers of the left atrium (posterior aspect). A main circular fascicle (a, a', a", and a"') runs peripherally around the area of the openings of the pulmonary veins. An interatrial fascicle (b) runs between the right (RA) and the left (LA) atrium. Some fibers (c) descend from the left atrium into the left part (a') of the main circular fascicle. Circular fibers leaving the main fascicle turn around the openings of the pulmonary veins, forming sphincter-like structures; other fibers extend over the https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 20/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate veins as myocardial sleeves. Loops of fibers coming from the atrium are seen over the right superior pulmonary vein (RSPV) and returning to the atrium. Oblique, vertical (e), and transverse (f, f') fascicles of fibers are also seen on the posterior atrial surface. LA: left atrium; RA: right atrium; SVC: superior vena cava; IVC: inferior vena cava; RSPV: right superior pulmonary vein; LSPV: left superior pulmonary vein; RIPV: right inferior pulmonary vein; LIPV: left inferior pulmonary vein. From: Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. Circulation 1966; 34:412. DOI: 10.1161/01.cir.34.3.412. Copyright 1966. Adapted with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 127240 Version 3.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 21/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc 2 2 (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients Stroke and 2 2 (n = 73,538) thromboembolism event rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 5 8942 15.26 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 22/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 23/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Intraprocedural risks of ablation for atrial fibrillation Complication Incidence Diagnostic testing Air embolism <1% Nothing or cardiac catheterization Asymptomatic cerebral emboli 2 to 15% Brain MRI Cardiac tamponade 0.2 to 5% Echocardiography Coronary stenosis/occlusion <0.1% Cardiac catheterization Death <0.1 to 0.4% N/A Mitral valve entrapment <0.1% Echocardiography Permanent phrenic nerve 0 to 0.4% Chest radiograph, sniff test paralysis Radiation injury <0.1% None Stroke or TIA 0 to 2% Head CT/MRI, cerebral angiography Vascular complications 0.2 to 1.5% Vascular ultrasound, CT scan MRI: magnetic resonance imaging; TIA: transient ischemic attack; CT: computed tomography. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127125 Version 1.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 24/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation Back pain Musculoskeletal, retroperitoneal hematoma Physical exam, CT imaging Chest pain Pericarditis, pericardial effusion, coronary stenosis (ablation Physical exam, chest radiograph, ECG, related), pulmonary vein stenosis, musculoskeletal (after echocardiogram, stress test, cardiac catheterization, chest CT cardioversion), worsening reflux Cough Infectious process, bronchial Physical exam, chest irritation (mechanical, cryoballoon), pulmonary vein stenosis radiograph, chest CT Dysphagia Esophageal irritation (related to transesophageal Physical exam, chest CT, MRI echocardiography), atrioesophageal fistula Early satiety, nausea Gastric denervation Physical exam, gastric emptying study Fever Infectious process, pericarditis, atrioesophageal fistula Physical exam, chest radiograph, chest CT, urinalysis, laboratory blood work Fever, dysphagia, neurological Atrial esophageal fistula Physical exam, laboratory blood symptoms work, chest CT or MRI; avoid endoscopy with air insufflation Groin pain Pseudoaneurysm, AV fistula, Ultrasound of the groin, hematoma laboratory blood work; consider CT scan if ultrasound negative Hypotension Pericardial effusion/tamponade, bleeding, sepsis, persistent Echocardiography, laboratory blood work vagal reaction Hemoptysis Pulmonary vein stenosis or occlusion, pneumonia Chest radiograph, chest CT or MR scan, VQ scan Neurological symptoms Cerebral embolic event, atrial esophageal fistula Physical exam, brain imaging, chest CT or MRI Shortness of breath Volume overload, pneumonia, Physical exam, chest pulmonary vein stenosis, radiograph, chest CT, laboratory https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 25/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate phrenic nerve injury blood work CT: computed tomography; ECG: electrocardiogram; MRI: magnetic resonance imaging; AV: atrioventricular. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127127 Version 1.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 26/27 7/6/23, 2:49 PM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 27/27

7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 05, 2022. INTRODUCTION Ischemic stroke and systemic embolization are major causes of death and disability in patients with atrial fibrillation (AF). This topic will focus on the role of anticoagulant therapy to prevent embolization in patients scheduled to undergo catheter ablation (CA). The role of anticoagulant therapy in the broad population of patients with AF is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Other aspects of CA are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation" and "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy" and "Overview of catheter ablation of cardiac arrhythmias" and "Patient education: Catheter ablation for the heart (The Basics)" and "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists".) OUR APPROACH TO ANTICOAGULATION There are three periods when a decision or decisions have to be made about anticoagulation in a patient scheduled for catheter ablation (CA). Preprocedural We effectively anticoagulate most patients, irrespective of CHA DS -VASC 2 2 score ( table 1) or presence or absence of sinus rhythm, with either a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC; also referred to as non-vitamin K oral https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 1/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate anticoagulants [NOAC]) for at least three weeks prior to CA. It is reasonable to not use preprocedural anticoagulation in AF patients in sinus rhythm (and who are likely to remain in sinus rhythm for three weeks prior to the procedure) with a CHA DS -VASC score of 0. 2 2 (See 'Preprocedural issues' below.) Periprocedural We continue VKA in the periprocedural period. For most patients taking once-a-day DOACs, we hold the dose the day before and the morning of the procedure. For twice-a-day DOACs, some of our experts hold both doses the day before the procedure while others hold only the evening dose before the procedure; no drug is given the morning of the procedure. Uninterrupted DOAC may be reasonable for the uncommon patient who is at very high risk of a periprocedural stroke. Studies support the fact that uninterrupted DOACs may be superior to uninterrupted warfarin for patients who require continued anticoagulation due to high risk of thromboembolism. All patients receive a continuous infusion of unfractionated heparin (UFH); the activated clotting time is maintained at greater than 300 seconds during the procedure. (See 'Periprocedural issues' below.) Postprocedural UFH is stopped at the end of the procedure and the sheaths are pulled when the activated clotting time is <180 to 200 seconds. For patients previously taking a VKA, the next dose is given approximately 24 hours after the prior dose. For those patients in whom the international normalized ratio was <2.0 prior to the procedure, we restart UFH without a bolus six hours after sheath pull, increase the oral warfarin the night of the procedure, and we continue UFH until the INR is 2.0. Another reasonable approach is to stop UFH the morning after the procedure and start low molecular weight heparin, usually at half the normal dose (0.5 mg/kg twice daily) to avoid bleeding. (See 'Postprocedural anticoagulation' below.) For patients previously taking a DOAC, we suggest restarting it - six hours after sheath removal (and in the absence of any related bleeding). Some experts give intravenous heparin (no bolus; drip at 1000 to 1200 units per hour) or low molecular weight heparin (enoxaparin 0.5 mg/kg) starting six hours after sheath pull, that is uncomplicated by bleeding, and continue until the morning after the ablation. Other experts no longer give a heparin after sheath pull. Long-term We continue oral therapy with the previously prescribed oral anticoagulant for two to three months regardless of CHA DS -VASc score. After this period, the decision 2 2 to continue on long-term anticoagulation is based on the patients underlying stroke risk regardless of whether rhythm control has been achieved. For those patients whose risk for https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 2/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate embolization is very low, such as those with a CHA DS -VASc score of 0 ( table 1), we stop 2 2 anticoagulation at the two-to-three-month visit. INCIDENCE, TIMING, AND MECHANISM OF EMBOLISM The risk of stroke, transient ischemic attack, or other manifestation of embolization is increased at the time of catheter ablation (CA) and is in the range of 0.4 to 2.0 percent [1-3]. These rates come from studies of patients who are receiving anticoagulant therapy and would be higher off such treatment. Most strokes occur within 24 to 48 hours after the procedure [3]. However, embolic events thought attributable to the procedure have been reported to occur for up to one week [4]. The following are potential causes of periprocedural embolization: Withdrawal of anticoagulation before the procedure Catheter manipulation within the left atrium, which may dislodge preexisting thrombus Catheter trauma to the left atrial endothelium, which increases the risk of thrombus formation Thrombus formation on the ablation catheters or left atrial guide sheaths Conversion to sinus rhythm during the procedure in some patients (see "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation") Asymptomatic embolism Not all emboli to the brain are symptomatic. Multiple magnetic resonance imaging (MRI) studies performed within 24 hours after CA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [5-10]. These lesions are presumed secondary to microemboli [11]. Studies of the subsequent impact of these lesions on neurocognitive function have come to somewhat differing conclusions as to the significance of these lesions: The prevalence of cognitive impairment after radiofrequency CA (RFA) was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal atrial fibrillation (AF), 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [12]. All CA patients received periprocedural enoxaparin and most patients with AF had a CHADS score of 0 or 1 ( table 1). All patients underwent eight 2 neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively, in these four groups of patients. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 3/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate In a study of 37 patients with paroxysmal AF who underwent 41 CA procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [8]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing performed after six months. PREPROCEDURAL ISSUES All patients not at low risk of stroke should be treated with long-term anticoagulant therapy using one of the novel oral anticoagulants or warfarin. Thus, many patients will be receiving anticoagulation when scheduled for catheter ablation (CA) and should continue their anticoagulant. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) For patients not taking long-term anticoagulant therapy due to a low risk of stroke, there are no studies that have compared differing anticoagulant strategies prior to CA; thus, the optimal preprocedural anticoagulation strategy is not known. For these patients, including those in sinus rhythm, most of our experts carry out a minimum of three weeks of effective oral anticoagulation prior to the procedure. The rationale for doing so is that many episodes of atrial fibrillation (AF) are asymptomatic and these episodes will have placed the patient at risk of embolization at the time of catheter manipulation. We also believe it is reasonable to not use preprocedural anticoagulation in AF patients in sinus rhythm (and who are likely to remain in sinus rhythm for three weeks prior to the procedure) with a CHA DS -VASc score of 0. 2 2 When three weeks of effective anticoagulant therapy has not been carried out, preprocedural transesophageal echocardiography (TEE) should be performed (see 'Role of transesophageal echocardiography' below); patients with evidence of left atrial thrombus are not candidates for CA unless it resolves with anticoagulation. Choice of anticoagulant For patients started on oral anticoagulant therapy prior to catheter ablation, we prefer one of the direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) group to warfarin. This preference is based on our preference for these agents in the general AF population. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Most but not all observational studies comparing one NOAC to warfarin have found similar efficacy [13] and safety [14-21]. At least three meta-analyses of observational studies comparing https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 4/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate warfarin to dabigatran have come to similar conclusions [22-24]. A 2016 meta-analysis of 25 studies (11,686 patients) comparing DOACs with uninterrupted VKAs found no significant difference in the rate of stroke or transient ischemic attacks (odds ratio 1.35, 95% CI 0.62-2.94) and major bleeding (odds ratio 0.80, 95% CI 0.65-1.00) [25]. Switching oral anticoagulant As stated directly above, we prefer one of the DOAC group to warfarin for patients undergoing catheter ablation. For patients receiving long-term warfarin therapy, there is no evidence that switching to DOAC prior to catheter ablation improves outcomes. Thus, we do not switch from warfarin to an DOAC. We do not have a preference for one DOAC over another and thus we do not switch DOAC. Based on the evidence presented above that suggests that uninterrupted dabigatran is superior to uninterrupted warfarin, we switch patients from warfarin to dabigatran. Role of transesophageal echocardiography Most patients, including those with effective preprocedural oral anticoagulation, should have a TEE performed prior to (generally the day before) CA. The presence of left atrial thrombus is a contraindication to the procedure [26,27]. Transthoracic echocardiography is not a replacement for TEE in this setting. Two reasons to perform TEE prior to (generally the day before) CA are that it adds significant length to the CA, and some complications of TEE, such as a retropharyngeal hematoma, can be aggravated by the unfractionated heparin used during the procedure. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism", section on 'LA/LAA thrombi'.) We acknowledge that some experts will omit a TEE in the lowest-risk patients who have been taking effective anticoagulant therapy for at least three weeks, such as those in sinus rhythm who have no significant structural heart disease or those with a CHA DS -VASc score of 0 2 2 ( table 1) [27]. These experts often prefer that a pre-ablation magnetic resonance image confirms the absence of left atrial appendage thrombus in these patients who do not undergo preprocedural TEE. In a study of 97 patients undergoing pulmonary vein isolation, contrast- enhanced MRI demonstrated 100 percent concordance with TEE for the presence and absence of left atrial appendage thrombus [28,29]. An attempt to determine the need for preprocedural TEE in patients at low risk for embolization was made in an analysis of 1058 patients who had TEE performed within 24 hours of pulmonary vein isolation [30]. The frequency of left atrial thrombus or sludge was evaluated according to the CHADS score. (See "Echocardiography in detection of cardiac and aortic sources of systemic 2 embolism".) A CHADS score of 0 was present in 47 percent of patients. Left atrial or left atrial 2 appendage thrombus or sludge was found in 0.6 and 1.5 percent of all patients and the https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 5/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate frequency increased with ascending CHADS scores (percents in parentheses): 0 (0), 1 (2), 2 (5), 3 2 (9), 4 to 6 (11). We do not use intracardiac echocardiography or computed tomography as a substitute for TEE. Each of these has been shown to be inferior in this setting [31,32]. PERIPROCEDURAL ISSUES The two principal periprocedural anticoagulant issues are how to manage the oral anticoagulant and whether/how to use parenteral anticoagulant. Management of oral anticoagulants For patients taking long-term oral anticoagulant who present for catheter ablation, the approach depends on which anticoagulant the patient has been taking. Patients taking long-term vitamin K antagonist For patients taking a VKA prior to catheter ablation, we prefer the strategy of uninterrupted VKA to a strategy of a heparin bridge. We do not hold doses of VKA unless the international normalized ratio (INR) is >3.0. (See "Perioperative management of patients receiving anticoagulants", section on 'Bridging anticoagulation'.) One randomized trial [33] and most observational studies [3,34,35] have shown that continuous anticoagulation with warfarin, compared with warfarin discontinuation with a heparin bridge, is associated with a lower rate of embolization and an equivalent or lower bleeding rate [36]. In the COMPARE trial, 1584 patients with paroxysmal or persistent atrial fibrillation (AF) (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology') and CHADS score 1 were randomly assigned to warfarin discontinuation two 2 to three days before ablation and bridging with low molecular weight heparin (1 mg/kg enoxaparin twice daily until the evening before the procedure) or continuation of therapeutic warfarin (three to four weeks with an INR 2.0 to 3.0) [33]. The primary end point of the incidence of thromboembolic events (stroke, transient ischemic attack, or systemic thromboembolism) in the 48 hours after ablation occurred more frequently with warfarin discontinuation (4.9 versus 0.25 percent; odds ratio 13, 95% CI 3.1-55.6). The incidence of major bleeding complications was similar in the two groups (0.76 versus 0.38 percent, respectively). The majority of events occurred in patients with persistent AF. One limitation of the trial is that operators were not blinded to the anticoagulation strategy. For patients in whom a strategy of continuous anticoagulation with warfarin has been chosen, the optimal immediate-preprocedural range for the INR is not known. In a retrospective study of https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 6/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 1113 patients undergoing radiofrequency catheter ablation for AF, bleeding and vascular complications were less prevalent when the INR was 2.0 and 3.0 (5 percent), compared with 2.0 (10 percent) or 3.0 (12 percent) [37]. The optimal INR range was calculated to be 2.1 to 2.5. Patients taking DOACs In most studies that have evaluated periprocedural outcomes in patients taking direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]), the DOAC was held prior to the procedure. In one trial, 326 patients undergoing AF ablation were randomized to uninterrupted DOAC, procedure day single-dose skipped DOAC, or 24-hour skipped DOAC [38]. The intraprocedural heparin dose was higher in the 24-hour skipped group, but the incidence of major bleeding and postprocedural hemoglobin levels were not significantly different among the treatment groups and different DOACs. There were no fatal events or thromboembolic complications. For most patients taking once-a-day DOACs in the morning, we hold the dose the day before and also the day of the procedure. For those that take once-a-day DOACs with the evening meal or later, we hold only a single dose the day before the procedure. For twice-a-day DOACs, some of our experts hold both doses the day before the procedure while others hold only the evening dose before the procedure and the morning of the procedure. For a small minority of patients, such as those at particularly high risk of a periprocedural stroke, including those with a high CHA DS -VASc score in whom intraprocedural cardioversion is 2 2 planned, no interruption of (continuous) oral anticoagulation with a DOAC is a reasonable alternative to interruption. (See 'Choice of anticoagulant' above.) Small randomized trials of dabigatran, rivaroxaban, edoxaban, and apixaban suggest that outcomes with uninterrupted DOACs are similar to those with uninterrupted warfarin [39-42]. Use of intravenous heparin As catheter ablation (CA) is associated with an increase (from baseline) in the risk of a periprocedural thromboembolic event, we recommend that all patients receive intraprocedural heparin. (See 'Incidence, timing, and mechanism of embolism' above.) We start with a loading dose of 100 units/kg at the beginning of the procedure. Others start the loading dose before transeptal puncture, while others give half the dose before and half the dose after transeptal puncture [43]. A continuous infusion is used to maintain the activated clotting time greater than 300 seconds; the first activated clotting time is performed 10 to 15 minutes after the loading dose. Heparin is stopped at the end of the procedure and the sheaths are pulled when the activated clotting time is <180 to 200 seconds. Protamine can be given after the procedure before removing vascular sheaths. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 7/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Intracardiac echocardiography is done at the end of the CA procedure to ensure that there is no pericardial effusion. If a pericardial effusion is found we take the following approach: For small effusions, we observe and continue with the anticoagulation protocol. If moderate, we reverse anticoagulation and observe. If large, we reverse anticoagulation and perform pericardiocentesis. (See "Diagnosis and treatment of pericardial effusion", section on 'Treatment'.) For patients with hemodynamic compromise, regardless of the size of the effusion, we perform pericardiocentesis and reverse anticoagulation. POSTPROCEDURAL ANTICOAGULATION The approach to anticoagulation within the first 24 hours after a successful procedure is determined in large part by preprocedural anticoagulant approach (see 'Preprocedural issues' above). There have been no studies comparing one approach to another. In the absence of any related bleeding, we suggest the following approach: For those previously taking warfarin, and for whom the management of the international normalized ratio was not problematic, we suggest continuing warfarin. The first postprocedural dose should be the day after the procedure, assuming a dose was given the morning of the procedure. (See 'Patients taking long-term vitamin K antagonist' above.) For patients taking warfarin whose procedure was done with a subtherapeutic international normalized ratio, we restart intravenous heparin without a bolus six hours after sheath pull and start low molecular weight heparin the morning after the procedure. Low molecular weight heparin is continued until the international normalized ratio is therapeutic. When low molecular weight heparin is used, some of our experts give the first dose at 50 percent. For patients previously taking a direct oral anticoagulant (DOAC; also referred to as non- vitamin K oral anticoagulants [NOAC]), DOAC may be restarted four to six hours after sheath pull. Alternatively, some experts delay restarting these newer agents until the morning after the procedure. If the DOAC is restarted the morning after the procedure, we give either intravenous unfractionated heparin (no bolus; drip at 1000 to 1200 units per hour starting six hours after sheath pull and continued until the morning after the procedure) or low https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 8/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate molecular weight heparin (enoxaparin 0.5 mg/kg; typically a single dose administered six hours after sheath pull). For patients previously not taking any oral agent, we suggest starting either a DOAC or warfarin. A first dose of either agent can be given six hours after an uncomplicated procedure. Patients started on warfarin will need to receive bridging treatment for a few days with low molecular weight heparin, as described directly above. LONG-TERM ANTICOAGULATION We continue oral therapy with the previously prescribed oral anticoagulant [44] for at least two months to ensure that the increased risk of embolization associated with the procedure, which lasts for about four weeks, has returned to a baseline risk and that there has been adequate time to document an absence of recurrence of atrial fibrillation (AF) for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [45]. (See 'Incidence, timing, and mechanism of embolism' above.) After this two-month period of mandatory oral anticoagulation, we generally restore the anticoagulant regimen in place prior to the procedure. For those patients without evidence of recurrent AF and whose risk for embolization is very low, such as those with a CHA DS -VASc 2 2 score of 0 ( table 1), we stop anticoagulation. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) Some experts are comfortable stopping anticoagulation in patients with a CHA DS -VASc score 2 2 of 1 ( table 1) after sufficient documentation of the absence of recurrent episodes of AF. We believe this approach has not been adequately tested. Therefore, we tell patients and referring physicians that the desire to stop long-term anticoagulation is not an indication for catheter ablation (CA) by itself. For all patients with a CHA DS -VASc score of >1 ( table 1) after CA, irrespective of whether or 2 2 not recurrence has been documented, we maintain the patient on long-term oral anticoagulation [46,47]. The optimal approach to chronic anticoagulation after successful CA, defined as no evidence of recurrence, is uncertain [48]. It is known that late recurrent AF occurs in 20 to 30 percent of patients, but the methods used in some studies likely underestimate the incidence [49-52]. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 9/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate In a 2019 meta-analysis of five studies with nearly 4000 patients that evaluated safety and efficacy of long-term oral anticoagulation (OAC) compared with no OAC, the following was found during a mean follow-up of nearly 40 months [53]: In patients with a CHA DS -VASc score 2, OAC continuation was associated with a 2 2 decrease in the risk of thromboembolic events (risk ratio [RR] 0.41, 95% CI 0.21-0.82) but an increased risk of intracranial hemorrhage (ICH; RR 5.78, 95% CI 1.33-25.08). The absolute risk decrease in thromboembolic risk was 1.14 percent, while the increase in ICH was 0.7 percent. In patients with a CHA DS -VASc score of 0 or 1, the risk of ICH from OAC exceeded any 2 2 potential decrease in thromboembolic risk. The issue of the role of long-term anticoagulation was indirectly addressed by at least three studies that found a lower incidence of stroke comparing successful CA to antiarrhythmic drug therapy [54-56]. In a retrospective study of 174 matched pairs of AF individuals with a CHA2DS2- VASc score 1 who were treated with either antiarrhythmic drug therapy or CA and treated for at least three months with warfarin, the rate of stroke/transient ischemic attack was lower with the CA group (0.59 versus 2.21 percent per year) [54]. In those individuals treated with CA and in whom there was no AF recurrence, the stroke rate was very low compared to those with recurrence (0.8 versus 5.4 percent) after a mean follow-up period of 47 months. In addition, it is not known if asymptomatic recurrences result in a persistent thromboembolic risk in patients who have undergone CA. A low risk of stroke was reported in a series of 755 patients with longstanding persistent AF who underwent CA or a tailored approach [57]. In this cohort, anticoagulation was discontinued three months after the procedure in the majority of the 522 patients who did not have evidence of recurrent AF. During a median follow-up of 25 months, none of the patients who stopped anticoagulation had a stroke. Although these results are encouraging, the study cohort had a low baseline thromboembolic risk, with most having a CHADS2-VASc score of 0 to 2 ( table 1). Some of these patients, such as those with lone AF, would not require chronic oral anticoagulation whether or not they had a successful CA procedure. The following recommendations were made in the 2019 update of the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline [58,59]: Systemic anticoagulation was recommended for at least two months in all patients following CA. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 10/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate After two months, the decision to continue anticoagulation should be based on the patient s risk factors for stroke and risk of bleeding, and not on the type of AF. The guideline acknowledges that recurrent episodes of AF, which may be asymptomatic, occur. The 2012 focused update of the European Society of Cardiology AF guideline recommends long- term oral anticoagulation CHA DS -VASc score of 2 [60]. The 2015 position document on 2 2 antithrombotic management in patients undergoing electrophysiological procedures states " the decision for oral anticoagulation depends on the patient s stroke risk profile and not the perceived success or failure of ablation " [43]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Catheter ablation of atrial fibrillation".) SUMMARY AND RECOMMENDATIONS The risk of stroke, transient ischemic attack, or other significant manifestation of embolization is increased, compared to baseline risk, at the time of catheter ablation (CA) for atrial fibrillation. (See 'Incidence, timing, and mechanism of embolism' above.) We perform a preprocedural transesophageal echocardiogram in most patients undergoing CA. The finding of intracardiac thrombus is a contraindication to the procedure. (See 'Role of transesophageal echocardiography' above.) Most patients scheduled to undergo CA who have been receiving long-term oral anticoagulation should continue to do so until the procedure. For those low-risk patients who have not been receiving long-term anticoagulation, including those in sinus rhythm at the time of the procedure, we suggest at least three weeks of effective anticoagulation prior to CA rather than no preprocedural anticoagulation (Grade 2C). An alternate approach is presented above. (See 'Preprocedural issues' above.) All patients should receive intraprocedural anticoagulation with intravenous heparin, irrespective of the patient s baseline thromboembolic risk and whether or not the procedure is performed on uninterrupted warfarin. (See 'Periprocedural issues' above.) https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 11/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate For patients taking long-term oral anticoagulant with warfarin who present for CA, we recommend continuing such therapy rather than stopping and using a heparin bridge (Grade 1A). For patients taking long-term oral anticoagulant with a newer oral anticoagulant who present for CA, we suggest discontinuing such therapy before the procedure rather than continuing it (Grade 2B). (See 'Periprocedural issues' above.) For the uncommon patient who is at very high risk of a periprocedural stroke, it is reasonable to not discontinue direct oral anticoagulants (DOAC; also referred to as non- vitamin K oral anticoagulants [NOAC]). (See 'Patients taking DOACs' above.) DOAC may be restarted four to six hours after sheath pull. Alternatively, DOAC may be restarted the morning after the procedure in patients who are treated overnight with either intravenous unfractionated heparin (no bolus; drip at 1000 to 1200 units per hour starting six hours after sheath pull and continued until the morning after the procedure) or low molecular weight heparin (enoxaparin 0.5 mg/kg; typically a single dose at six hours after sheath pull). (See 'Patients taking DOACs' above.) Oral anticoagulation is continued for at least two months after the procedure in all patients. After two months, the decision to continue anticoagulation should be based on the patient s risk factors for stroke and risk of bleeding and not on the type of AF or outcome of the procedure. (See 'Long-term anticoagulation' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 2. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798. 3. Page SP, Herring N, Hunter RJ, et al. Periprocedural stroke risk in patients undergoing catheter ablation for atrial fibrillation on uninterrupted warfarin. J Cardiovasc Electrophysiol 2014; 25:585. 4. Kosiuk J, Kornej J, Bollmann A, et al. Early cerebral thromboembolic complications after radiofrequency catheter ablation of atrial fibrillation: incidence, characteristics, and risk factors. Heart Rhythm 2014; 11:1934. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 12/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 5. Michaud GF. Silent cerebral embolism during catheter ablation of atrial fibrillation: how concerned should we be? Circulation 2010; 122:1662. 6. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 7. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 8. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. Circ Arrhythm Electrophysiol 2013; 6:843. 9. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 10. Ichiki H, Oketani N, Ishida S, et al. The incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation: comparison of warfarin and dabigatran. Pacing Clin Electrophysiol 2013; 36:1328. 11. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 12. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 13. Shah RR, Pillai A, Schafer P, et al. Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation. Am J Cardiol 2017; 120:404. 14. Kim JS, She F, Jongnarangsin K, et al. Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm 2013; 10:483. 15. Nin T, Sairaku A, Yoshida Y, et al. A randomized controlled trial of dabigatran versus warfarin for periablation anticoagulation in patients undergoing ablation of atrial fibrillation. Pacing Clin Electrophysiol 2013; 36:172. 16. Winkle RA, Mead RH, Engel G, et al. The use of dabigatran immediately after atrial fibrillation ablation. J Cardiovasc Electrophysiol 2012; 23:264. 17. Bassiouny M, Saliba W, Rickard J, et al. Use of dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 13/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 2013; 6:460. 18. Maddox W, Kay GN, Yamada T, et al. Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013; 24:861. 19. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014; 63:982. 20. Dillier R, Ammar S, Hessling G, et al. Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures. Circ Arrhythm Electrophysiol 2014; 7:576. 21. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012; 59:1168. 22. Provid ncia R, Albenque JP, Combes S, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart 2014; 100:324. 23. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace 2013; 15:1412. 24. Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace 2013; 15:1407. 25. Wu S, Yang YM, Zhu J, et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants Compared With Uninterrupted Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation. Am J Cardiol 2016; 117:926. 26. Knight BP. Transesophageal echocardiography before atrial fibrillation ablation: looking before cooking. J Am Coll Cardiol 2009; 54:2040. 27. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 14/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thor 28. Rathi VK, Reddy ST, Anreddy S, et al. Contrast-enhanced CMR is equally effective as TEE in the evaluation of left atrial appendage thrombus in patients with atrial fibrillation undergoing pulmonary vein isolation procedure. Heart Rhythm 2013; 10:1021. 29. Chen J, Zhang H, Zhu D, et al. Cardiac MRI for detecting left atrial/left atrial appendage thrombus in patients with atrial fibrillation : Meta-analysis and systematic review. Herz 2019; 44:390. 30. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. 31. Saksena S, Sra J, Jordaens L, et al. A prospective comparison of cardiac imaging using intracardiac echocardiography with transesophageal echocardiography in patients with

1. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 2. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798. 3. Page SP, Herring N, Hunter RJ, et al. Periprocedural stroke risk in patients undergoing catheter ablation for atrial fibrillation on uninterrupted warfarin. J Cardiovasc Electrophysiol 2014; 25:585. 4. Kosiuk J, Kornej J, Bollmann A, et al. Early cerebral thromboembolic complications after radiofrequency catheter ablation of atrial fibrillation: incidence, characteristics, and risk factors. Heart Rhythm 2014; 11:1934. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 12/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 5. Michaud GF. Silent cerebral embolism during catheter ablation of atrial fibrillation: how concerned should we be? Circulation 2010; 122:1662. 6. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 7. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 8. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. Circ Arrhythm Electrophysiol 2013; 6:843. 9. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 10. Ichiki H, Oketani N, Ishida S, et al. The incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation: comparison of warfarin and dabigatran. Pacing Clin Electrophysiol 2013; 36:1328. 11. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 12. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 13. Shah RR, Pillai A, Schafer P, et al. Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation. Am J Cardiol 2017; 120:404. 14. Kim JS, She F, Jongnarangsin K, et al. Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm 2013; 10:483. 15. Nin T, Sairaku A, Yoshida Y, et al. A randomized controlled trial of dabigatran versus warfarin for periablation anticoagulation in patients undergoing ablation of atrial fibrillation. Pacing Clin Electrophysiol 2013; 36:172. 16. Winkle RA, Mead RH, Engel G, et al. The use of dabigatran immediately after atrial fibrillation ablation. J Cardiovasc Electrophysiol 2012; 23:264. 17. Bassiouny M, Saliba W, Rickard J, et al. Use of dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 13/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 2013; 6:460. 18. Maddox W, Kay GN, Yamada T, et al. Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013; 24:861. 19. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014; 63:982. 20. Dillier R, Ammar S, Hessling G, et al. Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures. Circ Arrhythm Electrophysiol 2014; 7:576. 21. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012; 59:1168. 22. Provid ncia R, Albenque JP, Combes S, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart 2014; 100:324. 23. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace 2013; 15:1412. 24. Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace 2013; 15:1407. 25. Wu S, Yang YM, Zhu J, et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants Compared With Uninterrupted Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation. Am J Cardiol 2016; 117:926. 26. Knight BP. Transesophageal echocardiography before atrial fibrillation ablation: looking before cooking. J Am Coll Cardiol 2009; 54:2040. 27. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 14/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thor 28. Rathi VK, Reddy ST, Anreddy S, et al. Contrast-enhanced CMR is equally effective as TEE in the evaluation of left atrial appendage thrombus in patients with atrial fibrillation undergoing pulmonary vein isolation procedure. Heart Rhythm 2013; 10:1021. 29. Chen J, Zhang H, Zhu D, et al. Cardiac MRI for detecting left atrial/left atrial appendage thrombus in patients with atrial fibrillation : Meta-analysis and systematic review. Herz 2019; 44:390. 30. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. 31. Saksena S, Sra J, Jordaens L, et al. A prospective comparison of cardiac imaging using intracardiac echocardiography with transesophageal echocardiography in patients with atrial fibrillation: the intracardiac echocardiography guided cardioversion helps interventional procedures study. Circ Arrhythm Electrophysiol 2010; 3:571. 32. Martinez MW, Kirsch J, Williamson EE, et al. Utility of nongated multidetector computed tomography for detection of left atrial thrombus in patients undergoing catheter ablation of atrial fibrillation. JACC Cardiovasc Imaging 2009; 2:69. 33. Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation 2014; 129:2638. 34. Santangeli P, Di Biase L, Horton R, et al. Ablation of atrial fibrillation under therapeutic warfarin reduces periprocedural complications: evidence from a meta-analysis. Circ Arrhythm Electrophysiol 2012; 5:302. 35. Kuwahara T, Takahashi A, Takahashi Y, et al. Prevention of periprocedural ischemic stroke and management of hemorrhagic complications in atrial fibrillation ablation under continuous warfarin administration. J Cardiovasc Electrophysiol 2013; 24:510. 36. Di Biase L, Gaita F, Toso E, et al. Does periprocedural anticoagulation management of atrial fibrillation affect the prevalence of silent thromboembolic lesion detected by diffusion cerebral magnetic resonance imaging in patients undergoing radiofrequency atrial https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 15/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate fibrillation ablation with open irrigated catheters? Results from a prospective multicenter study. Heart Rhythm 2014; 11:791. 37. Kim JS, Jongnarangsin K, Latchamsetty R, et al. The optimal range of international normalized ratio for radiofrequency catheter ablation of atrial fibrillation during therapeutic anticoagulation with warfarin. Circ Arrhythm Electrophysiol 2013; 6:302. 38. Yu HT, Shim J, Park J, et al. When is it appropriate to stop non-vitamin K antagonist oral anticoagulants before catheter ablation of atrial fibrillation? A multicentre prospective randomized study. Eur Heart J 2019; 40:1531. 39. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med 2017; 376:1627. 40. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36:1805. 41. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019; 40:3013. 42. Kirchhof P, Haeusler KG, Blank B, et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J 2018; 39:2942. 43. Sticherling C, Marin F, Birnie D, et al. Antithrombotic management in patients undergoing electrophysiological procedures: a European Heart Rhythm Association (EHRA) position document endorsed by the ESC Working Group Thrombosis, Heart Rhythm Society (HRS), and Asia Pacific Heart Rhythm Society (APHRS). Europace 2015; 17:1197. 44. Eitel C, Koch J, Sommer P, et al. Novel oral anticoagulants in a real-world cohort of patients undergoing catheter ablation of atrial fibrillation. Europace 2013; 15:1587. 45. Karasoy D, Gislason GH, Hansen J, et al. Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long- term follow-up in nationwide cohort of Denmark. Eur Heart J 2015; 36:307. 46. Schreiber D, Rostock T, Fr hlich M, et al. Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success. Circ Arrhythm Electrophysiol 2015; 8:308. 47. Jacobs V, May HT, Bair TL, et al. The impact of risk score (CHADS2 versus CHA2DS2-VASc) on long-term outcomes after atrial fibrillation ablation. Heart Rhythm 2015; 12:681. 48. Kaufman ES, Waldo AL. The impact of asymptomatic atrial fibrillation. J Am Coll Cardiol 2004; 43:53. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 16/21 7/6/23, 2:49 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 49. Saad EB, Marrouche NF, Saad CP, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome. Ann Intern Med 2003; 138:634. 50. Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001; 104:2539. 51. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 52. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 53. Romero J, Cerrud-Rodriguez RC, Diaz JC, et al. Oral anticoagulation after catheter ablation of atrial fibrillation and the associated risk of thromboembolic events and intracranial hemorrhage: A systematic review and meta-analysis. J Cardiovasc Electrophysiol 2019; 30:1250. 54. Lin YJ, Chao TF, Tsao HM, et al. Successful catheter ablation reduces the risk of cardiovascular events in atrial fibrillation patients with CHA2DS2-VASc risk score of 1 and higher. Europace 2013; 15:676. 55. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol 2011; 22:839. 56. Hunter RJ, McCready J, Diab I, et al. Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associated with a lower risk of stroke and death. Heart 2012; 98:48. 57. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006; 114:759. 58. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 59. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:104. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 17/21 7/6/23, 2:50 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 60. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14:1385. Topic 94502 Version 27.0 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 18/21 7/6/23, 2:50 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or aortic plaque) 1 5 7.2 Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 19/21 7/6/23, 2:50 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 Actual rates of stroke in contemporary cohorts might vary from these estimates. . References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 20/21 7/6/23, 2:50 PM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 21/21

7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Chronic bifascicular blocks : William H Sauer, MD : N A Mark Estes, III, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 06, 2022. INTRODUCTION Bifascicular block, a pattern seen on the surface electrocardiogram (ECG), results when normal physiologic activation in the His-Purkinje system is interrupted. The normal sequence of activation is altered dramatically in patients with bifascicular block, with a resultant characteristic appearance on the ECG that varies depending upon the exact fascicles which are blocked. Interruptions in conduction may result in right bundle branch block (RBBB), left anterior fascicular block (LAFB), or left posterior fascicular block (LPFB), with bifascicular block resulting when two of these three are identified from the ECG. A 2009 American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society (AHA/ACCF/HRS) scientific statement on the standardization and interpretation of the electrocardiogram recommends against using the term bifascicular block (and also trifascicular block) since these patterns do not have unique anatomic and pathologic substrates [1]. However, these terms are still widely entrenched in clinical practice and scientific literature, meriting their discussion here. The anatomy, clinical manifestations, differential diagnosis, prognostic implications, and treatment of bifascicular block (RBBB with either LAFB or LPFB) will be reviewed here. Though technically a type of bifascicular block, complete LBBB is discussed separately, as are conduction system abnormalities involving only a single fascicle. (See "Left bundle branch block" and "Right bundle branch block" and "Left anterior fascicular block" and "Left posterior fascicular block" and "Left septal fascicular block".) https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 1/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate DEFINITIONS Bifascicular block The term bifascicular block most commonly refers to conduction disturbances below the atrioventricular (AV) node in which the right bundle branch and one of the two fascicles (anterior or posterior) of the left bundle branch are involved. Although this definition is most commonly used, left bundle branch block (LBBB) is also a type of bifascicular block since LBBB, as noted, implies block in both fascicles [2,3]. Trifascicular block The term trifascicular block is most commonly used to describe bifascicular block associated with prolongation of the PR interval (ie, first degree AV block). However, this description, though commonly used in clinical practice, is inaccurate as the conduction delay resulting in the PR interval prolongation does not usually occur in a fascicle, but in the AV node. True trifascicular block would involve block of the right bundle branch and both fascicles of the left bundle branch; this manifests as third degree (complete) heart block and is referred to as such. Sinus rhythm with alternating left/right bundle branch block or right bundle branch block (RBBB) with alternating fascicular blocks on a beat-to-beat basis is a very rare manifestation of trifascicular block, usually heralding complete AV block. (See "Third-degree (complete) atrioventricular block".) ANATOMY AND BLOOD SUPPLY Anatomy The bundle of His divides at the juncture of the fibrous and muscular boundaries of the intraventricular septum into the left and right bundle branches ( figure 1). The right bundle branch is a long, thin, discrete structure that courses down the right side of interventricular septum near the endocardium in its upper third, deeper in the muscular portion of the septum in the middle third, and then again near the endocardium in its lower third. The right bundle branch does not divide throughout most of its course, but begins to ramify as it approaches the base of the right anterior papillary muscle with fascicles going to the septal and free walls of the right ventricle. The main left bundle branch penetrates the membranous portion of the interventricular septum under the aortic ring and then divides into several fairly discrete branches. The components of the left bundle branch are ( figure 1) [4-8]: A pre-divisional segment An anterior fascicle that crosses the left ventricular outflow tract and terminates in the Purkinje system of the anterolateral wall of the left ventricle https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 2/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate A posterior fascicle that fans out extensively inferiorly and posteriorly into Purkinje fibers In some hearts, a median fascicle to the interventricular septum Blood supply The blood supply to the fascicles is complex and somewhat variable between patients: The right bundle branch receives most of its blood supply from septal branches of the left anterior descending coronary artery, particularly in its initial course. In most patients, it also receives some collateral supply from either the right or circumflex coronary systems depending upon the dominance of the coronary system ( figure 2). The left anterior fascicle (and median fascicle, when present) is supplied either by septal branches of the left anterior descending artery or by the atrioventricular (AV) nodal artery ( figure 2). The proximal part of the left posterior fascicle is supplied by the artery to the AV node and, at times, by septal branches of the left anterior descending artery. The distal portion has a dual blood supply from both anterior and posterior septal perforating arteries. As is true for the right bundle branch, the left fascicles may receive some collateral flow from the right and circumflex coronary systems. ETIOLOGY The right bundle branch is vulnerable to stretch and trauma for two-thirds of its course when it is near the subendocardial surface ( figure 1). Additionally, conduction in both the right and left bundle branches can be compromised by both structural and functional factors (eg, chronic ventricular pressure or volume overload, myocardial ischemia, myocarditis, etc). A more extensive discussion of the etiologies of conduction disturbances in the right and left bundles is presented elsewhere. (See "Right bundle branch block", section on 'Etiology' and "Left bundle branch block", section on 'Etiology'.) CLINICAL PRESENTATION, DIAGNOSIS, AND EVALUATION ECG findings Bifascicular block may present with one of three potential appearances on the surface electrocardiogram (ECG): Right bundle branch block (RBBB) and left anterior fascicular block (LAFB) ( waveform 1) RBBB and left posterior fascicular block (LPFB) ( waveform 2) LAFB and LPFB (ie, left bundle branch block [LBBB]) ( waveform 3) https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 3/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate Detailed descriptions of the ECG findings associated with RBBB, LAFB, LPFB, and LBBB are presented separately. (See "Right bundle branch block", section on 'ECG findings and diagnosis' and "Left anterior fascicular block", section on 'Electrocardiographic findings' and "Left posterior fascicular block", section on 'Electrocardiographic findings' and "Left bundle branch block", section on 'ECG findings and diagnosis'.) Asymptomatic patients In nearly all instances, the clinical presentation of bifascicular block is asymptomatic and fairly benign, as bifascicular block in and of itself does not produce symptoms, and there are no specific signs of bifascicular block during physical examination. As such, bifascicular block is identified when patients are undergoing an ECG for another indication. For asymptomatic patients with bifascicular block, no further diagnostic evaluation or therapy is required. However, patients should be carefully screened for symptoms and signs suggesting occult cardiac disease, as concomitant structural heart disease is frequently present. If underlying cardiac disease is suspected, additional diagnostic testing and therapy would proceed accordingly. Symptomatic patients For patients who present with presyncope or syncope and are noted to have bifascicular block on ECG, additional monitoring and evaluation are required, as such patients may have intermittent complete heart block that results in hemodynamic instability leading to their symptoms of presyncope or syncope. In those patients with syncope or presyncope who have suspected advanced conduction disease, we perform continuous ECG monitoring for 24 to 48 hours, usually in an inpatient setting, to monitor for high-grade AV block that would require a permanent pacemaker [3]. Additionally, cardiac imaging with echocardiography is indicated, as this presentation could be the initial manifestation of structural heart disease [3]. In our opinion, patients presenting with unexplained syncope and bifascicular block should be evaluated immediately as possible progression to heart block is unknown at initial presentation. In those patients with a structurally normal heart and unexplained syncope with bifascicular block, an electrophysiologic study (EPS) could identify occult infranodal conduction disease and prompt permanent pacemaker implantation [2,9]. Patients with an abnormal EPS (HV >70 msec or His-Purkinje AV block with pacing or pharmacologic challenge) would generally benefit from permanent pacemaker implantation. In those patients with unexplained syncope and no obvious etiology, long-term monitoring with an insertable cardiac monitor (also sometimes referred to as an implantable cardiac monitor or an implantable loop recorder) is indicated. (See "Ambulatory ECG monitoring".) https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 4/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate Limited data suggest that tilt table testing is not helpful in patients with bifascicular block with unexplained syncope, and as such we do not recommend tilt table testing in this population. In a study comparing such patients with control subjects with bifascicular block and no syncope, no difference in the incidence of a positive tilt table test (28 versus 32 percent) was observed, suggesting that test specificity in this population is poor [10]. DIFFERENTIAL DIAGNOSIS While bifascicular block has one of two fairly characteristic appearances on electrocardiogram (ECG), there are other conditions in which the ECG may have a similar appearance that need to be excluded prior to confirming the diagnosis of bifascicular block. Ventricular tachycardia and accelerated idioventricular rhythm If the dominant ventricular rhythm originates from a pacemaker in the ventricle, the QRS will be widened and can have the appearance of bifascicular block. However, both ventricular tachycardia (heart rate greater than 100 beats per minute) ( waveform 4) and accelerated idioventricular rhythm (heart rate between 60 and 100 beats per minute) ( waveform 5) are associated with atrioventricular (AV) dissociation, which should distinguish the rhythm from a supraventricular rhythm with bifascicular block. (See "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation" and "ECG tutorial: Ventricular arrhythmias", section on 'Accelerated idioventricular rhythm'.) Ventricular pacing Ventricular pacing from the right ventricle typically results in a QRS complex resembling that seen with LBBB on the surface ECG. Biventricular pacing, in theory, could also result in the appearance of bifascicular block. In nearly all patients, however, the presence of pacemaker spikes preceding the QRS complex differentiates a paced complex from bifascicular block. Ventricular pre-excitation (Wolff-Parkinson-White syndrome) In some patients with manifest accessory pathways, the pre-excitation pattern can mimic bifascicular block. In Wolff- Parkinson-White (WPW) syndrome, however, the PR interval is typically short, which is generally not the case with bifascicular block. NATURAL HISTORY AND PROGNOSIS Progression of chronic bifascicular block and bifascicular block with a prolonged PR interval to complete heart block appears to be infrequent among asymptomatic patients [11,12]. In one https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 5/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate study of 554 patients with bifascicular or trifascicular block who were followed for an average of 42 months, only 1 percent per year progressed to complete heart block [11]. Among patients with syncope or other symptoms at baseline, the likelihood of progression to symptomatic high-grade heart block appears high. In a study of 249 patients with bifascicular block (of which 41 percent were left bundle branch block [LBBB]), 57 patients required a permanent pacemaker for "significant atrioventricular (AV) block" over a median follow-up of 4.5 years (5 percent per year) [13]. Otherwise unexplained syncope in the presence of bifascicular block is an indication for a permanent pacemaker [2,14]. However, because unexplained syncope can be due to nonarrhythmic causes, it is possible for those with a pacemaker to continue to experience syncope, and thus an accurate diagnosis is desirable [15]. Despite the expectation for prevention of syncope with pacing, patients who receive a pacemaker with fascicular block do not have a different mortality rate compared with those without pacers [16]. This is likely due to competing causes of cardiac death independent of heart block progression. The significance and treatment of bifascicular or trifascicular block appearing during acute myocardial infarction is considered separately. (See "Conduction abnormalities after myocardial infarction".) TREATMENT Management of patients with chronic bifascicular block begins by looking for and correcting reversible causes of impaired conduction such as myocardial ischemia and drugs that may slow conduction or prolong the refractory period of fascicular tissue. (See "Etiology of atrioventricular block".) If no reversible causes are present, management involves the avoidance of medications that impair atrioventricular (AV) nodal conduction (when possible). Consideration of additional treatment with a permanent pacemaker depends on the presence or absence of symptoms: For patients with bifascicular block and no apparent symptoms, no specific treatment is required. For patients with bifascicular block and symptoms of syncope or presyncope of suspected cardiac etiology (specifically due to suspected intermittent complete heart block with bradyarrhythmia), we suggest permanent pacemaker implantation. Our approach is consistent with the guideline recommendations of various professional societies for patients with unexplained syncope in the setting of chronic bifascicular block if https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 6/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate other likely causes of syncope have been excluded [9,14]. (See 'Natural history and prognosis' above.) A randomized trial of permanent pacing versus implantable loop recorder monitoring in patients with bifascicular block and syncope demonstrated a significant reduction in a composite endpoint of cardiovascular death, syncope, bradycardia, and device-related complications with empiric pacing [17]. Interestingly, syncope was still observed in 29 percent of patients who received a pacemaker, indicating a vasodepressor etiology in many of these patients. This clinical trial adds to the clinical evidence supporting the pacing recommendation. A number of neuromuscular diseases are associated with conduction abnormalities. These include myotonic muscular dystrophy, Kearns-Sayre syndrome, Erb dystrophy (limb-girdle), and peroneal muscular atrophy. These patients represent a special class and are treated more aggressively with pacemakers due to the potential for unpredictably rapid progression of conduction disease. (See "Inherited syndromes associated with cardiac disease" and "Permanent cardiac pacing: Overview of devices and indications", section on 'Neuromuscular diseases'.) Detailed reviews of the indications for permanent pacemaker placement and of the modes of cardiac pacing are presented separately. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Acquired AV block' and "Modes of cardiac pacing: Nomenclature and selection".) SUMMARY AND RECOMMENDATIONS Bifascicular block, a pattern seen on the surface electrocardiogram (ECG), results when normal electrical activity in the His-Purkinje system is interrupted. Interruptions in conduction may result in right bundle branch block (RBBB), left anterior fascicular block (LAFB), or left posterior fascicular block (LPFB), with bifascicular block resulting when two of these three are identified on the ECG. Bifascicular block most commonly refers to conduction disturbances involving the right bundle branch and one of the two fascicles (anterior or posterior) of the left bundle branch. (See 'Introduction' above.) In nearly all instances, the clinical presentation of bifascicular block is asymptomatic and fairly benign, as bifascicular block in and of itself does not produce symptoms, and there are no specific signs of bifascicular block during physical examination. As such, bifascicular block is identified when patients are undergoing an ECG for another indication. For asymptomatic patients with bifascicular block, no further diagnostic evaluation or therapy is required, although patients should be screened carefully for symptoms and signs suggesting occult cardiac disease. (See 'Asymptomatic patients' above.) https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 7/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate For patients who present with presyncope or syncope and are noted to have bifascicular block on ECG, additional monitoring and evaluation are required, as intermittent complete heart block may result in hemodynamic instability leading to their symptoms. In such patients, we perform continuous ECG monitoring for 24 to 48 hours, usually in an inpatient setting, to monitor for high-grade atrioventricular (AV) block. We also perform echocardiography to assess for underlying structural heart disease. (See 'Symptomatic patients' above.) Progression of chronic bifascicular block and bifascicular block with a prolonged PR interval to complete heart block is infrequent, with an annual rate of approximately 1 percent in asymptomatic patients and up to 5 percent in symptomatic patients. (See 'Natural history and prognosis' above.) Management of patients with chronic bifascicular block begins by looking for and correcting reversible causes of impaired conduction such as myocardial ischemia and drugs that may slow conduction or prolong the refractory period of fascicular tissue. If no reversible causes are present, treatment involves the avoidance of medications that impair AV nodal conduction (when possible) and evaluation for permanent pacemaker placement. (See 'Treatment' above and "Permanent cardiac pacing: Overview of devices and indications", section on 'Acquired AV block'.) For patients with bifascicular block and no apparent symptoms, no specific treatment is required. For patients with bifascicular block and symptoms of syncope or presyncope of suspected cardiac etiology (specifically due to suspected intermittent complete heart block with bradyarrhythmia), we suggest permanent pacemaker implantation (Grade 2C). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Surawicz B, Childers R, Deal BJ, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part III: intraventricular conduction disturbances: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation 2009; 119:e235. https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 8/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate 2. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018; 39:1883. 3. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. 4. Tawara S. Das Reizleitungssystem des S uegetierherzens. Gustav Fischer, Jena 1906. 5. Rosenbaum M, Elizari MV, Lazzari JO. The Hemiblocks. Tampa Tracings, Tampa 1970. 6. Uhley HN. Some controversy regarding the peripheral distribution of the conduction system. Am J Cardiol 1972; 30:919. 7. Hecht HH, Kossmann CE, Childers RW, et al. Atrioventricular and intraventricular conduction. Revised nomenclature and concepts. Am J Cardiol 1973; 31:232. 8. Demoulin JC, Kulbertus HE. Histopathological examination of concept of left hemiblock. Br Heart J 1972; 34:807. 9. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013; 34:2281. 10. Englund A, Fredrikson M, Rosenqvist M. Head-up tilt test. A nonspecific method of evaluating patients with bifascicular block. Circulation 1997; 95:951. 11. McAnulty JH, Rahimtoola SH, Murphy E, et al. Natural history of "high-risk" bundle-branch block: final report of a prospective study. N Engl J Med 1982; 307:137. 12. Schneider JF, Thomas HE, Kreger BE, et al. Newly acquired right bundle-branch block: The Framingham Study. Ann Intern Med 1980; 92:37. 13. Mart -Almor J, Cladellas M, Baz n V, et al. [Novel predictors of progression of atrioventricular block in patients with chronic bifascicular block]. Rev Esp Cardiol 2010; 63:400. 14. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 15. Kalscheur MM, Donateo P, Wenzke KE, et al. Long-Term Outcome of Patients with Bifascicular Block and Unexplained Syncope Following Cardiac Pacing. Pacing Clin Electrophysiol 2016; 39:1126. https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 9/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate 16. Moulki N, Kealhofer JV, Benditt DG, et al. Association of cardiac implantable electronic devices with survival in bifascicular block and prolonged PR interval on electrocardiogram. J Interv Card Electrophysiol 2018; 52:335. 17. Sheldon R, Talajic M, Tang A, et al. Randomized Pragmatic Trial of Pacemaker Versus Implantable Cardiac Monitor in Syncope and Bifascicular Block. JACC Clin Electrophysiol 2022; 8:239. Topic 1063 Version 26.0 https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 10/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate GRAPHICS Normal conduction system Schematic representation of the normal intraventricular conduction system (His- Purkinje system). The Bundle of His divides into the left bundle branch and right bundle branch. The left bundle branch divides into anterior, posterior, and, in some cases, median fascicles. AV: atrioventricular; RA: right atrium; LA: left atrium; RV: right ventricle; LV: left ventricle. Graphic 63340 Version 6.0 https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 11/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate Coronary artery anatomy Graphic 70956 Version 2.0 https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 12/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate 12-lead electrocardiogram (ECG) showing bifascicular block with right bundle branch block and left anterior fascicular block The 12-lead ECG from a patient with a history of an anteroseptal myocardial infarction (Q waves seen in lead V1-V3) shows bifascicular block with RBBB and LAFB. A typical RBBB is seen with a QRS duration of 0.16 seconds and an rSR' configuration in lead V1 and a deep S wave in V6. The QRS complexes in leads II, III, and avF are negative, with a rS morphology, diagnostic of a pathologic left axis deviation, known as LAFB. ECG: electrocardiogram; RBBB: right bundle branch block; LAFB: left anterior fascicular block. Reproduced with permission by Samuel Levy, MD. Graphic 69886 Version 4.0 https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 13/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate ECG bifascicular block RBBB and LPFB The 12-lead ECG from a patient with bifascicular block with RBBB and LPFB. ECG: electrocardiogram; RBBB: right bundle branch block; LPFB: left posterior fascicular block. Reproduced with permission from: Nathanson LA, McClennen S, Safran C, Goldberger AL. ECG Wave-Maven: Self-Assessment Program f Clinicians. Available at: http://ecg.bidmc.harvard.edu (Accessed on January 11, 2017). Graphic 111524 Version 2.0 https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 14/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate 12-lead electrocardiogram (ECG) showing typical left bundle branch block Electrocardiogram in typical complete left bundle branch block. The asynchronous activation of the 2 ventricles increases the QRS duration (0.16 seconds in this example). The abnormal initial vector results in loss of "normal" septal forces as manifested by absence of q waves in leads I, aVL, and V6. The late activation of the left ventricle prolongs the dominant leftward progression of the middle and terminal forces, leading to a positive and widened R wave in the lateral leads. Both the ST segment and T wave vectors are opposite in direction from the QRS, a "secondary" repolarization abnormality. Courtesy of Ary Goldberger, MD. Graphic 61594 Version 9.0 Normal ECG https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 15/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate Normal electrocardiogram showing normal sinus rhythm at a rate of 75 beats/minute, a PR interval of 0.14 seconds, a QRS interval of 0.10 seconds, and a QRS axis of approximately 75 . Courtesy of Ary Goldberger, MD. Graphic 76183 Version 4.0 https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 16/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate Single lead electrocardiogram (ECG) showing monomorphic ventricular tachycardia Three or more successive ventricular beats are defined as ventricular tachycardia (VT). This VT is monomorphic since all of the QRS complexes have an identical appearance. Although the P waves are not distinct, they can be seen altering the QRS complex and ST-T waves in an irregular fashion, indicating the absence of a relationship between the P waves and the QRS complexes (ie, AV dissociation is present). AV: atrioventricular. Graphic 63176 Version 7.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 17/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate ECG 12-lead accelerated idioventricular rhythm 12-lead ECG showing idioventricular rhythm with AV dissociation and wide QRS complexes occurring at a rate faster than the sinus rate but slower than 100 bpm (hence not meeting the criteria for ventricular tachycardia). ECG: electrocardiogram. Graphic 118943 Version 2.0 https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 18/19 7/6/23, 2:48 PM Chronic bifascicular blocks - UpToDate Contributor Disclosures William H Sauer, MD Grant/Research/Clinical Trial Support: Biosense-Webster [Catheter ablation]; Boston Scientific [Catheter ablation]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/chronic-bifascicular-blocks/print 19/19

7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical uses of sotalol : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA, Rod Passman, MD, MSCE : Mark S Link, MD, Hugh Calkins, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 14, 2023. INTRODUCTION Sotalol, a methanesulfonanilide, is a class III antiarrhythmic drug ( table 1) that is used for the treatment of both atrial and ventricular arrhythmias. Sotalol was originally approved by the FDA (tradename Betapace) for the treatment of life-threatening ventricular arrhythmias. The present commercial product (tradename Betapace AF) is intended for use in atrial fibrillation (AF), with the caveat that sotalol is not effective for conversion of AF to sinus rhythm, but it may be used to prevent AF. Although both commercial presentations contain sotalol, Betapace should not be substituted for Betapace AF because of significant differences in the labeling sections on indications, dosing, administration, and safety profile. Additionally, an injectable form of sotalol was approved by the FDA in July 2009. The package inserts for Betapace and Betapace AF contain black box warnings regarding potential for QT prolongation and ventricular arrhythmias [1]. (See 'Cardiac toxicity' below.) This topic will review the electrophysiology and mechanisms of action of sotalol, and will discuss dosing, the different settings in which sotalol has been used as an antiarrhythmic drug, and major side effects. Recommendations for the role of sotalol in the treatment of atrial and ventricular arrhythmias are presented separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Choice of pharmacologic therapy'.) ELECTROPHYSIOLOGY AND MECHANISM OF ACTION https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 1/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Sotalol consists of a racemic mixture of d and l isomers in an approximate ratio of 1:1; this mixture is often called dl-sotalol. D- and l-stereoisomers of sotalol have been studied individually, but only dl-sotalol is commercially available. The two isomers contribute to the unique antiarrhythmic properties of sotalol [2-5]: The d isomer prolongs repolarization by blocking IKr ( figure 1), the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization of the action potential ( figure 2) [6,7]. This represents a class III effect. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) The l isomer has two actions: it prolongs repolarization and it has beta blocking activity. The beta blocker effect is dose-dependent, is not cardioselective, and is not associated with membrane stabilizing activity or intrinsic sympathomimetic activity. Class III activity The antiarrhythmic activity of sotalol is primarily mediated by its class III property ( table 1), which results in prolongation of the monophasic action potential duration as well as lengthening of the effective refractory period (ERP) in the atria, atrioventricular (AV) node (as reflected by the AH interval), ventricles, and antegrade and retrograde bypass tracts (when present) [4,8-10]. The class III effect results from blockade of the rapid component of the delayed rectifier potassium current (IKr) that is responsible for phase 3 repolarization of the action potential ( figure 2) [6,7].The prolongation of cardiac action potential duration does not appear to be related to concurrent beta blockade, since d-sotalol, which has little beta blocking activity, produces a similar delay in repolarization as l-sotalol [2]. The effect of sotalol on the action potential duration shows reverse use dependence, which is seen with other class III antiarrhythmic drugs except for amiodarone. Reverse use dependence is defined as an inverse correlation between the heart rate and the QT interval [11]. As a result, the QT interval is prolonged as the heart rate slows, which could explain the association between bradycardia and antiarrhythmic drug-induced torsades de pointes and the possible decrease in drug efficacy at higher heart rates. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Pathophysiology' and 'Proarrhythmia' below.) The clinical manifestations of sotalol-induced beta blockade include an increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness (prolonged PR interval) [4]. Effects on the ECG The combined actions of sotalol produce a variety of changes in the electrocardiogram (ECG) [4,12,13]: https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 2/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Because of its beta blocking activity, sotalol slows the sinus rate by approximately 25 percent and slightly prolongs the PR interval. The QRS duration is not altered, since ventricular conduction at normal sinus rates is unchanged [12,13]. This is thought to reflect a lack of effect of sotalol on the His-Purkinje (HV) interval [4,9,14]. The QT interval is prolonged in a dose-dependent fashion [15]. Since the QRS duration is not prolonged, the increase in QT interval results solely from delayed repolarization (ie, the JT interval) [12,13]. In a review of 114 patients given chronic oral sotalol therapy, the average increase in QT interval was 80 and 91 msec with 320 and 640 mg/day [12]. However, the increase in QTc, which is corrected for heart rate, was less prominent (21 and 30 msec, respectively). (See "Congenital long QT syndrome: Diagnosis", section on 'QT rate correction'.) PHARMACOKINETICS Sotalol is, essentially, completely absorbed and not metabolized. Consequently, bioavailability is close to 100 percent. Age and food have slight but unimportant effects on bioavailability. The maximum concentration of sotalol is achieved within 2 to 3 hours with a half-life between 7 and 15 hours. Excretion of sotalol is primarily through the kidneys, with no metabolism by liver and no first-pass effect. Therefore, sotalol plasma levels and half-life are directly related to creatinine clearance and glomerular filtration rate. Appropriate dose adjustments must be made for patients with impaired renal function or increased renal blood flow, as in pregnancy. The beta- adrenoceptor antagonistic effects of sotalol are directly related to plasma levels, which, in turn, are directly related to dose. However, the beta-adrenoceptor antagonism half-life is longer than the sotalol plasma half-life [16]. DOSING The dose of sotalol should be individualized on the basis of therapeutic response and tolerance. Because of its beta blocking activity, sotalol should not be used in patients with uncontrolled asthma, sinus bradycardia, Mobitz II second degree AV block or third degree AV block (unless the patient is treated with a pacemaker), cardiogenic shock, or uncontrolled heart failure [5]. In addition, because sotalol prolongs the QT interval, it should not be used in patients with congenital or acquired long QT syndrome, and should be used with caution in patients taking other medications known to prolong the QT interval ( table 2). (See 'Proarrhythmia' below.) https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 3/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Initiation of therapy Bradycardic and proarrhythmic events can occur after the initiation of sotalol therapy and with each upward dosing adjustment [17,18]. As a result, sotalol should be initiated in a hospital with facilities for cardiac rhythm monitoring and assessment. The package insert for sotalol contains a black box warning regarding initiation of the drug in a center with QT monitoring and cardiac resuscitation capabilities. However, some providers have initiated sotalol (or uptitrated doses) in an off-label manner in the outpatient setting in patients felt to be at low risk of QT prolongation or polymorphic VT. Before beginning sotalol, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of two to three half-lives, if clinically possible. (See 'Proarrhythmia' below.) The recommended initial dose of oral sotalol in adults is 80 mg twice daily whether used for the treatment of ventricular arrhythmias or atrial fibrillation. If necessary, the initial dose can be increased gradually to a maximum daily of 240 mg or 320 mg. Dose adjustments should be made at three day intervals so that steady-state plasma concentrations can be attained and the QT interval monitored. In a retrospective analysis, this standard approach was compared with initiating sotalol at 120 to 160 mg orally twice per day [19]. The accelerated dosing regimen neither shortened hospitalization nor had any effect on treatment efficacy. Due to the marginally increased risk of cardiac and non-cardiac side effects with an accelerated regimen, we favor the traditional starting dose of 80 mg twice daily. As of March 2020, intravenous sotalol has an updated FDA-approved dosing regimen for in- hospital initiation and reinitiation of patients on sotalol therapy. The key change is that with the use of intravenous sotalol, patients can now be initiated (titrated to steady-state blood levels) on sotalol therapy in the hospital in one day (versus three days). In addition, with intravenous sotalol (unlike with oral sotalol), patients can be initiated at either 80 or 120 mg. In other words, with intravenous sotalol, patients may be initiated at 120 mg without titrating up from 80 mg. Dose adjustment with chronic kidney disease Oral sotalol is primarily excreted unchanged in the urine, since it is not appreciably metabolized in the liver [3]. As a result, the elimination half-life is prolonged in patients with renal insufficiency. When sotalol is given for the treatment of ventricular arrhythmias, the dosing interval should be modified based upon the reduction in creatinine clearance: >60 mL/min 12 hours 30 to 60 mL/min 24 hours 10 to 29 mL/min 36 to 48 hours <10 mL/min should be individualized https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 4/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Patients with severe renal disease are at risk for potentially life-threatening ventricular arrhythmia even if low doses are used [20,21]. When used for the treatment of atrial fibrillation, sotalol is considered contraindicated when the creatinine clearance is less than 40 mL/min. Intravenous sotalol Intravenous sotalol has primarily been used to terminate supraventricular tachyarrhythmias [22-24]. It has also been used to terminate spontaneous sustained ventricular tachycardia (VT) and to suppress inducible ventricular tachyarrhythmia during electrophysiology study [25,26]. Several reports have described the value and limitations of intravenous sotalol to convert arial fibrillation to sinus rhythm. A review concerning the effectiveness of antiarrhythmic drugs administered intravenously indicates that sotalol has a modest success on cardioversion of AF to sinus rhythm approximating 30 percent; it is less effective than class I agents or ibutilide [27]. In particular, high-dose ibutilide showed a greater conversion rate than intravenous sotalol [23]. A meta-analysis concluded that intravenous and oral sotalol for conversion of AF of varied duration are as effective as class IA or class IC agents, and as effective as amiodarone for pharmacological conversion of AF [28]. Another report found sotalol less efficient than flecainide, propafenone, or ibutilide and likely as effective as intravenous amiodarone [29]. A prospective study from Australia compared intravenous administration of digoxin, amiodarone, and sotalol [30]. The results at 24 hours revealed conversion to sinus rhythm was 50 percent for digoxin, 69 percent for amiodarone, and 80 percent for sotalol. In addition, the conversion at 48 hours was 58 percent for digoxin, 77 percent for amiodarone, and 88 percent for sotalol. Monitoring After the sotalol loading dose is complete, generally the patient is asked to return for an electrocardiogram (ECG) within one and two weeks, looking for QT interval prolongation and bradyarrhythmia. Patients should typically have an ECG performed every six months while taking sotalol, and whenever any additional QT prolonging medications are newly prescribed. Routine laboratory studies are not needed to monitor sotalol levels or for potential toxicities. CLINICAL INDICATIONS https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 5/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Oral sotalol is used for the treatment of documented ventricular arrhythmias (ie, sustained ventricular tachycardia [VT]) that, in the judgment of the clinician are life-threatening, and for the maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation (AF) and atrial flutter who are currently in sinus rhythm. What follows is a brief review of the major settings in which sotalol is given with links to the topic reviews in which the role of sotalol therapy is discussed in detail. Ventricular arrhythmias Sotalol is used to prevent recurrence of sustained VT or ventricular fibrillation (VF) [12,31- 33]. The main setting in which sotalol is used for VT/VF is as adjunctive therapy to an ICD to reduce the frequency of appropriate shocks or of inappropriate shocks due to supraventricular arrhythmias. However, sotalol may be used as primary therapy in patients who do not want or are not candidates for an ICD (eg, due to marked comorbidities or end- stage heart failure that make death likely). Although sotalol reduces both recurrent arrhythmia and the frequency of ICD shocks [34], sotalol is typically second-line therapy to empiric amiodarone. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Antiarrhythmic drugs' and "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Choice of pharmacologic therapy'.) Sotalol is effective in patients with arrhythmogenic right ventricular cardiomyopathy who have either inducible or noninducible non-life-threatening VT; in contrast, other antiarrhythmic drugs have little efficacy [35]. Thus, initial therapy with sotalol is a reasonable option for many such patients. For those that do not respond to sotalol, response to other drugs is unlikely, and consideration should be given to nonpharmacologic therapy such as radiofrequency catheter ablation. (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis", section on 'Antiarrhythmic drugs'.) A preparation containing only the d isomer has been developed as a "pure" class III drug [36,37]. However, in the Survival with Oral D-sotalol (SWORD) trial of patients with a reduced left ventricular ejection fraction and either a recent myocardial infarction (MI) or symptomatic heart failure and a remote MI, d-sotalol therapy, compared with placebo, was associated with a significant increase in mortality that was largely due to an increase in presumed arrhythmic deaths [37]. This observation suggests an important contribution from the beta blocking activity that is seen with dl-sotalol. Atrial arrhythmias Both the class III and beta blocking activity of dl-sotalol contribute to its use in the treatment of atrial arrhythmias, mostly atrial fibrillation (AF). https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 6/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Sotalol promotes maintenance of sinus rhythm after cardioversion in patients with AF. The main indication for sotalol, if a rhythm control strategy is chosen, is in patients with underlying coronary heart disease ( algorithm 1). (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) In comparison, oral sotalol has limited efficacy for pharmacologic cardioversion of AF to sinus rhythm [38] and, where available, intravenous sotalol is less effective than other drugs [23,24]. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.) Sotalol appears to be effective for the prevention of AF after cardiac surgery (eg, coronary artery bypass graft or valve surgery) [39]. In a meta-analysis of 15 studies involving sotalol for the prevention of AF after cardiac surgery, sotalol was significantly more effective in preventing AF than no treatment, placebo, or beta blockers, and it was equally as effective as amiodarone [40]. Recommendations about the choice of a particular agent for the prevention of AF after cardiac surgery are presented separately. (See "Atrial fibrillation and flutter after cardiac surgery".) The safety of sotalol was compared with dronedarone after AF ablation. Propensity-score matching resulted in 1815 patients receiving dronedarone matched 1:1 to patients receiving sotalol. Patients on dronedarone had lower risk of cardiovascular hospitalization compared with patients treated with sotalol, predominantly attributable to lower rates of ATA-related hospitalization. In addition, dronedarone-treated patients had a better safety profile after ablation compared with sotalol patients because of lower rates of combined proarrhythmia, predominantly driven by lower rates of bradycardic proarrhythmia and need for pacemaker implantation [41]. The DASH-AF study compared the safety and feasibility of intravenous sotalol compared with the traditional five-dose inpatient titration of oral sotalol for the treatment of atrial arrhythmias. The nonrandomized study compared QT interval changes, safety outcomes, and cost in 120 patients receiving inpatient oral loading with 120 patients receiving intravenous sotalol at a loading dose of 125 mg for all patients with a CrCL >60 m/min for an intended maintenance regimen of 120 mg twice daily and 82.5 mg for CrCL >60 mL/min for an intended maintenance dose of 80 mg twice daily; oral sotalol was started four hours after the intravenous sotalol infusion. The majority (60 percent) of oral loading was at the 120 mg twice-daily dose. Patients were matched on AF type and CrCL. There was no significant change in QTc in both groups, and the risk of adverse events was also similar. The estimated cost savings with intravenous sotalol was $3,500.68 per admission. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 7/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Fetal arrhythmias Fetal tachycardia is a serious condition for which treatment should be initiated, especially in the presence of hydrops fetalis. The management of fetal arrhythmias is discussed in detail separately. (See "Fetal arrhythmias".) MAJOR SIDE EFFECTS Sotalol is generally well tolerated. It has been estimated that sotalol is discontinued because of side effects in approximately 15 percent of patients [4,42]. The major causes for cessation of therapy are fatigue (4 percent), bradycardia, dyspnea, proarrhythmia (each 3 percent), and dizziness and asthenia (each 2 percent) [4]. However, some of these side effects, such as dizziness, fatigue, and anxiety, may not be more common than with placebo [34]. The potential for cardiac toxicity is clearly of greatest concern. Bradycardic and proarrhythmic events can occur after the initiation of sotalol therapy and with each upward dosing adjustment. As a result, sotalol should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. (See 'Initiation of therapy' above.) Cardiac toxicity The two major cardiac side effects of sotalol are proarrhythmia, most often torsades de pointes, and bradycardia. In addition, the beta blocking activity of sotalol can cause new or worsened heart failure. The arrhythmic and bradycardic complications often occur within the first three days after the initiation of sotalol therapy and with each upward dosing adjustment [17,18]. As a result, sotalol should generally be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. (See 'Initiation of therapy' above.) Proarrhythmia Sotalol, like other class III drugs, has the potential to be arrhythmogenic due to marked prolongation of the duration of the action potential that is manifested on the surface electrocardiogram (ECG) by prolongation of the QT interval [3,43]. This effect is mediated by blockade of IKr ( figure 1), the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization of the action potential ( figure 2) [6,7]. (See 'Class III activity' above.) At standard doses between 160 and 320 mg/day, sotalol increases by QT interval by 40 to 100 msec [3]. However, the amount of change in the QT interval is highly variable and difficult to predict in an individual patient. In a cohort of 541 patients starting sotalol, the average change in corrected QT interval (QTc using the Bazett formula) was 3 42 milliseconds at two hours and 11 37 milliseconds at 48 hours following the initial dose [44]. The maximum recommended QTc interval on sotalol is 500 to 520 msec [3,4,45]. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 8/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate The effect of sotalol on the action potential duration shows reverse use dependence, which is seen with other class III antiarrhythmic drugs except for amiodarone. Reverse use dependence is defined as an inverse correlation between the heart rate and the QT interval [11]. As a result, the QT interval is prolonged as the heart rate slows, which could explain the association between bradycardia and antiarrhythmic drug-induced torsades de pointes. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Pathophysiology'.) The most important clinical manifestation of sotalol-induced proarrhythmia is torsades de pointes, characterized by a "twisting" of the peaks of the QRS complexes around the isoelectric line of the ECG ( waveform 1). Triggered activity caused by early afterdepolarizations is thought to be responsible for the induction of this arrhythmia, which is most likely to occur in patients with prolongation of the QT interval. The reported risk of torsades de pointes has varied from 1 to 4 percent [34,42,46]. The incidence of and risk factors for torsades de pointes were described in a 1996 review of 3135 patients who were treated with sotalol for sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) (41 percent) or non-life-threatening arrhythmias such as ventricular premature beats, atrial fibrillation (AF), nonsustained VT, or paroxysmal supraventricular tachycardia (59 percent) [46]. The overall rate of torsades de pointes was 2.5 percent at a median follow-up of 164 days. However, a number of groups at significantly increased risk were identified: Sotalol dose above 320 mg/day (3.7 versus 1.8 and 0.1 percent at doses of 161 to 320 mg/day and 160 mg/day, respectively). Serum creatinine above 1.4 mg/dL [124 micromol/L] in women and 1.6 mg/dL [141 micromol/L] in men (5.1 versus 2.2 percent). Sustained VT/VT as the presenting arrhythmia (4.5 versus 1.1 percent with other arrhythmias such as atrial fibrillation). History of heart failure (5.0 versus 1.7 percent without heart failure) or coronary heart disease (3.1 versus 1.9 percent). Female gender (4.1 versus 1.9 percent in men). The gender difference was independent of dose-related bradycardic responses and was similar in women greater than 50 and 50 years of age, which suggests that estrogen may not be responsible for the increased risk in women. An increase in risk in females has also been noted with torsades de pointes due to other antiarrhythmic drugs, noncardiac drugs, and the congenital long QT syndrome [47-49]. In each of these settings, females constitute approximately 70 percent of affected patients. Compared https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 9/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate with males, females have a longer corrected QT interval and a greater response to drugs that block IKr, potentiating the development of torsades de pointes [50]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for drug-induced long QT syndrome'.) There are also general predisposing factors such as bradycardia, which is thought to result from reverse use dependence in which the QT interval is prolonged as the heart rate slows, and other factors that prolong the baseline QT interval such as hypokalemia, hypomagnesemia, and the concomitant use of other drugs that prolong the QT interval, including antiarrhythmic drugs such as procainamide, quinidine, and the other class III agents (amiodarone, dofetilide, ibutilide) ( table 2). All of these drugs predispose to torsades de pointes except for amiodarone. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects' and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Bradycardia Sotalol has the potential to cause all of the rhythm effects induced by beta blockade, including sinus bradycardia and atrioventricular (AV) block. Bradyarrhythmias, mostly sinus bradycardia, occur in approximately 10 to 15 percent of patients [3,4,17,18,34,42]. By comparison, sinus node arrest and second or third degree heart block occur in 1 percent [4,42]. Heart failure Many patients treated with sotalol, particularly for ventricular arrhythmias, have underlying cardiac disease. Fortunately, impairment of myocardial contractility in patients treated with sotalol is less than might be expected with a beta blocker. Most patients have no significant decrease in left ventricular ejection fraction [3], and it has been estimated that clinically significant heart failure aggravation occurs in only 1.5 to 3 percent of patients [42,45,51]. The risk is greater in patients with a prior history of heart failure, particularly those with a baseline ejection fraction of <30 percent [4,5,42,46]. In the review of 3135 patients cited above, the incidence to torsades de pointes was much higher in patients with heart failure (5.0 versus 1.7 percent without heart failure) [46]. Because of the concern related to the safety of sotalol in patients with heart failure, amiodarone is generally preferred for the treatment of ventricular arrhythmias and for maintenance of sinus rhythm in atrial fibrillation when pharmacologic therapy is given. However, sotalol safely reduces the frequency of recurrent arrhythmia and appropriate shocks in patients with an implantable cardioverter-defibrillator (ICD) [34]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "The management of atrial fibrillation in patients with heart failure".) https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 10/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Contraindications Sotalol should not be used in patients with uncontrolled asthma, sinus bradycardia, Mobitz II second degree AV block and third degree AV block, congenital long QT syndrome, acquired long QT syndrome ( table 2), cardiogenic shock, or uncontrolled heart failure. In addition, it should be used with caution in patients with reduced renal function, since decreased clearance can result in drug accumulation and possible proarrhythmia [46]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Introduction Sotalol consists of a racemic mixture of d and l isomers in an approximate ratio of 1:1. The two isomers contribute to the unique antiarrhythmic properties of sotalol, with d isomer prolonging repolarization by blocking the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization of the action potential, while the l isomer both prolongs repolarization and has beta blocking activity. (See 'Electrophysiology and mechanism of action' above.) Mechanism The effect of sotalol on the action potential duration shows reverse use dependence, which is seen with other class III antiarrhythmic drugs, except for amiodarone. Reverse use dependence is defined as an inverse correlation between the heart rate and the QT interval. As a result, the QT interval is prolonged as the heart rate slows, with an associated risk of drug-induced torsades de pointes and a possible decrease in drug efficacy at higher heart rates. (See 'Class III activity' above.) Dosing Bradycardic and proarrhythmic events occur in up to 20 percent of patients after the initiation of sotalol therapy and with each upward dosing adjustment. As a result, sotalol should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. (See 'Dosing' above.) The recommended initial dose of oral sotalol in adults is 80 mg twice daily whether used for the treatment of ventricular arrhythmias or atrial fibrillation (AF). If necessary, the initial dose can be increased gradually to a total daily dose of 240 mg or 320 mg. Dose adjustments should be made at three day intervals so that steady-state plasma https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 11/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate concentrations can be attained and the QT interval monitored. The dosing interval requires modification in patients with impaired renal function and reduced creatinine clearance. (See 'Dosing' above.) Proarrhythmia Sotalol should not be given to patients with congenital or acquired long QT syndrome unless the cause can be reversed because of the risk of further QT interval prolongation and proarrhythmia, particularly torsades de pointes ( table 2). (See 'Proarrhythmia' above.) Clinical indications Oral sotalol is used for the treatment of ventricular arrhythmias (ie, sustained VT) that are potentially life-threatening and for the maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation and atrial flutter who are currently in sinus rhythm. (See 'Clinical indications' above.) Side effects Sotalol is generally well tolerated, being discontinued because of side effects in approximately 15 percent of patients. The major causes for intolerance are fatigue, bradycardia, dyspnea, proarrhythmia, dizziness and asthenia. (See 'Major side effects' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019865s021lbl.pdf. 2. Kato R, Ikeda N, Yabek SM, et al. Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics. J Am Coll Cardiol 1986; 7:116. 3. Hohnloser SH, Woosley RL. Sotalol. N Engl J Med 1994; 331:31. 4. Anderson JL, Prystowsky EN. Sotalol: An important new antiarrhythmic. Am Heart J 1999; 137:388. 5. Singh BN. Sotalol: Current Status and Expanding Indications. J Cardiovasc Pharmacol Ther 1999; 4:49. 6. Numaguchi H, Mullins FM, Johnson JP Jr, et al. Probing the interaction between inactivation gating and Dd-sotalol block of HERG. Circ Res 2000; 87:1012. 7. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 1990; 96:195. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 12/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate 8. Brodsky M, Saini R, Bellinger R, et al. Comparative effects of the combination of digoxin and dl-sotalol therapy versus digoxin monotherapy for control of ventricular response in chronic atrial fibrillation. dl-Sotalol Atrial Fibrillation Study Group. Am Heart J 1994; 127:572. 9. Nademanee K, Feld G, Hendrickson J, et al. Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias. Circulation 1985; 72:555. 10. Mitchell LB, Wyse DG, Duff HJ. Electropharmacology of sotalol in patients with Wolff- Parkinson-White syndrome. Circulation 1987; 76:810. 11. Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990; 81:686. 12. Anastasiou-Nana MI, Gilbert EM, Miller RH, et al. Usefulness of d, I sotalol for suppression of chronic ventricular arrhythmias. Am J Cardiol 1991; 67:511. 13. Creamer JE, Nathan AW, Shennan A, Camm AJ. Acute and chronic effects of sotalol and propranolol on ventricular repolarization using constant-rate pacing. Am J Cardiol 1986; 57:1092. 14. Touboul P, Atallah G, Kirkorian G, et al. Clinical electrophysiology of intravenous sotalol, a beta-blocking drug with class III antiarrhythmic properties. Am Heart J 1984; 107:888. 15. Wang T, Bergstrand RH, Thompson KA, et al. Concentration-dependent pharmacologic properties of sotalol. Am J Cardiol 1986; 57:1160. 16. Antonaccio MJ, Gomoll A. Pharmacology, pharmacodynamics and pharmacokinetics of sotalol. Am J Cardiol 1990; 65:12A. 17. Maisel WH, Kuntz KM, Reimold SC, et al. Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med 1997; 127:281. 18. Chung MK, Schweikert RA, Wilkoff BL, et al. Is hospital admission for initiation of antiarrhythmic therapy with sotalol for atrial arrhythmias required? Yield of in-hospital monitoring and prediction of risk for significant arrhythmia complications. J Am Coll Cardiol 1998; 32:169. 19. Kim RJ, Juriansz GJ, Jones DR, et al. Comparison of a standard versus accelerated dosing regimen for D,L-sotalol for the treatment of atrial and ventricular dysrhythmias. Pacing Clin Electrophysiol 2006; 29:1219. 20. Rizza C, Valderrabano M, Singh BN. Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease. J Cardiovasc Pharmacol Ther 1999; 4:129. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 13/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate 21. Reiffel JA, Appel G. Importance of QT interval determination and renal function assessment during antiarrhythmic drug therapy. J Cardiovasc Pharmacol Ther 2001; 6:111. 22. Sung RJ, Tan HL, Karagounis L, et al. Intravenous sotalol for the termination of supraventricular tachycardia and atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled study. Sotalol Multicenter Study Group. Am Heart J 1995; 129:739. 23. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL- sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568. 24. Reisinger J, Gatterer E, Heinze G, et al. Prospective comparison of flecainide versus sotalol for immediate cardioversion of atrial fibrillation. Am J Cardiol 1998; 81:1450. 25. Ho DS, Zecchin RP, Richards DA, et al. Double-blind trial of lignocaine versus sotalol for acute termination of spontaneous sustained ventricular tachycardia. Lancet 1994; 344:18. 26. Singh BN, Kehoe R, Woosley RL, et al. Multicenter trial of sotalol compared with procainamide in the suppression of inducible ventricular tachycardia: a double-blind, randomized parallel evaluation. Sotalol Multicenter Study Group. Am Heart J 1995; 129:87. 27. L vy S. Cardioversion of recent-onset atrial fibrillation using intravenous antiarrhythmics: A European perspective. J Cardiovasc Electrophysiol 2021; 32:3259. 28. Milan DJ, Saul JP, Somberg JC, Molnar J. Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis. Cardiology 2017; 136:52. 29. Kpaeyeh JA Jr, Wharton JM. Sotalol. Card Electrophysiol Clin 2016; 8:437. 30. Joseph AP, Ward MR. A prospective, randomized controlled trial comparing the efficacy and safety of sotalol, amiodarone, and digoxin for the reversion of new-onset atrial fibrillation. Ann Emerg Med 2000; 36:1. 31. Roden DM. Usefulness of sotalol for life-threatening ventricular arrhythmias. Am J Cardiol 1993; 72:51A. 32. Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993; 329:452. 33. Haverkamp W, Martinez-Rubio A, Hief C, et al. Efficacy and safety of d,l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997; 30:487. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 14/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate 34. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Engl J Med 1999; 340:1855. 35. Wichter T, Borggrefe M, Haverkamp W, et al. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia. Circulation 1992; 86:29. 36. Hohnloser SH, Meinertz T, Stubbs P, et al. Efficacy and safety of d-sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy. Results of a multicenter, randomized, double-blind, placebo-controlled dose-finding study. The d-Sotalol PVC Study Group. Circulation 1995; 92:1517. 37. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996; 348:7. 38. Ferreira E, Sunderji R, Gin K. Is oral sotalol effective in converting atrial fibrillation to sinus rhythm? Pharmacotherapy 1997; 17:1233. 39. Crystal E, Connolly SJ, Sleik K, et al. Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery: a meta-analysis. Circulation 2002; 106:75. 40. Kerin NZ, Jacob S. The efficacy of sotalol in preventing postoperative atrial fibrillation: a meta-analysis. Am J Med 2011; 124:875.e1. 41. Wharton JM, Piccini JP, Koren A, et al. Comparative Safety and Effectiveness of Sotalol Versus Dronedarone After Catheter Ablation for Atrial Fibrillation. J Am Heart Assoc 2022; 11:e020506. 42. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol 1990; 65:74A. 43. Multicentre randomized trial of sotalol vs amiodarone for chronic malignant ventricular

4. Anderson JL, Prystowsky EN. Sotalol: An important new antiarrhythmic. Am Heart J 1999; 137:388. 5. Singh BN. Sotalol: Current Status and Expanding Indications. J Cardiovasc Pharmacol Ther 1999; 4:49. 6. Numaguchi H, Mullins FM, Johnson JP Jr, et al. Probing the interaction between inactivation gating and Dd-sotalol block of HERG. Circ Res 2000; 87:1012. 7. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 1990; 96:195. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 12/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate 8. Brodsky M, Saini R, Bellinger R, et al. Comparative effects of the combination of digoxin and dl-sotalol therapy versus digoxin monotherapy for control of ventricular response in chronic atrial fibrillation. dl-Sotalol Atrial Fibrillation Study Group. Am Heart J 1994; 127:572. 9. Nademanee K, Feld G, Hendrickson J, et al. Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias. Circulation 1985; 72:555. 10. Mitchell LB, Wyse DG, Duff HJ. Electropharmacology of sotalol in patients with Wolff- Parkinson-White syndrome. Circulation 1987; 76:810. 11. Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990; 81:686. 12. Anastasiou-Nana MI, Gilbert EM, Miller RH, et al. Usefulness of d, I sotalol for suppression of chronic ventricular arrhythmias. Am J Cardiol 1991; 67:511. 13. Creamer JE, Nathan AW, Shennan A, Camm AJ. Acute and chronic effects of sotalol and propranolol on ventricular repolarization using constant-rate pacing. Am J Cardiol 1986; 57:1092. 14. Touboul P, Atallah G, Kirkorian G, et al. Clinical electrophysiology of intravenous sotalol, a beta-blocking drug with class III antiarrhythmic properties. Am Heart J 1984; 107:888. 15. Wang T, Bergstrand RH, Thompson KA, et al. Concentration-dependent pharmacologic properties of sotalol. Am J Cardiol 1986; 57:1160. 16. Antonaccio MJ, Gomoll A. Pharmacology, pharmacodynamics and pharmacokinetics of sotalol. Am J Cardiol 1990; 65:12A. 17. Maisel WH, Kuntz KM, Reimold SC, et al. Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med 1997; 127:281. 18. Chung MK, Schweikert RA, Wilkoff BL, et al. Is hospital admission for initiation of antiarrhythmic therapy with sotalol for atrial arrhythmias required? Yield of in-hospital monitoring and prediction of risk for significant arrhythmia complications. J Am Coll Cardiol 1998; 32:169. 19. Kim RJ, Juriansz GJ, Jones DR, et al. Comparison of a standard versus accelerated dosing regimen for D,L-sotalol for the treatment of atrial and ventricular dysrhythmias. Pacing Clin Electrophysiol 2006; 29:1219. 20. Rizza C, Valderrabano M, Singh BN. Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease. J Cardiovasc Pharmacol Ther 1999; 4:129. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 13/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate 21. Reiffel JA, Appel G. Importance of QT interval determination and renal function assessment during antiarrhythmic drug therapy. J Cardiovasc Pharmacol Ther 2001; 6:111. 22. Sung RJ, Tan HL, Karagounis L, et al. Intravenous sotalol for the termination of supraventricular tachycardia and atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled study. Sotalol Multicenter Study Group. Am Heart J 1995; 129:739. 23. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL- sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568. 24. Reisinger J, Gatterer E, Heinze G, et al. Prospective comparison of flecainide versus sotalol for immediate cardioversion of atrial fibrillation. Am J Cardiol 1998; 81:1450. 25. Ho DS, Zecchin RP, Richards DA, et al. Double-blind trial of lignocaine versus sotalol for acute termination of spontaneous sustained ventricular tachycardia. Lancet 1994; 344:18. 26. Singh BN, Kehoe R, Woosley RL, et al. Multicenter trial of sotalol compared with procainamide in the suppression of inducible ventricular tachycardia: a double-blind, randomized parallel evaluation. Sotalol Multicenter Study Group. Am Heart J 1995; 129:87. 27. L vy S. Cardioversion of recent-onset atrial fibrillation using intravenous antiarrhythmics: A European perspective. J Cardiovasc Electrophysiol 2021; 32:3259. 28. Milan DJ, Saul JP, Somberg JC, Molnar J. Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis. Cardiology 2017; 136:52. 29. Kpaeyeh JA Jr, Wharton JM. Sotalol. Card Electrophysiol Clin 2016; 8:437. 30. Joseph AP, Ward MR. A prospective, randomized controlled trial comparing the efficacy and safety of sotalol, amiodarone, and digoxin for the reversion of new-onset atrial fibrillation. Ann Emerg Med 2000; 36:1. 31. Roden DM. Usefulness of sotalol for life-threatening ventricular arrhythmias. Am J Cardiol 1993; 72:51A. 32. Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993; 329:452. 33. Haverkamp W, Martinez-Rubio A, Hief C, et al. Efficacy and safety of d,l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997; 30:487. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 14/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate 34. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Engl J Med 1999; 340:1855. 35. Wichter T, Borggrefe M, Haverkamp W, et al. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia. Circulation 1992; 86:29. 36. Hohnloser SH, Meinertz T, Stubbs P, et al. Efficacy and safety of d-sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy. Results of a multicenter, randomized, double-blind, placebo-controlled dose-finding study. The d-Sotalol PVC Study Group. Circulation 1995; 92:1517. 37. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996; 348:7. 38. Ferreira E, Sunderji R, Gin K. Is oral sotalol effective in converting atrial fibrillation to sinus rhythm? Pharmacotherapy 1997; 17:1233. 39. Crystal E, Connolly SJ, Sleik K, et al. Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery: a meta-analysis. Circulation 2002; 106:75. 40. Kerin NZ, Jacob S. The efficacy of sotalol in preventing postoperative atrial fibrillation: a meta-analysis. Am J Med 2011; 124:875.e1. 41. Wharton JM, Piccini JP, Koren A, et al. Comparative Safety and Effectiveness of Sotalol Versus Dronedarone After Catheter Ablation for Atrial Fibrillation. J Am Heart Assoc 2022; 11:e020506. 42. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol 1990; 65:74A. 43. Multicentre randomized trial of sotalol vs amiodarone for chronic malignant ventricular tachyarrhythmias. Amiodarone vs Sotalol Study Group. Eur Heart J 1989; 10:685. 44. Weeke P, Delaney J, Mosley JD, et al. QT variability during initial exposure to sotalol: experience based on a large electronic medical record. Europace 2013; 15:1791. 45. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003; 42:20. 46. Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996; 94:2535. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 15/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate 47. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270:2590. 48. Zeltser D, Justo D, Halkin A, et al. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine (Baltimore) 2003; 82:282. 49. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998; 97:2237. 50. Drici MD, Cl ment N. Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome. Drug Saf 2001; 24:575. 51. Kehoe RF, Zheutlin TA, Dunnington CS, et al. Safety and efficacy of sotalol in patients with drug-refractory sustained ventricular tachyarrhythmias. Am J Cardiol 1990; 65:58A. Topic 925 Version 33.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 16/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 17/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 18/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 19/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Myocardial action potential Representation of a ventricular action potential. There are 5 phases of the action potential beginning with phase 0, rapid depolarization by sodium influx. Phase 1 is a rapid repolarization via potassium efflux followed by phase 2 or the plateau phase. The plateau phase results from entry of calcium into the cell and potassium efflux. Phase 3 repolarization is dominated by potassium currents which polarize the cell and potassium inward rectifier maintains the resting potential or phase 4. See text for full description. Graphic 71390 Version 4.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 20/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or infarction, especially with prominent T-wave inversions GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders Starvation particularly hypokalemia and hypomagnesemia Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga (ibogaine), licorice extract in overuse via electrolyte disturbances Intracranial disease Hypothyroidism Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate insecticides AV block: Second or third degree Medications* High risk Adagrasib Cisaparide (restricted Lenvatinib Selpercatinib Ajmaline Levoketoconazole Sertindole availability) Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 21/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Certinib Escitalopram Levofloxacin (systemic) Risperidone Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole (systemic) Romidepsin Anagrelide Foscarnet Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- lumefantrine Glasdegib Mizolastine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine (rare reports) Nortriptyline Benperidol Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus (systemic) Olodaterol Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 22/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide overdose in Eliglustat Primaquine Vorinostat Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 073161.pdf with additional data from CredibleMeds QT drugs list [1,2] . The use of other classification criteria may lead to some agents being classified differently by other sources. Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 23/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 24/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Strategies for rhythm control in patients with paroxysmal* and persistent AF AF: atrial fibrillation; CAD: coronary artery disease; HF: heart failure; LVH: left ventricular hypertrophy; AV: atrioventricular. Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (Class IIa recommendation). Drugs are listed alphabetically. Depending on patient preference when performed in experienced centers. Not recommended with severe LVH (wall thickness >1.5 cm). Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. Should be combined with AV nodal blocking agents. Reproduced from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. DOI: 10.1016/j.jacc.2014.03.021. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 95079 Version 3.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 25/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 26/27 7/6/23, 2:48 PM Clinical uses of sotalol - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 27/27

7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Treatment : Peter J Schwartz, MD, Michael J Ackerman, MD, PhD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 02, 2022. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1]. The primary symptoms in patients with LQTS include syncope, seizures, sudden cardiac arrest (SCA), and SCD. This syndrome is associated with an increased risk of a characteristic life- threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" ( waveform 2) [2]. LQTS may be congenital or acquired [1,3-7]. Pathogenic variants in at least 17 genes have been identified thus far in patients with congenital LQTS. An estimated 75 to 80 percent of all congenital LQTS is accounted for by LQTS-causative variants in either KCNQ1-encoded Kv7.1 (LQT1), KCNH2-encoded Kv11.1 (LQT2), or SCN5A-encoded Nav1.5 (LQT3). The minor LQTS genotypes account for at most 5 percent of LQTS and are best referred to by their genetic cause rather than their numerical subtype (eg, CACNA1C-LQTS rather than LQT8) ( table 1) [7]. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2). The treatment of congenital LQTS will be reviewed here. The epidemiology, clinical manifestations, diagnosis, and genetics of congenital LQTS, as well as issues related to the management of acquired LQTS, are discussed separately. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Diagnosis" and https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 1/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate "Congenital long QT syndrome: Pathophysiology and genetics" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) TREATMENT Regardless of genotype, age, and previous symptomatic/asymptomatic status, all patients with congenital LQTS should be advised of simple QT preventive measures and implement them whenever possible. These include avoidance of medications with QT-prolonging potential ( www.crediblemeds.org); replacing electrolytes during vomiting and diarrheal illnesses, as both hypokalemia and hypomagnesemia can be QT aggravating; and lowering fever. Like the 2015 Heart Rhythm Society (HRS) guidelines, the 2017 American Heart Association/American College of Cardiology (AHA/ACC) guidelines continue to recommend universal beta-blocker therapy for all patients with congenital LQTS, whether asymptomatic or symptomatic, in the absence of a contraindication [8]. In the setting of breakthrough cardiac events while on beta-blocker therapy or in the setting of beta-blocker intolerance, patient- specific tailoring of therapy is appropriate, based on the assessed risk from the disease and the potential comorbidities of the various treatments under consideration with the patients and their families also involved in the shared decision making. Recommended options for treatment intensification may include one or more of the following: Other medications (such as mexiletine) Left cardiac sympathetic denervation (LCSD) Placement of a pacemaker to enable intentional atrial pacing Placement of an implantable cardioverter-defibrillator (ICD) The treatment of patients with congenital and acquired LQTS differs greatly because of pathophysiologic differences between the two forms. As an example, bradycardia is usually associated with torsades de pointes (TdP) in acquired LQTS, whereas catecholamine surges trigger TdP in congenital LQTS. The following discussion is limited to the treatment of congenital LQTS. The management of acquired LQTS is presented separately; it involves acute therapy of arrhythmia, discontinuation of any precipitating drug, and correction of any metabolic abnormalities such as hypokalemia or hypomagnesemia. The acute management of TdP is also discussed in detail elsewhere. (See "Overview of the acute management of tachyarrhythmias", section on 'Polymorphic ventricular tachycardia' and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 2/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Our approach to symptomatic patients Because of the appreciable risk of symptoms and SCD without treatment, all previously symptomatic patients with congenital LQTS should be treated [9,10]. Our general approach is as follows: All patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval ( www.crediblemeds.org) and the aggressive treatment of electrolyte imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Initial management'.) Athletes with LQTS who desire to remain athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. For all patients with congenital LQTS and a history of syncope or seizures, we recommend treatment with a beta blocker. We prefer propranolol or nadolol, given their superior efficacy in this patient population. All patients with congenital LQTS who present with resuscitated SCA should be treated with a beta blocker, preferably propranolol or nadolol, given their superior efficacy in this patient population. Additionally, for most patients with congenital LQTS who present with resuscitated SCA while previously undiagnosed and therefore untreated, the treatment program should also include an ICD as secondary prevention. Potential exceptions to this include patients with previously undiagnosed and therefore untreated LQT1. For patients with recurrent arrhythmic events in spite of maximally tolerated doses of a beta blocker, or for patients who discontinue beta blockers due to intolerable side effects, treatment intensification with either concomitant drug therapy, LCSD, and/or an ICD is recommended depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). The risks and benefits of each treatment intensification option need to be reviewed with the patient and shared decision making should be utilized to decide upon and implement the chosen therapeutic strategy. Physical activity and LQTS Before tailoring any LQTS-specific therapies or recommending activity modification, it is vital to confirm the diagnosis of LQTS. Athletes are often flagged for the possibility of LQTS based on their pre-sports participation ECG screen. While a subsequent evaluation is necessary and appropriate, studies show that exercise can elicit a maladaptive remodeling in the repolarization reserve, yielding an acquired, reversible form of QT https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 3/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate prolongation rather than congenital LQTS itself [11]. If such an athlete's genetic test is negative and if their QT normalizes after detraining, they should not be classified as having LQTS or restricted from activity [11]. After establishing the correct diagnosis of LQTS and implementing the initial treatment program, patients with LQTS can continue to be recreationally active, especially those with LQT2 and LQT3. In general, children and adolescents can resume participation in physical education classes and adults should be encouraged to stay aerobically active in accordance with national/international recommendations on active living. Athletes with LQTS who desire to remain competitive athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. There is a divergence of opinions on competitive athletics for individuals with congenital LQTS [12-15]. The 2015 AHA/ACC Scientific Statement on Eligibility and Disqualification Recommendations for Competitive Athletes discusses participation in competitive events and training sessions as allowable and dependent on the existence of an emergency action plan with an automated external defibrillator (AED) immediately available on site. However, a different approach is dictated by the previous European guidelines, which advise precautionary restriction from competitive sports in these instances. The differences in the American and European approaches are outlined as follows: The following approach is proposed in the 2015 AHA/ACC Scientific Statement [12,13]: Asymptomatic persons who are genotype positive/phenotype negative (ie, with normal QTc at rest) can reasonably participate in all competitive sports with appropriate safety precautions, including avoidance of drugs known to exacerbate LQTS; avoidance and/or treatment of fever, hyperthermia, or heat exhaustion/heat stroke; electrolyte repletion; avoidance of dehydration; and establishment of an emergency action plan with an AED immediately available. Symptomatic (or previously symptomatic) patients, or patients with LQTS (QTc >470 milliseconds in males or >480 milliseconds in females), may consider participation in competitive athletics (with the exception of swimming in patients with LQT1 genotype) if they remain asymptomatic after three months of treatment and with appropriate cautionary measures, including an emergency action plan with an AED immediately available. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 4/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate For patients with LQTS and an ICD who have had three or more months without ICD therapy, participation in class IA sports ( figure 1) may be reasonable. Experts disagree on participation in higher levels of sport for patients with an ICD in place. Some experts feel that participation in sports with higher levels of exertion might be considered following counselling of the patient of the potential risks and appropriate cautionary measures, including an emergency action plan to implement should arrhythmias arise. However, other experts disagree and feel it is unwise to expose patients to the risk of ventricular arrhythmias and multiple shocks just to perform a competitive sport. A different approach was stated in the previous European guidelines, which advise precautionary restriction from essentially all competitive sports, based in part on the considerations that the safety measures recommended by the 2015 AHA/ACC guidelines (ie, training and competing in places where an AED is available) are not always feasible in the real world [14]. In a single-center retrospective cohort study of nearly 500 patients with LQTS who were managed with a return-to-play protocol and shared decision-making, the rates of breakthrough cardiac events (ie, seizures, syncope, cardiac arrest) among patients who returned to competitive sport were low [16]. In 494 self-identified athletes who returned to play (mean age 14.8 10.8 years), during follow-up for 4.2 4.8 years, there were no sports-related deaths; 29 patients (5.9 percent) had nonlethal LQTS-associated breakthrough cardiac events, only three (0.6 percent) of which occurred during exercise. Gene-specific management There is an association between genotype and triggers of arrhythmia ( figure 2) [17-20]. In particular: Patients with LQT1 primarily have exercise-related arrhythmic events; in a review that included 371 patients with LQT1, exercise was the trigger in 62 percent of arrhythmic events [17]. In addition, events related to swimming (occurring either immediately after diving into water or during recreational or competitive swimming activities) may be specific for LQT1 [19,21,22]. The sensitivity of patients with LQT1 to exercise may be related to exaggerated prolongation of the QT interval during exercise [23]. Events triggered by auditory stimuli, such as an alarm clock or telephone ringing, are most typically seen in LQT2 [18,19]. Acute arousal events (such as exercise, emotion, or noise) are much more likely triggers in LQT1 and LQT2 than LQT3 (85 and 67 versus 33 percent in one report) [17,20]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 5/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Patients with LQT3 are at highest risk of events when at rest or asleep, while the risk is low during sleep in LQT1, accounting for only 3 percent of events [17]. Patients with LQT3 may have fewer events with exercise or stress because they significantly shorten their QTc with tachycardia [24] and therefore become less susceptible to catecholamine-induced arrhythmias. (See 'Beta blockers' below.) Initial therapy Beta blockers For all patients with congenital LQTS and a history of syncope, seizures, or resuscitated SCA, we recommend treatment with a beta blocker [8]. In general, we suggest propranolol or nadolol, given their superior efficacy in this patient population. The use of atenolol and metoprolol has been associated with an increased rate of recurrences [25]. In addition, if the symptom was resuscitated SCA, then an ICD as secondary prevention is indicated as well in most circumstances. (See 'Implantable cardioverter-defibrillator' below.) Beta blockers are a mainstay of therapy in both asymptomatic and symptomatic patients with congenital LQTS since they reduce both syncope and SCD [8]. Because of extensive observational data and expert consensus on the efficacy of beta blockers in this population, it is widely felt to be unethical to randomize patients to placebo, such that a randomized controlled trial in this population is unlikely. The overall benefit of beta-blocker therapy in congenital LQTS has been demonstrated in a number of observational studies, with many of the patients recruited from the International LQTS Registry [17,26-30]. In a series of 869 registry patients treated with a beta blocker, in whom clinical event rates for the five-year periods before and after beta-blocker therapy were compared, treatment with beta blockers reduced the rate of cardiac events (eg, syncope, aborted cardiac arrest, or SCD) in probands (0.31 events per patient per year on therapy versus 0.97 events per patient per year off therapy) and in affected family members [27]. Despite this benefit, 32 percent of patients with syncope or aborted SCA before beta-blocker therapy had another cardiac event during the five-year period while on a beta blocker (hazard ratio 5.8 compared with asymptomatic patients before therapy, 95% CI 3.7-9.1). Nearly one-half of these events occurred within the first six months of therapy ( figure 3). The importance of compliance with beta-blocker therapy in LQT1 was highlighted in a retrospective study of 216 genotyped patients followed for a median time of 10 years [31]. Among the 12 patients who suffered SCA or SCD after beta blockers were prescribed, 11 were either noncompliant with beta-blocker therapy and/or on a potentially contraindicated QT- prolonging drug. The only death in a beta-blocker-compliant patient not on a QT-prolonging drug occurred in a patient with Jervell and Lange-Nielsen syndrome, which is a more malignant form of LQT1. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Congenital sensorineural deafness'.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 6/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Differences among various beta blockers Propranolol (either given three times per day or extended-release formulations for improved compliance) and/or nadolol are the preferred beta blockers for therapy of LQTS, particularly for patients with LQT1 or LQT2. Because various beta blockers differ in their pharmacologic properties (eg, beta-1 selectivity, lipophilicity, half-life, etc), there appear to be differences in the efficacy of beta blockers on QT shortening and clinical outcomes. In a retrospective cohort study of 382 patients (56 percent female, median age 14 years) with LQT1 or LQT2 who were treated with propranolol (134 patients), metoprolol (147 patients), or nadolol (101 patients) and followed for up to eight years, the following findings were noted [25]: Patients receiving propranolol had more significant QTc shortening (27 versus 14 versus 12 milliseconds with metoprolol and nadolol, respectively). Patients receiving metoprolol had significantly more breakthrough clinical events (eg, syncope, aborted cardiac arrest, ICD shock, or SCD) compared with those receiving propranolol or nadolol (29 versus 8 versus 7 percent, respectively; odds ratio 3.9, 95% CI 1.2-13.1 for metoprolol versus any other beta blocker). Effect of genotype Patients with LQT1 derive the greatest benefit, but beta-blocker therapy is also very effective for both LQT2 and LQT3 patients [32]. The three genotypes (LQT1, LQT2, and LQT3) account for over 90 percent of known mutations in congenital LQTS [33]. The clinical efficacy of beta blockers in relation to these genotype has been examined in several observational studies. [17,27,28] LQT1 Beta blockers have relatively increased efficacy in LQT1 versus LQT3. This is probably related to the sympathetic sensitivity in this disorder. Most humans with LQT1 show paradoxical prolongation of the QT interval after an infusion of catecholamine, such as epinephrine or isoproterenol. The epinephrine QT stress test was used in the past to unmask patients with concealed LQT1 [34,35]. However, the test is subject to a large amount of interpretation error. Thus, genetic testing for LQTS has largely replaced the epinephrine QT stress test. LQT3 There is reduced efficacy of beta blockers in LQT3 compared with LQT1. Unlike patients with LQT1, patients with LQT3 shorten their QT interval with tachycardia [24], making them less susceptible to catecholamine-induced arrhythmias. This could explain the comparatively reduced efficacy of beta blockers in LQT3 versus LQT1 and the lower rate of events triggered by exercise or stress in patients with the LQT3 subtype ( figure 2) [17,27]. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 1 LQTS (LQT1)'.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 7/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate There is some evidence that females with LQT3 may have greater benefit from beta blockers compared with men, although current data are insufficient to draw definite conclusions. In a multicenter registry study, 391 LQT3 patients (aged 1 to 41 years) were followed for development of a first cardiac events or CE (syncope, aborted cardiac arrest, or long-QT- syndrome-related sudden death). Of these, 118 (77 females) patients experienced at least 1 CE, and 24 patients had LQT3-related aborted cardiac arrest/sudden death. Time-dependent beta-blocker therapy was associated with an 83 percent reduction in CEs in females but not in males (who had many fewer events). Efficacy in males could not be determined conclusively because of the low number of events. Oral contraceptive pills in females One observational study of 1600 females suggested that use of progestin-only oral contraceptive pills (OCPs) was associated with increased cardiac events in women not taking beta-blockers [36]. Use of progestin-only OCPs was associated with the highest burden of cardiac events per 100 patient-years: 14.1 for progestin only, 6.2 in estrogen-only, 7.5 for combined, and 7 events in the no-OCP group. In contrast, in women who were treated with beta blockers, progestin-only OCP use was associated with fewer cardiac events (4.5 events per 100 patient years). Possible misclassification of OCP type and non-randomized design limit our ability to draw firm conclusions from this analysis. Subsequent therapies For patients with recurrent arrhythmic events in spite of maximally tolerated doses of a beta blocker or in the setting of unacceptable beta-blocker-associated side effects, treatment intensification is pursued with either concomitant drug therapy, LCSD, and/or an ICD depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). Treatment intensification for patients with recurrent arrhythmic events should ideally take place in a center with expertise in the management of congenital LQTS, or for patients without access to an expert center, in consultation with a specialist with expertise in congenital LQTS. Other pharmacologic therapies There is a role for select other pharmacologic therapies targeted to specific subsets of congenital LQTS patients. Potassium and/or spironolactone Routine potassium supplementation/replacement and/or use of potassium-retaining medications like spironolactone is not generally indicated. However, for patients with malignant LQTS who continue to receive appropriate ICD shocks or who have a high-risk phenotype but prefer to avoid an ICD, potassium retention strategies are implemented, regardless of the underlying LQTS genotype. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 8/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Mexiletine For patients with LQT3, mexiletine pharmacotherapy is not only QT- attenuating but also confers a significant protective effect. Increasingly, combination therapy with propranolol and mexiletine is utilized in patients with LQT3. Targeted dosing for mexiletine is generally 4 to 6 mg/kg/dose administered approximately every eight hours. Mexiletine trough levels can be obtained. Both mexiletine and propranolol are metabolized via cytochrome P4502D6 (CYP2D6) and approximately 10 percent of the White populations are either poor metabolizers of 2D6 substrates like mexiletine or are ultra-rapid metabolizers. CYP2D6 genotype status can be obtained to help guide dosing strategy. Although blocking the LQT3-associated accentuation of the late sodium current with mexiletine makes sense, in our authors experience, a significant QTc attenuation effect has also been seen in patients with other LQTS genotypes, particularly LQT2. As such, for patients with higher-risk LQT2, combination drug therapy with a beta blocker and mexiletine can be considered as well [37]. Left cardiac sympathetic denervation LCSD is an effective therapy in patients with congenital LQTS and persistent arrhythmias on beta blockers as well as in those who cannot tolerate beta blockers [8,38-41]. While LCSD produces significant reductions in the number of subsequent cardiac events per patient overall, postdenervation recurrences can occur especially when the predenervation expressivity was malignant and extreme [42]. However, in most patients, LCSD offers an additional risk reduction prior to considering an ICD, although it does not preclude ICD placement in appropriate high-risk patients. LCSD interrupts the major source of norepinephrine released in the heart via preganglionic denervation [43]. Since denervation is preganglionic, there is no reinnervation. The procedure does not completely eliminate catecholamines in the ventricles, and it does not lead to post- denervation supersensitivity to catecholamines [44]. LCSD is similarly effective across genotypes, when infants with events in the first year of life are not considered [45-47]. LCSD is similarly effective in LQT1 and LQT2 patients [41]. Implantable cardioverter-defibrillator ICDs are an important component of therapy for patients with congenital LQTS, particularly among patients who present with resuscitated SCA or those who have recurrent major events [48-51]. However, complications, including infection, lead fracture and dislodgement, inappropriate discharges, and psychiatric sequelae, are not uncommon with ICDs (25 percent within five years) [52]. For these reasons, it is not appropriate to consider ICDs in all patients with congenital LQTS. In fact, most patients with LQTS (90 percent or more in LQTS expert centers) do not need and should not receive an ICD just because they have been diagnosed with LQTS in general or even LQT3 in particular (where highest ICD implant https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 9/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate rates have been noted). Instead, our approach to the utilization of ICDs in this population is as follows [8]: We recommend an ICD in most patients whose initial presentation was SCA and in whom a reversible cause is not identified. We recommend an ICD in patients with LQTS-associated SCA while compliant with beta- blocker therapy. If an ICD was chosen instead of additional medications or LCSD following this on-therapy SCA, then LCSD therapy is often kept as a subsequent treatment option if an appropriate ICD shock occurs. Although we generally recommend an ICD for patients with resuscitated SCA occurring prior to diagnosis of and treatment for their LQTS, it may be possible to assemble a non- ICD treatment program for some of these patients. However, this should be considered only in LQTS specialty centers because guidelines essentially recommend an ICD for any LQTS patient (diagnosed or previously undiagnosed) who experiences SCA [8,12,13]. For example, one potential exception to this in our practices are patients with a sentinel event of SCA with previously undiagnosed and therefore untreated LQT1 substrate. For such LQT1 patients who are trying to avoid an ICD if at all possible, we have configured beta- blocker therapy plus LCSD as part of their initial treatment program. We suggest an ICD for patients with recurrent cardiac syncope in spite of beta blockers and LCSD, or for patients with recurrent cardiac syncope while taking beta blockers in whom LCSD is not an option. Importantly, an ICD is never indicated based solely on the family history. A family history of LQTS-associated SCD is not a personal risk factor for the patient with LQTS. Overall, most patients with LQTS do not need and should not receive an ICD. The vast majority of LQTS patients can be treated effectively without an ICD. Combined, among all of the patients with LQTS that are evaluated, risk stratified, and treated at expert LQTS centers, approximately 3 to 10 percent of them have an ICD [47]. Cardiac pacing Cardiac pacing is seldom utilized in isolation when treating patients with LQTS. For the patient with an indication for an ICD, a single-lead system is generally advised. If the patient then goes on to experience an appropriate ventricular fibrillation (VF)-terminating ICD shock where a bradycardia or long-short-long pause mechanism is documented, an upgrade to the device to include atrial pacing is sometimes performed. In our experience, the therapeutic role of atrial pacing, with an intentional lower rate limit of 80 beats per minute, may be best realized in women with LQT2 [53]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 10/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Our approach to asymptomatic patients Asymptomatic patients with congenital LQTS have different levels of risk for experiencing an LQTS-associated sentinel event, and it can be difficult to identify patients who will become symptomatic. Our general approach to asymptomatic patients with congenital LQTS is as follows: As with symptomatic patients, asymptomatic patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval and the aggressive treatment of electrolyte imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). As with symptomatic patients, the 2015 AHA/ACC Scientific Statement supports continuation of competitive sports in asymptomatic patients with LQTS with appropriate cautionary measures, including an AED safety plan, while the European guidelines remain more restrictive. Some disagreement among experts persists, however. (See 'Physical activity and LQTS' above.) For most asymptomatic patients with congenital LQTS, we suggest treatment with a beta blocker [1]. In general, we prefer propranolol or nadolol. However, for asymptomatic patients with a QTc <470 milliseconds, beta-blocker therapy may not always be required. Accordingly, there may be times when the risk-benefit calculus clearly favors intentional non-therapy with implementation of only the aforementioned preventative measures. As one example, beta-blocker therapy may not be necessary in the asymptomatic 55-year-old male with LQT1 and a resting QTc <440 milliseconds. For asymptomatic patients who wish to follow preventative measures only and intentionally forego beta-blocker therapy, an evaluation with an LQTS specialist may be beneficial to best assess the potential for a sentinel event and the comfort/confidence with intentional non-therapy [54]. (See 'Beta blockers' above.) In asymptomatic patients with either LQT2 or LQT3 whose resting QTc is >550 milliseconds or postpubertal women with LQT2, a prophylactic LCSD at a lower QTc threshold (QTc >500 milliseconds) is reasonable. These profiles in asymptomatic patients may warrant more aggressive surgical or device-related interventions. However, if the addition of QT-shortening therapies like mexiletine produced a now-on- therapy baseline QTc <500 ms, we continue with pharmacotherapy alone, or add additional anti-fibrillatory protection with LCSD (rather than adding a prophylactic ICD) [37,45,55]. Patients with high-risk genetic mutations such as those in the KCNQ1 S6 region require closer and more aggressive therapy to prevent SCA/SCD [56]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 11/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the ECG ( waveform 1). LQTS can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD). (See 'Introduction' above.) Symptomatic patients Our general approach to treatment of symptomatic (or previously symptomatic) patients with congenital LQTS is as follows: General measures All patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval ( www.crediblemeds.org) and the aggressive treatment of electrolyte https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 12/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). (See 'Our approach to symptomatic patients' above.) Activity After establishing the correct diagnosis of LQTS and implementing the initial treatment program, patients with LQTS can continue to be recreationally active, especially those with LQT2 and LQT3. Athletes with LQTS who desire to remain athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. (See 'Physical activity and LQTS' above.) Asymptomatic persons who are genotype positive/phenotype negative (ie, with normal QTc at rest) can reasonably participate in all competitive sports with appropriate safety precautions. Symptomatic (or previously symptomatic) patients, or patients with LQTS (QTc >470 milliseconds in males or >480 milliseconds in females) may consider participation in competitive athletics (with the possible exception of swimming in patients with LQT1 genotype) if they remain asymptomatic after three months of treatment and with appropriate cautionary measures, including an emergency action plan with an automated external defibrillator immediately available. Local laws and regulations may apply. Experts disagree on participation in higher levels of sport for patients with an implantable cardioverter-defibrillator (ICD) in place, with some experts allowing participation following counselling of the patient of potential risks and appropriate cautionary measures, while other experts feel it is unwise to expose patients to the risk of ventricular arrhythmias and multiple shocks just to perform a competitive sport. Beta blockers For all patients with congenital LQTS and a history of syncope or seizures, we recommend treatment with a beta blocker (Grade 1B). We suggest propranolol or nadolol, given their superior efficacy in this patient population (Grade 2C). (See 'Beta blockers' above.) Implantable cardiac defibrillator Patients with LQTS-associated sudden cardiac arrest (SCA), while compliant with beta-blocker therapy, should generally receive an ICD. Importantly, self-limiting syncope/seizures, even if assessed to be LQTS-triggered (ie, secondary to TdP) are not equivalent to SCA. (See 'Implantable cardioverter-defibrillator' https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 13/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Treatment intensification For patients with recurrent, LQTS-triggered arrhythmic events in spite of maximally tolerated doses of a beta blocker, or for patients who discontinue beta blockers due to intolerable side effects, treatment intensification is pursued with either concomitant drug therapy, left cardiac sympathetic denervation, and/or an ICD depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). Treatment intensification for patients with recurrent arrhythmic events should ideally take place in a center with expertise in the management of congenital LQTS, or for patients without access to an expert center, in consultation with a specialist with expertise in congenital LQTS. (See 'Subsequent therapies' above.) Asymptomatic patients Our general approach to treatment of asymptomatic patients with congenital LQTS is as follows (see 'Our approach to asymptomatic patients' above): For most asymptomatic patients with congenital LQTS, we suggest a beta blocker (Grade 2C). In general, the choice of a beta blocker is the same as in symptomatic patients (ie, propranolol or nadolol). However, for asymptomatic patients with a QTc <470 milliseconds, beta-blocker therapy may not be required. If an asymptomatic patient with either LQT2 or LQT3 maintains a QTc >550 ms while on pharmacotherapy, we suggest either a prophylactic left cardiac sympathetic denervation (LCSD) or a prophylactic ICD (Grade 2C). For postpubertal women with LQT2, either prophylactic LCSD or a prophylactic ICD at a lower QTc threshold (QTc >500 milliseconds) is reasonable again if pharmacotherapy (namely mexiletine) has not attenuated the QTc to <500 ms. Importantly, an ICD is never indicated based solely on a family history of LQTS-associated SCD, as family history is not a personal risk factor for the patient. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 14/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate 3. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 4. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 5. Camm AJ, Janse MJ, Roden DM, et al. Congenital and acquired long QT syndrome. Eur Heart J 2000; 21:1232. 6. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 7. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. 8. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 9. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical

th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the ECG ( waveform 1). LQTS can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD). (See 'Introduction' above.) Symptomatic patients Our general approach to treatment of symptomatic (or previously symptomatic) patients with congenital LQTS is as follows: General measures All patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval ( www.crediblemeds.org) and the aggressive treatment of electrolyte https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 12/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). (See 'Our approach to symptomatic patients' above.) Activity After establishing the correct diagnosis of LQTS and implementing the initial treatment program, patients with LQTS can continue to be recreationally active, especially those with LQT2 and LQT3. Athletes with LQTS who desire to remain athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. (See 'Physical activity and LQTS' above.) Asymptomatic persons who are genotype positive/phenotype negative (ie, with normal QTc at rest) can reasonably participate in all competitive sports with appropriate safety precautions. Symptomatic (or previously symptomatic) patients, or patients with LQTS (QTc >470 milliseconds in males or >480 milliseconds in females) may consider participation in competitive athletics (with the possible exception of swimming in patients with LQT1 genotype) if they remain asymptomatic after three months of treatment and with appropriate cautionary measures, including an emergency action plan with an automated external defibrillator immediately available. Local laws and regulations may apply. Experts disagree on participation in higher levels of sport for patients with an implantable cardioverter-defibrillator (ICD) in place, with some experts allowing participation following counselling of the patient of potential risks and appropriate cautionary measures, while other experts feel it is unwise to expose patients to the risk of ventricular arrhythmias and multiple shocks just to perform a competitive sport. Beta blockers For all patients with congenital LQTS and a history of syncope or seizures, we recommend treatment with a beta blocker (Grade 1B). We suggest propranolol or nadolol, given their superior efficacy in this patient population (Grade 2C). (See 'Beta blockers' above.) Implantable cardiac defibrillator Patients with LQTS-associated sudden cardiac arrest (SCA), while compliant with beta-blocker therapy, should generally receive an ICD. Importantly, self-limiting syncope/seizures, even if assessed to be LQTS-triggered (ie, secondary to TdP) are not equivalent to SCA. (See 'Implantable cardioverter-defibrillator' https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 13/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Treatment intensification For patients with recurrent, LQTS-triggered arrhythmic events in spite of maximally tolerated doses of a beta blocker, or for patients who discontinue beta blockers due to intolerable side effects, treatment intensification is pursued with either concomitant drug therapy, left cardiac sympathetic denervation, and/or an ICD depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). Treatment intensification for patients with recurrent arrhythmic events should ideally take place in a center with expertise in the management of congenital LQTS, or for patients without access to an expert center, in consultation with a specialist with expertise in congenital LQTS. (See 'Subsequent therapies' above.) Asymptomatic patients Our general approach to treatment of asymptomatic patients with congenital LQTS is as follows (see 'Our approach to asymptomatic patients' above): For most asymptomatic patients with congenital LQTS, we suggest a beta blocker (Grade 2C). In general, the choice of a beta blocker is the same as in symptomatic patients (ie, propranolol or nadolol). However, for asymptomatic patients with a QTc <470 milliseconds, beta-blocker therapy may not be required. If an asymptomatic patient with either LQT2 or LQT3 maintains a QTc >550 ms while on pharmacotherapy, we suggest either a prophylactic left cardiac sympathetic denervation (LCSD) or a prophylactic ICD (Grade 2C). For postpubertal women with LQT2, either prophylactic LCSD or a prophylactic ICD at a lower QTc threshold (QTc >500 milliseconds) is reasonable again if pharmacotherapy (namely mexiletine) has not attenuated the QTc to <500 ms. Importantly, an ICD is never indicated based solely on a family history of LQTS-associated SCD, as family history is not a personal risk factor for the patient. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 14/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate 3. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 4. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 5. Camm AJ, Janse MJ, Roden DM, et al. Congenital and acquired long QT syndrome. Eur Heart J 2000; 21:1232. 6. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 7. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. 8. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 9. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998; 97:2237. 10. Zareba W, Moss AJ, Schwartz PJ, et al. Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med 1998; 339:960. 11. Dagradi F, Spazzolini C, Castelletti S, et al. Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome. Circulation 2020; 142:2405. 12. Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 10: The Cardiac Channelopathies: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2424. 13. Zipes DP, Link MS, Ackerman MJ, et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 9: Arrhythmias and Conduction Defects: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2412. 14. Pelliccia A, Fagard R, Bj rnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 15/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005; 26:1422. 15. Turkowski KL, Bos JM, Ackerman NC, et al. Return-to-Play for Athletes With Genetic Heart Diseases. Circulation 2018; 137:1086. 16. Tobert KE, Bos JM, Garmany R, Ackerman MJ. Return-to-Play for Athletes With Long QT Syndrome or Genetic Heart Diseases Predisposing to Sudden Death. J Am Coll Cardiol 2021; 78:594. 17. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103:89. 18. Wilde AA, Jongbloed RJ, Doevendans PA, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999; 33:327. 19. Moss AJ, Robinson JL, Gessman L, et al. Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol 1999; 84:876. 20. Ali RH, Zareba W, Moss AJ, et al. Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome. Am J Cardiol 2000; 85:457. 21. Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc 1999; 74:1088. 22. Batra AS, Silka MJ. Mechanism of sudden cardiac arrest while swimming in a child with the prolonged QT syndrome. J Pediatr 2002; 141:283. 23. Takenaka K, Ai T, Shimizu W, et al. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation 2003; 107:838. 24. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation 1995; 92:3381. 25. Chockalingam P, Crotti L, Girardengo G, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol 2012; 60:2092. 26. Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol 2007; 49:329. 27. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 2000; 101:616. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 16/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate 28. Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004; 292:1341. 29. Hobbs JB, Peterson DR, Moss AJ, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA 2006; 296:1249. 30. Goldenberg I, Moss AJ, Peterson DR, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 2008; 117:2184. 31. Vincent GM, Schwartz PJ, Denjoy I, et al. High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta- blocker treatment "failures". Circulation 2009; 119:215. 32. Wilde AA, Moss AJ, Kaufman ES, et al. Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. Circulation 2016; 134:872. 33. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102:1178. 34. Ackerman MJ, Khositseth A, Tester DJ, et al. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc 2002; 77:413. 35. Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol 2003; 41:633. 36. Goldenberg I, Younis A, Huang DT, et al. Use of oral contraceptives in women with congenital long QT syndrome. Heart Rhythm 2022; 19:41. 37. Bos JM, Crotti L, Rohatgi RK, et al. Mexiletine Shortens the QT Interval in Patients With Potassium Channel-Mediated Type 2 Long QT Syndrome. Circ Arrhythm Electrophysiol 2019; 12:e007280. 38. Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 2004; 109:1826. 39. Collura CA, Johnson JN, Moir C, Ackerman MJ. Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery. Heart Rhythm 2009; 6:752. 40. Schwartz PJ. 1970-2020: 50 years of research on the long QT syndrome-from almost zero knowledge to precision medicine. Eur Heart J 2021; 42:1063. 41. Dusi V, Pugliese L, De Ferrari GM, et al. Left Cardiac Sympathetic Denervation for the Long QT Syndrome. 50 Years experience provides guidance for management. JACC Clin https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 17/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Electrophysiol 2021. 42. Bos JM, Bos KM, Johnson JN, et al. Left cardiac sympathetic denervation in long QT syndrome: analysis of therapeutic nonresponders. Circ Arrhythm Electrophysiol 2013; 6:705. 43. Schwartz PJ. The rationale and the role of left stellectomy for the prevention of malignant arrhythmias. Ann N Y Acad Sci 1984; 427:199. 44. Schwartz PJ, Stone HL. Left stellectomy and denervation supersensitivity in conscious dogs. Am J Cardiol 1982; 49:1185. 45. Dusi V, Pugliese L, De Ferrari GM, et al. Left Cardiac Sympathetic Denervation for Long QT Syndrome: 50 Years' Experience Provides Guidance for Management. JACC Clin Electrophysiol 2022; 8:281. 46. Schwartz PJ, Snebold NG, Brown AM. Effects of unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold. Am J Cardiol 1976; 37:1034. 47. Schwartz PJ, Ackerman MJ. Cardiac sympathetic denervation in the prevention of genetically mediated life-threatening ventricular arrhythmias. Eur Heart J 2022; 43:2096. 48. Wedekind H, Burde D, Zumhagen S, et al. QT interval prolongation and risk for cardiac events in genotyped LQTS-index children. Eur J Pediatr 2009; 168:1107. 49. Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol 2003; 14:337. 50. Etheridge SP, Sanatani S, Cohen MI, et al. Long QT syndrome in children in the era of implantable defibrillators. J Am Coll Cardiol 2007; 50:1335. 51. Proclemer A, Ghidina M, Facchin D, et al. Use of implantable cardioverter-defibrillator in inherited arrhythmogenic diseases: data from Italian ICD Registry for the years 2001-6. Pacing Clin Electrophysiol 2009; 32:434. 52. Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation 2010; 122:1272. 53. Kowlgi GN, Giudicessi JR, Barake W, et al. Efficacy of intentional permanent atrial pacing in the long-term management of congenital long QT syndrome. J Cardiovasc Electrophysiol 2021; 32:782. 54. MacIntyre CJ, Rohatgi RK, Sugrue AM, et al. Intentional nontherapy in long QT syndrome. Heart Rhythm 2020; 17:1147. 55. Mazzanti A, Maragna R, Faragli A, et al. Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3. J Am Coll Cardiol 2016; https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 18/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate 67:1053. 56. Schwartz PJ, Moreno C, Kotta MC, et al. Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. Eur Heart J 2021; 42:4743. Topic 988 Version 32.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 19/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate GRAPHICS Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 20/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 21/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Summary of heritable arrhythmia syndrome susceptibility genes: Long QT syndrome (LQTS) Gene Locus Protein Major LQTS genes KCNQ1 (LQT1) 11p15.5 I Ks Kv7.1) potassium channel alpha subunit (KVLQT1, KCNH2 (LQT2) 7q35-36 I Kr Kv11.1) potassium channel alpha subunit (HERG, SCN5A (LQT3) 3p21-p24 Cardiac sodium channel alpha subunit (NaV1.5) Minor LQTS genes AKAP9 7q21-q22 Yotiao CACNA1C 12p13.3 Voltage gated L-type calcium channel (CaV1.2) CALM1 14q32.11 Calmodulin 1 CALM2 2p21 Calmodulin 2 CALM3 19q13.2-q13.3 Calmodulin 3 CAV3 3p25 Caveolin-3 KCNE1 21q22.1 Potassium channel beta subunit (MinK) KCNE2 21q22.1 Potassium channel beta subunit (MiRP1) KCNJ5 11q24.3 Kir3.4 subunit of I channel KACH SCN4B 11q23.3 Sodium channel beta 4 subunit SNTA1 20q11.2 Syntrophin-alpha 1 TRDN 6q22.31 Triadin Adapted from: Tester DJ, Ackerman MJ. Genetics of cardiac arrhythmias. In: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10th ed, Mann DL, Zipes DP, Libby P, et al (Eds), Elsevier, Philadelphia 2015. Graphic 114927 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 22/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or infarction, GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders especially with prominent T-wave Starvation particularly hypokalemia and hypomagnesemia Anorexia nervosa Herbs inversions Liquid protein diets Cinchona (contains quinine), iboga Intracranial Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances disease Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine (intracoronary) Vandetanib Dofetilide Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 23/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine antimoniate Clarithromycin Flecainide Sparfloxacin Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil (systemic) Terbutaline Nilotinib Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate Dasatinib Vemurafenib oral) dimeglumine Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine (rare reports) Nortriptyline Benperidol Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 24/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- Periciazine Tropisetron norethindrone Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 25/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 26/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Classification of sports based on peak static and dynamic components during competition This classification is based on peak static and dynamic components achieved during competition; however, higher values may be reached during training. The increasing dynamic component is defined in terms of the estimated percentage of maximal oxygen uptake (VO max) achieved and results in an increasing cardiac output. The increasing static component is related to the estimated percentage of maximal 2 voluntary contraction reached and results in an increasing blood pressure load. The lowest total cardiovascular demands (cardiac output and blood pressure) are shown in the palest color, with increasing dynamic load depicted by increasing blue intensity and increasing static load by increasing red intensity. Note the graded transition between categories, which should be individualized on the basis of player position and style of play. Danger of bodily collision (refer to UpToDate content regarding sports according to risk of impact and educational background). https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 27/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Increased risk if syncope occurs. Reproduced from: Levine BD, Baggish AL, Kovacs RJ. Eligibility and disquali cation recommendations for competitive athletes with cardiovascular abnormalities: Task force 1: Classi cation of sports: Dynamic, static, and impact: A scienti c statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2350. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 105651 Version 9.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 28/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Triggers for cardiac events in long QT syndrome are related to genotype In a study of 670 patients with long QT syndrome and known genotype, all symptomatic (syncope, aborted cardiac arrest, or sudden death), the occurrence of a lethal cardiac event (n = 110) provoked by a specific trigger (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced most of their events (90%) during exercise or emotion. These percentages were almost reversed among LQT2 and LQT3 patients who had most of their events during rest or sleep (63 and 80%, respectively); by contrast, they were at almost no risk of major events during exercise (arrows), which is explained by their having a normal I current. Ks ACA: aborted cardiac arrest; SCD: sudden cardiac death. Modi ed from: Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-speci c triggers for life-threatening arrhythmias. Circulation 2001; 103:89. Graphic 64239 Version 3.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 29/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Outcome with beta blocker in the long QT syndrome is good in asymptomatic patients During a five-year follow-up of 869 patients with a long QT syndrome, the estimated cumulative probability of experiencing aborted cardiac arrest or death on beta blocker therapy was significantly reduced in those who were asymptomatic (0.97 versus 0.31 events per year on therapy in probands and 0.26 versus 0.15 events per year in affected family members). Recurrent events despite beta blocker therapy were significantly higher in those with a history of syncope (hazard ratio 3.1) or aborted sudden death (hazard ratio 12.9). Data from Moss AJ, Zareba W, Hall WJ, et al, Circulation 2000; 101:616. Graphic 78184 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 30/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Contributor Disclosures Peter J Schwartz, MD No relevant financial relationship(s) with ineligible companies to disclose. Michael J Ackerman, MD, PhD Consultant/Advisory Boards: Abbott [Education around ICD/device therapy for genetic heart diseases including LQTS]; ARMGO Pharma [Novel therapies for genetic heart diseases, CPVT in particular]; Boston Scientific [Education around ICD/device therapy for genetic heart diseases including LQTS]; Daiichi Sankyo [Drug-induced QT prolongation for one of their drugs]; Invitae [Genetic testing for genetic heart diseases]; LQT Therapeutics [Development of a novel QT-shortening medication]; Medtronic [Education around ICD/device therapy for genetic heart diseases including LQTS]; UpToDate [Genetic heart diseases, especially LQTS]. Other Financial Interest: AliveCor [QTc analytics for smartphone-enabled mobile ECG]; Anumana [Artificial intelligence ECG for early detection of hypertrophic cardiomyopathy]; Pfizer [Gene therapy for genetic heart diseases including LQTS]. All of the relevant financial relationships listed have been mitigated. John K Triedman, MD Consultant/Advisory Boards: Biosense Webster and Sentiar [Supraventricular and ventricular topics]. All of the relevant financial relationships listed have been mitigated. Samuel Asirvatham, MD Grant/Research/Clinical Trial Support: Medtronic [Defibrillators]; St Jude's [Sudden Cardiac Death]. Consultant/Advisory Boards: BioTronik [Defibrillators]; Boston Scientific [Sudden Cardiac Death]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 31/31

7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Control of ventricular rate in atrial flutter : Jordan M Prutkin, MD, MHS, FHRS : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jul 19, 2022. INTRODUCTION Atrial flutter is a relatively common supraventricular arrhythmia characterized by rapid, regular atrial depolarizations at a characteristic rate around 300 beats/min and a regular ventricular rate corresponding to one-half or one-quarter of the atrial rate (150 or 75 beats/minute). It may remain as atrial flutter, it may degenerate into atrial fibrillation, or it may revert to sinus rhythm within hours or days. In patients who present with or who have recurrent episodes associated with a rapid ventricular rate, slowing of the rate may be necessary to either reduce symptoms or prevent tachycardia-mediated cardiomyopathy. For the purpose of this topic, rate control means lowering the heart rate, which in the case of atrial flutter is usually difficult to achieve. Thus, for many patients, radiofrequency ablation (and permanent restoration of sinus rhythm) is the preferred long-term approach to patients with atrial flutter. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.) The physiologic and clinical rationales for ventricular rate control in atrial flutter and the modalities used to achieve this goal will be reviewed here. Other issues such as the causes of atrial flutter, the embolic risk associated with this arrhythmia, and the restoration and maintenance of sinus rhythm are discussed separately. (See "Overview of atrial flutter" and "Restoration of sinus rhythm in atrial flutter" and "Embolic risk and the role of anticoagulation in atrial flutter" and "Atrial flutter: Maintenance of sinus rhythm".) PHYSIOLOGIC BASIS FOR THERAPY https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 1/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate The ventricular rate in atrial flutter is principally determined by the rate at which impulses exit the atrioventricular (AV) node. With a regular atrial rate of 300 beats/min, the ventricular rate is usually about 150 beats/min. This ventricular rate is determined by the refractory period of a healthy AV node, such that every other impulse (2:1) traverses the AV node and travels to the ventricles. In the absence of drugs that slow AV nodal conduction, a higher degree of AV block (eg, 3:1 or 4:1) suggests AV nodal disease; in these settings, the ventricular rates would be roughly 100 and 75 beats/min, respectively. Even input/output ratios (eg, 2:1 or 4:1 conduction) are more common than odd ratios (eg, 3:1 or 5:1). Odd ratios probably reflect bilevel block in the AV node. Sometimes, variable conduction may occur with alternating or seemingly random patterns of 2:1, 3:1, 4:1, or other conduction patterns, again due to varying levels of block in the AV node. On the other hand, a 1:1 response with typical atrial flutter usually suggests possible hyperthyroidism, catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract. (See "Anatomy, pathophysiology, and localization of accessory pathways in the preexcitation syndrome".) An important exception can occur in patients taking antiarrhythmic drugs, which can slow the atrial flutter rate so that 1:1 conduction occurs. This occurs most commonly with the class IC drugs, particularly when used in the absence of concomitant AV nodal blocking agents, but can also occur with dronedarone or even amiodarone. Also, 1:1 conduction of "slow" atrial flutter can occur in patients with marked right atrial enlargement. The AV node has been called a "slow response" tissue, since its action potential depends on calcium ions flowing through kinetically slow channels ( figure 1). The activation and reactivation characteristics of these channels limit the rate of conduction through the AV node. The autonomic nervous system can modify the rate of conduction, which is increased by sympathetic activity and reduced by parasympathetic activity. It is useful to consider the electrophysiologic differences between atrial fibrillation and atrial flutter, since they can impact therapy: Atrial fibrillation is characterized by multiple wandering wavelets, which result in the AV node being bombarded by 400 to 600 impulses per minute. Some impulses traverse the AV node and reach the specialized infranodal conduction system and then the ventricles. However, most of the atrial impulses penetrate the AV node for varying distances and then are extinguished by encountering the refractoriness of an earlier wavefront; this phenomenon of concealed conduction in turn creates a refractory wave that affects succeeding impulses. The lack of shortening of the refractory period with increasing rate https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 2/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate (as occurs in the atria) further decreases the likelihood of an impulse traversing the AV node. (See "The electrocardiogram in atrial fibrillation".) In comparison, typical atrial flutter is a macroreentrant arrhythmia, resulting in approximately 300 impulses/min reaching the AV node. This slower rate produces less refractoriness within the AV node and therefore less concealed conduction than in atrial fibrillation. Based upon these observations, it would be expected that atrial fibrillation would be more sensitive than atrial flutter to drugs that affect AV nodal refractoriness; this prediction has been confirmed clinically. Stated another way, control of the ventricular rate in atrial flutter is more difficult than in atrial fibrillation. (See 'Rate control with drugs' below.) INDICATIONS FOR RATE CONTROL There are three principle situations in which rate control should be considered: Immediate rate control to reduce symptoms during a first or subsequent episode in which a patient has not reverted to sinus rhythm (or spontaneously converted to atrial fibrillation); cardioversion should be considered, as it has a high likelihood of success. (See "Restoration of sinus rhythm in atrial flutter", section on 'Indications'.) It should be kept in mind that acute rate control in asymptomatic/minimally symptomatic patients with atrial flutter rarely works in the absence of coincident atrioventricular node disease. In the majority of patients, we focus on restoring sinus rhythm with cardioversion. Chronic therapy to prevent symptoms in patients who are likely to have recurrent atrial flutter and are not scheduled to undergo radiofrequency ablation of the atrial flutter. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.) Chronic therapy to prevent tachycardia-mediated cardiomyopathy (see "Arrhythmia- induced cardiomyopathy") in the uncommon patient with chronic atrial flutter who does not undergo radiofrequency ablation of the atrial flutter. Atypical atrial flutter may result after an atrial fibrillation ablation procedure. Frequently, these patients may be more symptomatic with faster heart rates than when in atrial fibrillation. It may be difficult to rate control these patients, and antiarrhythmic agents, cardioversion, and/or atrial flutter ablation are frequently necessary. (See "Atrial fibrillation: Catheter ablation", section on 'Arrhythmic complications'.) https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 3/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate The following two characteristics of atrial flutter render the need to decide about the initiation of rate slowing uncommon: Atrial flutter may be an electrically unstable rhythm, meaning that it may degenerate into the less organized atrial fibrillation or revert to sinus rhythm within hours or days. Spontaneous reversion of paroxysmal atrial flutter to a sinus mechanism may occur after predisposing problems are improved, such as decompensated heart failure and the sequelae of cardiac surgery. Persistent atrial flutter is less common than persistent atrial fibrillation and is frequently associated with structural heart disease, atrial enlargement, prior cardiac surgery or atrial fibrillation ablation, or congenital heart disease. In these patients, chronic therapy to control the ventricular response is generally difficult unless there is concomitant atrioventricular (AV) node dysfunction. Atrial flutter, particularly the typical cavotricuspid-isthmus-dependent variety, is usually curable with catheter ablation. If patients have both atrial flutter and fibrillation, ablation of the cavotricuspid isthmus will not necessarily eliminate recurrent atrial fibrillation. This strategy may still be useful in selected patients in whom rapid rates during atrial flutter are highly symptomatic, but episodes of atrial fibrillation are well tolerated. RATE CONTROL GOALS Although rate control targets have been described for atrial fibrillation [1], they are less useful in atrial flutter since, as noted above, atrioventricular block tends to go in steps (eg, 2:1, 3:1, and 4:1). For most patients, we believe a ventricular rate at rest of less than 80 beats/min is reasonable for symptomatic patients and less than 110 beats/min may be reasonable for asymptomatic patients with normal left ventricular systolic function. Rate control should be assessed both at rest and with exertion. RATE CONTROL WITH DRUGS The goal of therapy with drugs that slow atrioventricular (AV) conduction is to improve symptoms and prevent the development of a tachycardia-mediated cardiomyopathy. For patients who require immediate rate slowing, and for whom cardioversion (and the restoration of sinus rhythm) is not chosen, we prefer intravenous diltiazem or esmolol to other options. For patients who will be placed on long-term oral therapy for rate control, we prefer either diltiazem or verapamil. https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 4/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate The rate at which impulses from the atria exit the AV node is the principle determinant of the ventricular rate. (See 'Physiologic basis for therapy' above.) Thus, rate control in atrial flutter is achieved principally with drugs that slow conduction through the AV node. The pharmacologic agents for controlling the ventricular rate in atrial flutter are based as follows: Blockade of the calcium channel with the nondihydropyridine calcium channel blockers diltiazem and verapamil. Decrease sympathetic tone using beta-blockers. Enhancement of parasympathetic tone with vagotonic drugs, most frequently digoxin. The use of amiodarone, which slows AV nodal conduction and increases AV nodal refractoriness. However, as discussed above, the smaller amount of concealed conduction in the AV node because of the slower atrial rate in atrial flutter means that greater AV nodal refractoriness must be produced. As a result, higher doses of a single drug are required, and combination therapy at conventional doses is frequently needed to minimize toxicity. Difficulties with pharmacologic rate control make patients with atrial flutter excellent candidates for a catheter ablation procedure, which is often curative. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.) Nonpharmacologic therapy to convert back to normal sinus rhythm including direct current cardioversion, pace termination, or catheter ablation are reasonable treatments if the patient is having adverse hemodynamic consequences from the arrhythmia, if pharmacologic therapies are unsuccessful or not tolerated, or if the patient has pre-excitation syndrome. Calcium channel blockers The nondihydropyridine calcium channel blockers diltiazem and verapamil may be useful for acute rate control in non-pre-excited atrial flutter when given intravenously and can produce long-term rate slowing when given orally (see "Major side effects and safety of calcium channel blockers" and "Calcium channel blockers in the treatment of cardiac arrhythmias" and "Calcium channel blockers in the treatment of cardiac arrhythmias", section on 'Atrial fibrillation and flutter'): Diltiazem Intravenous diltiazem is often the drug of choice for acutely controlling the rapid ventricular response in atrial flutter [2-4]. Diltiazem increases AV nodal refractoriness and slows conduction velocity in the AV node, thereby decreasing the ventricular response. Diltiazem has a less pronounced negative inotropic effect than verapamil [5]. https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 5/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate There is a Food and Drug Administration-approved regimen for a continuous 24-hour intravenous diltiazem infusion [2-4]. This regimen consists of an intravenous bolus of 0.25 mg/kg (average adult dose 20 mg) over two minutes followed 15 minutes later by a second bolus of 0.35 mg/kg (average adult dose 25 mg) over two minutes if the first dose is tolerated but does not produce the desired response (20 percent reduction in heart rate from the baseline, conversion to sinus rhythm, or a heart rate less than 100 beats/min); this is followed by a continuous infusion at a rate of 10 to 15 mg/h in responders but not nonresponders; some patients respond to a 5 mg/h infusion [4]. This regimen usually controls the ventricular rate within four to five minutes [2]. Oral diltiazem is used far more commonly than verapamil for chronic rate control. Monotherapy with oral diltiazem can be used to treat patients with persistent atrial flutter, as well as patients who have recurrent or persistent atrial fibrillation with episodic atrial flutter. The initial dose is 30 mg every six hours, and is increased to a maximum of 360 mg/day. Sustained release diltiazem is most commonly used as a once a day drug. Verapamil Intravenous verapamil is very rarely used for acute control. Its use is associated with a higher frequency of hypotension than that with diltiazem. Verapamil, like diltiazem, increases refractoriness and decreases conduction velocity in the AV node, leading to reductions in the ventricular response in atrial flutter [6-10]. Intravenous verapamil can be given acutely in a dose of 5 to 10 mg over two to three minutes; this dose can be repeated every 15 to 30 minutes as necessary. The maintenance infusion rate is approximately 5 mg/hour. The onset of action is within two minutes and the peak effect occurs in 10 to 15 minutes. Control of the ventricular response is lost in roughly 90 minutes if repeated boluses or a maintenance infusion are not given. Similar to diltiazem, oral verapamil may be used to treat patients with persistent atrial flutter or patients with recurrent or persistent atrial fibrillation who have episodic atrial flutter. The initial dose of oral verapamil is 40 to 80 mg every six hours. This dose can be increased to a maximum of 360 mg/day if hepatic function is relatively normal. The sustained-release formulation is used for chronic therapy. Clinical cautions Diltiazem and verapamil should not be given to patients with severe heart failure (New York Heart Association class III or IV) and should be given with caution to patients with sinus node dysfunction, second- or third-degree AV block, the pre-excitation syndrome, hypotension, or the concurrent intake of other drugs that inhibit sinoatrial (SA) nodal function or slow AV nodal conduction. https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 6/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate Calcium channel blockers have a number of characteristics that need to be considered when they are administered to patients with atrial flutter: The effect on SA nodal function is variable, which is important if the patient has paroxysmal atrial flutter with episodes of normal sinus rhythm also. Although both verapamil and diltiazem have an inhibitory effect on the sinus node (which generates a slow action potential mediated by calcium fluxes), their vasodilator effects cause a reflex release of catecholamines that can maintain or slightly accelerate the SA nodal rate. However, SA nodal function is depressed in patients with the sinus node dysfunction, at least in part due to blockade of calcium channels and an inability of the sinus node to respond to catecholamines. Thus, if the normal reflex mechanism is impaired by therapy with a beta blocker, the addition of a calcium channel blocker can lead to slowing or, rarely, failure of SA nodal function. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Both drugs (verapamil perhaps more than diltiazem) can produce high-degree AV block and therefore should not be given to patients with underlying second- or third-degree AV block. For similar reasons, calcium channel blockers must be used with caution when given with other drugs that slow AV nodal conduction (eg, beta blockers, digoxin). Verapamil has a negative inotropic effect that is more pronounced than that of diltiazem. As a result, it should be used with caution in patients with heart failure and should not be given if the patient is hypotensive. It should also be used cautiously with other negative inotropes, such as beta blockers. Verapamil interacts with digoxin, resulting in an increase in serum digoxin. This interaction is dose-related (often occurring when verapamil doses are over 240 mg/day) and generally occurs after seven days of therapy with both agents. Similar to the digoxin-quinidine interaction, verapamil reduces the renal clearance of digoxin; it may also interfere with its hepatic metabolism [11-13]. Beta blockers There is little literature on the use of intravenous or oral beta blockers (excluding esmolol) as primary therapy for atrial flutter. Anecdotal reports suggest that these drugs can slow the ventricular rate, particularly if given in combination with digoxin or diltiazem. Among the beta blockers, atenolol and nadolol have the advantage of a long half-life, and atenolol, in our experience, has the least adverse effect on the sensorium. Long-acting propranolol and metoprolol preparations are also effective. We generally begin with atenolol, 25 mg/day, and increase the daily dose to 100 mg and sometimes 200 mg if necessary. Beta https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 7/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate blockers are particularly useful for patients who also have coronary artery disease or chronic heart failure. Beta blockers may have a variety of adverse effects. Some of these complications may be important in patients with atrial flutter, including worsening heart failure, hypotension, bradycardia, bronchospasm, and high-degree AV block. (See "Major side effects of beta blockers".) Esmolol Esmolol, a rapidly acting beta blocker with additional electrophysiologic properties, is administered intravenously, and is useful for rate control in acute non-pre- excited atrial flutter [14,15]. Esmolol is preferred to other intravenous beta blockers in this setting due to its rapid onset of action and a greater clinical experience. Esmolol begins to act in one to two minutes, is metabolized by red blood cell esterase, and has a short duration of action of 10 to 20 minutes. The following esmolol regimen is recommended for acute rate control: A bolus of 0.5 mg/kg is infused over one minute, followed by 50 mcg/kg per min If, after four minutes, the response is inadequate, another bolus is given followed by an infusion of 100 mcg/kg per min. If, after four minutes, the response is still inadequate, a third and final bolus can be given followed by an infusion of 150 mcg/kg per min. If necessary, the infusion can be increased to a maximum of 200 mcg/kg per min after another four minutes Alternatively, an infusion can be started at 50 mcg/kg per min without a bolus, and the rate of administration can be increased by 50 mcg/kg per min every 30 minutes. Digoxin Digoxin historically was the most commonly used drug to control the ventricular rate in atrial flutter in the nonemergent setting. However, calcium channel blockers and beta blockers, singly or in combination, have largely supplanted digoxin for both initial intravenous rate control and chronic oral therapy. The use of digoxin for the treatment of heart failure is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Optional therapies'.) We generally reserve digoxin for patients whose rate has not adequately been controlled with the use of a calcium channel blocker, a beta blocker, or both. It is not as effective as these two https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 8/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate categories of drug, and its use is associated with higher mortality in patients at higher digoxin levels. It may not be appropriate for use in older patients. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Digoxin can be administered orally, intravenously, or intramuscularly, although we do not use the intramuscular route because absorption is erratic. Intravenous digoxin begins to act within 15 to 30 minutes, with a peak effect attained in one to five hours. The relatively slow onset of action of digoxin is undesirable in patients with a rapid ventricular response. Since digoxin has a slow onset of action, there is rarely a reason for parenteral administration in patients who can take oral medications. A larger dose of digoxin than used in atrial fibrillation is required to control the ventricular rate in atrial flutter; as noted above, the smaller amount of concealed conduction in the AV node because of the slower atrial rate in atrial flutter means that greater AV nodal refractoriness must be produced [16]. Serum digoxin levels should be monitored periodically in patients on persistent therapy. Although the correlation between drug concentration and ventricular rate control is poor, the presence of a low value is useful since it allows a higher dose to be administered. The use of high doses of digoxin is potentially hazardous if electric cardioversion is performed, since this combination increases the risk of serious ventricular arrhythmias. Junctional escape beats (as detected by similarity of the longest observed recurring R-R intervals on the electrocardiogram [ECG]) are common when digoxin has successfully slowed the ventricular rate. Giving additional digoxin in this setting will increase the degree of AV nodal block and produce periods of regular junctional rhythm. The change from single junctional escapes to periodic junctional rhythm suggests the development of digoxin toxicity. If the pulse is palpated but ECG not reviewed, it may be mistakenly assumed that the patient is in sinus rhythm. However, it may be difficult to distinguish on the ECG between digoxin-induced complete heart block during atrial flutter and a slow, regular ventricular rate. In complete heart block, the R-R interval will not be an exact multiple of the atrial cycle length (A-A interval). In addition, the relationship between the QRS complex and flutter wave (ie, the point on the flutter wave where the QRS complex begins) is variable during complete heart block. Amiodarone Amiodarone can be used for rate control, but it should be remembered that intravenous amiodarone can possibly promote reversion to sinus rhythm, albeit infrequently. Since cardioversion is associated with an increased risk of thromboembolism, amiodarone should generally not be used in patients who are not candidates for conversion to sinus rhythm because of inadequate anticoagulation. (See "Prevention of embolization prior to and after https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 9/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate restoration of sinus rhythm in atrial fibrillation" and "Atrial fibrillation: Cardioversion", section on 'Less effective or ineffective drugs' and "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) Intravenous amiodarone slows conduction through the AV node and prolongs the effective refractory period of the AV node [17]. It has been used for rate control in critically ill patients with atrial tachyarrhythmias, mostly atrial fibrillation with some cases of atrial flutter [18,19]. This includes patients with heart failure, since amiodarone has less negative inotropic activity than beta blockers or calcium channel blockers [20]. (See "The management of atrial fibrillation in patients with heart failure".) The efficacy of slowing of the ventricular rate with amiodarone and diltiazem was compared in a study of 60 critically ill patients with recent onset atrial tachyarrhythmias, almost all atrial fibrillation [19]. Amiodarone was given as a 300 mg bolus, with or without a continuous infusion of 45 mg/h for 24 hours. Diltiazem was given as a 25 mg bolus, followed by a continuous infusion of 20 mg/h for 24 hours. Rate control was achieved with both drugs; the degree of slowing was somewhat better with diltiazem, an effect that was offset by a significantly higher incidence of hypotension that required discontinuation of diltiazem. Amiodarone may promote the appearance of "slow" atrial flutter in patients with atrial tachyarrhythmia. However, 1:1 AV conduction is generally not a problem in this setting due to the inhibitory effect of amiodarone on AV nodal conduction. In summary, amiodarone is an alternative rate control agent in patients with atrial flutter and severe hemodynamic compromise, although it has not been approved by the United States Food and Drug Administration for this purpose. Because of the long-term risk of adverse effects, amiodarone is generally not recommended for persistent rate control in patients with atrial flutter. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) RADIOFREQUENCY ABLATION OF THE ATRIOVENTRICULAR NODE Radiofrequency ablation of the AV junction (AV node and/or His bundle) is uncommonly performed in patients with pure atrial flutter because of the high rate of success with radiofrequency ablation of the re-entrant circuit, which maintains sinus rhythm [21,22]. The main indication for AV junction ablation is in patients with atrial flutter who have coincident atrial fibrillation. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.) PATIENTS WITH PRE-EXCITATION SYNDROME https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 10/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate Among patients with atrial flutter and pre-excitation, therapy is aimed at reversion to sinus rhythm and subsequent treatment of the accessory pathway rather than rate control. The atrioventricular (AV) nodal blocking drugs (calcium channel blockers, beta blockers, and digoxin) can paradoxically increase the ventricular response in patients with atrial flutter and pre- excitation by impairing conduction via the normal AV node-His-Purkinje system. This decreases retrograde concealed conduction in the accessory pathway, thereby improving antegrade conduction over the pathway. Acute treatment should be directed toward converting to normal sinus rhythm in these patients. (See "Treatment of arrhythmias associated with the Wolff- Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS There are three principle clinical situations for which rate control should be considered in patients with atrial flutter: to treat symptoms during a first episode or recurrent episode; to prevent symptoms in patients who are likely to have recurrent atrial flutter; and to prevent tachycardia-mediated cardiomyopathy in the patient with chronic atrial flutter. (See 'Indications for rate control' above.) Rate control in atrial flutter is often more difficult than in atrial fibrillation. For many patients, atrial flutter ablation, which permanently restores sinus rhythm in a high percentage of patients, is the preferred long-term approach. (See 'Indications for rate control' above.) For most patients, we believe a ventricular rate at rest of less than 80 beats/min is reasonable for symptomatic patients and less than 110 beats/min may be reasonable for asymptomatic patients with normal left ventricular systolic function. (See 'Rate control goals' above.) For patients who require immediate rate slowing, and for whom cardioversion is not chosen, we suggest intravenous diltiazem or esmolol rather than other drug options (Grade 2C). The choice between these two should take into account practitioner familiarity. (See 'Rate control with drugs' above.) https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 11/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate For patients who will be placed on long-term oral therapy for rate control, we suggest oral diltiazem or verapamil rather than other oral agents (Grade 2C). (See 'Rate control with drugs' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 2. Salerno DM, Dias VC, Kleiger RE, et al. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atrial flutter. The Diltiazem-Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1989; 63:1046. 3. Ellenbogen KA, Dias VC, Plumb VJ, et al. A placebo-controlled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atrial fibrillation and atrial flutter: a multicenter study. J Am Coll Cardiol 1991; 18:891. 4. Ellenbogen KA, Dias VC, Cardello FP, et al. Safety and efficacy of intravenous diltiazem in atrial fibrillation or atrial flutter. Am J Cardiol 1995; 75:45. 5. B hm M, Schwinger RH, Erdmann E. Different cardiodepressant potency of various calcium antagonists in human myocardium. Am J Cardiol 1990; 65:1039. 6. Dominic J, McAllister RG Jr, Kuo CS, et al. Verapamil plasma levels and ventricular rate response in patients with atrial fibrillation and flutter. Clin Pharmacol Ther 1979; 26:710. 7. Tommaso C, McDonough T, Parker M, Talano JV. Atrial fibrillation and flutter. Immediate control and conversion with intravenously administered verapamil. Arch Intern Med 1983; 143:877. 8. Hwang MH, Danoviz J, Pacold I, et al. Double-blind crossover randomized trial of intravenously administered verapamil. Its use for atrial fibrillation and flutter following open heart surgery. Arch Intern Med 1984; 144:491. 9. Plumb VJ, Karp RB, Kouchoukos NT, et al. Verapamil therapy of atrial fibrillation and atrial flutter following cardiac operation. J Thorac Cardiovasc Surg 1982; 83:590. https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 12/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate 10. Waxman HL, Myerburg RJ, Appel R, Sung RJ. Verapamil for control of ventricular rate in paroxysmal supraventricular tachycardia and atrial fibrillation or flutter: a double-blind randomized cross-over study. Ann Intern Med 1981; 94:1. 11. Klein HO, Lang R, Weiss E, et al. The influence of verapamil on serum digoxin concentration. Circulation 1982; 65:998. 12. Hori R, Okamura N, Aiba T, Tanigawara Y. Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. J Pharmacol Exp Ther 1993; 266:1620. 13. Hedman A, Angelin B, Arvidsson A, et al. Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance in humans. Clin Pharmacol Ther 1991; 49:256. 14. Platia EV, Michelson EL, Porterfield JK, Das G. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. Am J Cardiol 1989; 63:925. 15. Schwartz M, Michelson EL, Sawin HS, MacVaugh H 3rd. Esmolol: safety and efficacy in postoperative cardiothoracic patients with supraventricular tachyarrhythmias. Chest 1988; 93:705. 16. Smith TW. Digitalis. Mechanisms of action and clinical use. N Engl J Med 1988; 318:358. 17. Morady F, DiCarlo LA Jr, Krol RB, et al. Acute and chronic effects of amiodarone on ventricular refractoriness, intraventricular conduction and ventricular tachycardia induction. J Am Coll Cardiol 1986; 7:148. 18. Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Intravenous amiodarone for acute heart rate control in the critically ill patient with atrial tachyarrhythmias. Am J Cardiol 1998; 81:594. 19. Delle Karth G, Geppert A, Neunteufl T, et al. Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias. Crit Care Med 2001; 29:1149. 20. Deedwania PC, Singh BN, Ellenbogen K, et al. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHF-STAT). The Department of Veterans Affairs CHF-STAT Investigators. Circulation 1998; 98:2574. 21. Scheinman MM, Evans-Bell T. Catheter ablation of the atrioventricular junction: a report of the percutaneous mapping and ablation registry. Circulation 1984; 70:1024. 22. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 2000; 23:1020. Topic 1067 Version 32.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 13/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate GRAPHICS Physiology of the AV node in AF The atrioventricular (AV) node modulates the response between the atrium and the ventricle. In atrial fibrillation, the atrial rate is up to 600 beats per minute while the ventricular rate in response is 90 to 170 beats per minute; this difference in the rate results from several properties of the AV node that impede impulse conduction. The AV node generates a slow action potential (AP) that is mediated by calcium (Ca++) ion currents; the node is therefore slow response tissue. Parasympathetic innervation via the vagus nerve also slows conduction, while activation of the sympathetic nervous system speeds conduction. Graphic 75699 Version 1.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 14/15 7/6/23, 3:08 PM Control of ventricular rate in atrial flutter - UpToDate Contributor Disclosures Jordan M Prutkin, MD, MHS, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/control-of-ventricular-rate-in-atrial-flutter/print 15/15

7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy : Rachel Kaplan, MD, MS : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 27, 2023. INTRODUCTION In patients with atrial fibrillation (AF), the ventricular rate is modulated by the conduction properties of the atrioventricular (AV) node. In the typical patient with untreated AF, the ventricular rate can reach 150 beats/min or higher. The use of pharmacologic therapies to achieve rate control in AF will be reviewed here. Nonpharmacologic therapies for rate control in AF are discussed separately. (See "Atrial fibrillation: Atrioventricular node ablation".) Further information regarding the overall management of patients with AF, including anticoagulation and choice of rhythm versus rate control, is discussed separately: (See "Atrial fibrillation in adults: Use of oral anticoagulants".) (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) (See "Management of atrial fibrillation: Rhythm control versus rate control".) The control of ventricular rate of AF in patients with heart failure is discussed separately; thus, this topic focuses only on patients with AF who do not have heart failure. (See "The management of atrial fibrillation in patients with heart failure".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 1/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate PATHOPHYSIOLOGY Atrial fibrillation During AF, electrical activity in the atria can exceed 400 beats/min. The majority of these impulses do not conduct to the ventricles because of the electrophysiologic properties of the AV node. (See "Mechanisms of atrial fibrillation", section on 'Role of the atrioventricular node'.) AV nodal tissue consists of so-called "slow response" fibers, giving it decremental conduction properties. In most myocardial tissue, the initial depolarizing phase of the action potential (phase 0) is mediated by rapid sodium channels. In contrast, in the slow response fibers of the AV node, phase 0 is mediated by an inward calcium current, which uses a kinetically slow channel. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) The relatively slow kinetics of the inward calcium current limit conduction velocity through the AV node, and therefore the ventricular rate during AF. In addition to these intrinsic properties, the AV node is also richly supplied and affected by both components of the autonomic nervous system. AV conduction is enhanced by sympathetic fibers and slowed by parasympathetic fibers ( figure 1). In the typical patient with untreated AF, the ventricular rate during the day varies between 90 and 170 beats/min. The ventricular rate may be slower (eg, less than 60 beats/min) in the following settings: Increased vagal tone. Drugs that affect AV nodal conduction. AV nodal disease, which should be suspected if the ventricular rate is below 60 beats/min in the absence of a drug that slows AV conduction. A ventricular rate above 200 beats/min suggests one or more of the following: Catecholamine excess Enhanced AV nodal conduction Parasympathetic withdrawal Hyperthyroidism An accessory pathway as occurs in the preexcitation syndrome. (See "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) Drug mechanisms of action The ventricular rate in AF is slowed using beta blockers or calcium channel blockers, and to a lesser extent digoxin or amiodarone. In general, calcium https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 2/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate channel blockers are effective at rest and during exercise, beta blockers are similarly effective at rest but more effective during exercise, and digoxin is reasonably effective at rest but less effective than the other drugs during exercise. Thus, it is particularly important to assess ventricular rate with exertion in patients treated with digoxin alone. These agents slow AV nodal conduction based upon the following physiologic mechanisms ( figure 2) [1,2]: Calcium channel blockade Blockade of the calcium channel with the nondihydropyridine calcium channel blockers verapamil and diltiazem. Beta blockade Decreased sympathetic tone and slowed AV nodal conduction with beta blockers. Enhancement of parasympathetic tone This is done with vagotonic drugs, the most important of which is digoxin. RATIONALE FOR RATE LOWERING Specific reasons for slowing the ventricular rate in patients with AF include the following: Hemodynamic instability This may be acute and may require urgent therapy. This is discussed in detail separately. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Symptoms Patients with AF may or may not have associated symptoms, and the spectrum of symptoms is broad. Typical symptoms include palpitations, tachycardia, fatigue, weakness, dizziness, lightheadedness, reduced exercise capacity, increased urination, or mild dyspnea. Symptoms of AF are discussed in detail separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Symptoms'.) Tachycardia-mediated cardiomyopathy Persistently increased ventricular rates in AF have been associated with left ventricular cardiomyopathy. While this issue has not been well studied, we believe that this phenomenon is unlikely to occur if the ventricular rate is kept below 110 beats/min, which is the recommended ventricular rate goal. This is discussed in detail separately. (See "Arrhythmia-induced cardiomyopathy".) Potential mortality benefit There is some evidence to suggest a mortality benefit from rate control. In a large, population-based cohort study in Taiwan, mortality in individuals receiving beta blockers (43,879), nondihydropyridine calcium channel blockers (18,466), and digoxin (38,898) was compared with mortality in individuals not taking a rate-control https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 3/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate drug. Patients were excluded if they were taking more than one rate-slowing drug. After adjustment for baseline differences, the risk of death was lower in patients receiving beta blockers (adjusted hazard ratio [HR] 0.76; 95% CI 0.74-0.78) and calcium channel blockers (adjusted HR 0.93; 95% CI 0.90-0.96). However, the risk of death was higher in the group receiving digoxin (adjusted HR 1.12; 95% CI 1.10-1.14). We recommend caution in applying to clinical practice the findings in this nonrandomized study. Spontaneous conversion to sinus rhythm Some patients whose rate has been slowed and who then tolerate AF may spontaneously convert to normal sinus rhythm without the need for electrical cardioversion. Spontaneous conversion is most likely to occur in patients with a duration of AF of less than 48 hours, or in patients with a history of short, self- limited episodes [3]. The rate of spontaneous conversion has been reported to be around 50 percent at 48 hours [3]. In a retrospective study of 438 patients with AF, if the AF onset was <48 hours, spontaneous conversion occurred in 77 percent compared with 36 percent in the group with first onset AF >48 hours [4]. In a separate study of 943 patients, spontaneous conversion was shown to occur most frequently in patients with first-onset AF <24 hours, a lower body mass index, and normal left atrial size [5]. EVALUATION AND GOAL VENTRICULAR RATE Evaluation and monitoring of ventricular rate In practice, the ventricular rate can be assessed by measurement of both the resting ventricular rate and use of one of the following to assess exercise: Six-minute walk test (at moderate exercise) ( table 1). Either submaximal or maximal exercise electrocardiogram (ECG) testing. (See "Exercise ECG testing: Performing the test and interpreting the ECG results".) A 24-hour ambulatory monitor can also be used to evaluate efficacy. (See "Ambulatory ECG monitoring".) For patients with an implantable pacemaker or defibrillator, device interrogation provides useful diagnostic data to assess rate control, including a ventricular rate histogram during episodes of AF. For young active patients, we recommend either an exercise ECG test or ambulatory monitoring during exercise. For older or sedentary patients, measuring ventricular rate after walking briskly around the office or upstairs may provide sufficient information. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 4/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Wearable devices, such as an electronic watch that connects with a smartphone application, also can provide ventricular rate data. Caution is advised with relying entirely on photoplethysmography, which may undersense individual beats in AF and report an inaccurately low heart rate [6]. Heart rate reports should be verified with ECG strips, which may also be obtainable from some wearable technologies. These methods of assessing ventricular rate can be used both at the start of therapy and for long-term follow-up. In the assessment of ventricular rate control, average ventricular rate is considered the most important parameter. Ventricular rates during peak exercise may also be valuable. Assessment of rate control can be confusing when using monitors that display continuous beat-to-beat ventricular rate rather than average ventricular rate. Goal ventricular rate The optimal long-term ventricular rate for patients in AF has not been firmly established [7]. For most symptomatic patients with AF, we suggest a ventricular rate goal of 85 beats/min. In general, the goal is to control the rate during activity to prevent or treat symptoms. If the ventricular rate during AF is faster than would be expected during sinus rhythm and occurs at a time that correlates with the patient's symptoms, then rate control medications are usually titrated upwards. In the subset of patients with AF who are asymptomatic and have permanent AF, a less strict rate control goal of <110 beats/min may be reasonable. These patients should be monitored for the development of tachycardia-mediated cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".) Alternative goal rates that are similar to those recommended for patients in sinus rhythm with heart disease can also be used: resting heart rate 80 beats/min and 110 beats/min during moderate exercise such as with the six-minute walk. Goals similar to these were used in many of the trials of rate versus rhythm control, such as AFFIRM [8]. The AFFIRM study is discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'High cardiovascular risk'.) The prevention of symptoms during normal activities or exercise is a primary goal of therapy. It is important to consider that symptoms may be due to either inadequate rate control or relative bradycardia (eg, in patients with tachycardia-bradycardia syndrome). (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Thus, for those patients in whom a lenient strategy is chosen but who remain symptomatic, an attempt should be made to decrease symptoms by setting a lower rate goal. A more https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 5/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate lenient rate-control strategy offers the advantages of less medication (fewer drug side effects, lower cost) and fewer outpatient visits to achieve ventricular rate control. The recommended goal rate is based on the observation that 85 beats/min was the mean achieved rate for patients assigned lenient rate control in the RACE study [9]. In this trial of patients with permanent AF, adhering to a strict rather than lenient rate-control strategy did not improve cardiovascular or safety outcomes. This study also supports our practice in which achieving strict rate control is not necessary in many physically active patients with AF who are minimally symptomatic. In the RACE study, 614 physically active patients with permanent AF were randomly assigned either lenient rate control (resting heart rate <110 beats/min) or a strict rate control (resting heart rate <80 beats/min and heart rate during moderate exercise <110 beats per minute). Patients were followed for the primary outcome of cardiovascular death, hospitalization for heart failure, stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The following findings were noted: Similar efficacy of lenient and strict rate control After three years, the estimated cumulative incidence of the primary outcome was similar in both groups (12.9 versus 14.9 percent, respectively; hazard ratio [HR] 0.84; 90% CI 0.58-1.21). Fewer people in strict versus lenient group met heart rate target The percentage of patients was 98 and 75 percent, respectively [10]. More medical visits in strict rate-control group There were nearly nine times as many visits (684 versus 75) to achieve rate control target(s) in the strict control. Low resting heart rates were achieved in the lenient group too In patients assigned to lenient rate control, the mean resting rates at the end of follow-up was 85+14 beats/min compared with 76+14 beats/min in those assigned to strict control. The results of the RACE trial must be tempered given that the lenient-control group was in fact treated more aggressively than the protocol required. In addition, RACE included only patients with permanent AF, so the results are not generalizable to those with paroxysmal or persistent AF. INITIAL CONSIDERATIONS The initial management of patients with AF and a rapid ventricular response involves the following: Determining if urgent therapy is needed. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 6/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Choosing between a rate and rhythm control strategy. Determining if there is preexcitation. Determining urgency In a patient with new or recurrent AF with a rapid ventricular response, the immediate goals are to stabilize hemodynamics (if necessary) and to improve symptoms. Thus, the intensity of initial rate control therapy (eg, inpatient versus outpatient or oral versus intravenous therapy) depends upon the clinical scenario. Urgent therapy In patients who are clinically or hemodynamically unstable (eg, myocardial ischemia, pulmonary edema, hypotension) due to AF and a rapid ventricular response, treatment options include intravenous rate-control medications and/or immediate cardioversion. (See 'Urgent therapy' below.) Elective therapy Patients who have mild or no symptoms and whose ventricular rate is mildly to moderately elevated (eg, 120 beats/min) can be managed with the addition or increase of oral rate-control medications. (See 'Elective and long-term management' below.) Deciding on rate control The advantages and disadvantages of rhythm and rate control, as well as whether there are subgroups of patients for whom one or the other should be preferred, are discussed separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) Caution in preexcitation syndrome Among patients with AF and preexcitation, initial therapy is aimed at reversion to sinus rhythm. Usual treatments for rate control (ie, calcium channel blockers, beta blockers, digoxin, and amiodarone) should not be given because they may paradoxically increase the ventricular response in patients with AF. Intravenous procainamide or ibutilide should be given if hemodynamics are stable, and direct current cardioversion should be performed if the patient is unstable. This is discussed in detail separately. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.) The preferred long-term therapy of preexcited AF is ablation of the accessory pathway. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Catheter ablation'.) URGENT THERAPY https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 7/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate This section describes our approach to urgent ventricular rate control in patients with AF who do not have heart failure. Rate control of patients who have AF and heart failure is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Acute decompensation'.) Choice of initial urgent therapy Patients who require urgent therapy need to be in a monitored setting. In patients without symptomatic hypotension (eg, in those with ischemia without hypotension), we select diltiazem as the initial agent. Intravenous (IV) esmolol, verapamil, or other IV beta blockers such as metoprolol are reasonable alternatives to diltiazem. If it is uncertain whether the patient will become hypotensive with a beta blocker, we use esmolol since this medication has a very short half-life and can be immediately discontinued if needed. (See 'Hypotensive patient' below.) In the absence of larger randomized trials, much of the current management relies on clinical experience rather than evidence. Diltiazem may have a less pronounced negative inotropic effect than verapamil [11]. The IV preparation is convenient and effective for acute control of the ventricular rate in AF [12-14], while oral therapy is effective for chronic rate control [15,16]. In our experience, either a beta blocker or calcium channel blocker could result in hypotension, and therefore careful blood pressure monitoring is needed regardless of the choice of medication. Small, heterogenous studies of urgent control of ventricular rate in AF suggest higher efficacy for IV diltiazem versus IV beta blocker therapy: One meta-analysis of three studies including 160 patients and comparing effects of IV diltiazem versus IV metoprolol showed an average of 9 mm lower systolic blood pressure with diltiazem at 15 minutes following treatment but no differences at earlier or later timepoints (ie 5, 10, or 30 minutes) [17]. In a meta-analysis of 17 randomized and cohort studies (1214 patients), patients given IV diltiazem compared with IV metoprolol had higher efficacy of successful rate control (relative risk [RR] 1.11; 95% CI 1.06-1.16). Efficacy was defined differently in various studies (eg, achieving a heart rate <100 beats/min or lowering heart rate by at least 20 percent). Those treated with IV diltiazem also had shorter average onset time (RR per minute of onset -1.13; 95% CI -1.97 to -0.28) and lower ventricular rate (RR difference in beats/min -9.48; 95% CI -12.13 to -6.82) and less impact on (weighted mean difference 3.76 mmHg; 95% CI 0.20-7.33). There was no significant difference in adverse events between treatment regimens [17]. Normotensive patient In most normotensive patients with AF with a rapid ventricular rate, we first try IV diltiazem ( table 2). https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 8/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate The suggested regimen for IV diltiazem is derived from the Diltiazem Atrial Fibrillation/Atrial Flutter Study Group [12-14]. The efficacy of this regimen was evaluated in a report of 84 consecutive patients with AF, atrial flutter, or both [14]. The overall response rate was 94 percent. The continuous infusion maintained adequate rate control for 10 hours or longer in a dose- dependent fashion: 47 percent at 5 mg/hour; 68 percent after titration to 10 mg/hour; and 76 percent after titration to 15 mg/hour ( figure 3). Hypotension occurred in 13 percent and was symptomatic in almost 4 percent. All such patients responded to an infusion of normal saline. Weight-based dosing of IV diltiazem is further supported in a study of 252 patients who received IV diltiazem for acute rate control in the emergency department. Weight-based dosing (0.25 mg/kg) was associated with higher rates of rate control without increased adverse effects [18]. Hypotensive patient Asymptomatic and not on a vasopressor If the patient is mildly hypotensive but asymptomatic and does not require a vasopressor, we typically start metoprolol tartrate (short- acting) 25 mg by mouth every six hours and up-titrate as needed and as tolerated by 12.5 mg every six hours until the rate is controlled. Other IV beta blockers and calcium channel blockers may cause worsening hypotension. Patients with inadequate response Urgent combination therapy In patients who do not adequately respond to initial therapy with either an IV calcium channel blocker or IV beta blocker, we suggest the addition of IV digoxin as the second drug in combination therapy ( table 2). Digoxin should not be used if preexcitation is present. Urgent alternative therapy In patients who do not respond to or are intolerant of IV calcium channel blockers, beta blockers, and/or digoxin, we suggest IV amiodarone for acute control of the ventricular rate ( table 2). In such patients, the use of amiodarone for rate control is a short-term strategy (eg, hours to days). The drug should not be used if preexcitation is present. Careful attention to anticoagulation is also necessary because there is a small chance of cardioversion with amiodarone. If none of these therapies work, we typically opt for acute cardioversion rather than continued attempts at rate control (with evaluation of the left atrial appendage thrombus if warranted and clinically feasible and appropriate anticoagulation strategy). Symptomatic hypotension and/or on a vasopressor If the hypotension is symptomatic and requires a vasopressor, we typically opt for acute cardioversion rather than rate control (with evaluation of the left atrial appendage thrombus if warranted and appropriate https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 9/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate anticoagulation strategy). (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) If the patient is on a vasopressor that can exacerbate tachycardia (eg, epinephrine or norepinephrine), we may elect to switch the vasopressor to a vasoconstrictor (eg, phenylephrine) if this is a reasonable alternative. (See "Use of vasopressors and inotropes".) Management of patients in whom cardioversion is unsuccessful is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) Alternative therapies we do not suggest We do not use IV magnesium for control of ventricular rate in AF despite a small body of supporting evidence because very few patients are refractory to other therapies and would require it. Magnesium does have physiologic properties suggesting that it might have efficacy for rate control in AF. Initial small studies provided the rationale for a clinical trial in which 199 patients presenting with rapid AF (mean baseline ventricular rate 142 beats/min) were treated with usual therapy for rate control (most often digoxin) and randomly assigned to IV magnesium sulfate (2.5 g over 20 minutes followed by 2.5 g over two hours) or placebo [19]. Magnesium therapy increased the likelihood of achieving a ventricular rate <100 beats/min (65 versus 34 percent with placebo) and conversion to sinus rhythm (27 versus 12 percent with placebo). However, the difference in mean ventricular rate never exceeded 12 beats/min. The benefit of magnesium was modest, preferred primary therapies (calcium channel blocker, beta blocker) were used in only 12 to 13 percent of the patients, and magnesium was associated with side effects such as flushing and hypotension. A separate meta-analysis of six trials and 745 patients showed similar results [20]. Ivabradine blocks the pacemaker current, which is primarily thought to affect the sinoatrial node; however, some studies have shown that this current is also expressed in the atrioventricular node. Accordingly, a few studies are investigating the use of ivabradine for ventricular rate control in AF. One retrospective study of 18 patients with permanent AF showed average reduction in ventricular rate from 104.6 to 89 [21]. A randomized trial has been proposed to study ivabradine in patients with permanent AF (BRAKE-AF trial). At the present time, there is insufficient evidence to recommend the routine use of ivabradine for ventricular rate control in AF [22]. Transition to oral medications When making a transition from IV to oral therapy, we first ensure that the patient has tolerated the IV medication well. For instance, beta blockers may have a variety of adverse effects that can be important in patients with AF. (see "Major side effects of beta blockers") https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 10/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate When transitioning from IV to oral medications, we generally convert the total daily dose of the IV medication to an equivalent divided or long-acting oral dose of a medication in the same class. We often use pharmacy or pharmacist-based reference for appropriate conversion dosages. For example, if a patient is placed on IV diltiazem, we will usually convert the patient to a short or long-acting oral formulation of diltiazem that gives an equivalent daily dose of the medication. A general formula for approximate conversion from IV diltiazem to the daily oral dose is [(infusion rate x3)+3]x10 [23]. Example conversions from IV to oral dosing for diltiazem and metoprolol are shown in a table ( table 2). Other nuances of long-term rate control medications are discussed separately. (See 'Elective and long-term management' below.) ELECTIVE AND LONG-TERM MANAGEMENT Choice of nonurgent therapy Although there are differences in the efficacy of the various drugs, it is likely that monitoring and adjustments to therapy are more important components of successful rate-control strategies than the initial drug selection. Studies of specific pharmacologic agents for management of AF are small and heterogeneous. A study of 25 clinical trials showed no difference in effectiveness for different diltiazem or verapamil formulations (eg, immediate release, sustained release, or controlled delivery). There was also no evidence of differences in effectiveness for extended-release diltiazem and verapamil [24]. Long-acting or sustained-release formulations are typically preferred for chronic management to facilitate medication compliance. One study reviewed 54 trials that evaluated 17 different agents used for rate control [25]. The studies were all relatively small (6 to 239 patients) and had relatively short follow-up periods of eight weeks or less. Most compared single agents with placebo. Due to extensive variability in methods and outcome assessments, a meta-analysis of the trials could not be performed. However, the following observations were noted: Both beta blockers and calcium channel blockers were effective Diltiazem, verapamil, and most beta blockers (atenolol, metoprolol, timolol, pindolol, and nadolol) were all effective in reducing the ventricular rate during rest and exercise. The beta blockers labetalol, xamoterol, and celiprolol were less effective at rest but did reduce ventricular rates during exercise. Mixed results for digoxin versus placebo Trials comparing digoxin with placebo reported inconsistent results, particularly when heart rate during exercise was assessed. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 11/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Digoxin was effective when added to beta blocker or calcium channel blocker The combination of digoxin with a beta blocker or calcium channel blocker reduced heart rate both at rest and with exertion. Thus, pharmacologic therapy can achieve adequate rate control in approximately 80 percent of patients. However, achieving this goal requires close monitoring, medication adjustments, and often combination therapy. Although there are differences in the efficacy of the various drugs, it is likely that monitoring and adjustments to therapy are more important components of successful rate-control strategies than the initial drug selection. AFFIRM trial Among evaluations of rate-control drugs, the study with the largest sample size and longest follow-up is a post-hoc analysis from the AFFIRM trial [26]. The original AFFIRM trial assigned patients with AF to either rate or rhythm control, and a post-hoc analysis compared the efficacy of various rate-control medications. In this post-hoc study, over 2000 patients assigned to rate control were given medications according to physician preference. Effectiveness of rate control was defined as a resting heart rate 80 beats/minute, exertional heart rate 110 beats/min during six-minute walk test or average heart rate during 24-hour ambulatory Holter monitoring ECG 100 beats/min (at least 18 hours of interpretable monitoring), and no heart rate >110 percent maximum predicted age-adjusted exercise heart rate. The overall effectiveness (meeting both rest and exertion heart rate goals) of initial monotherapy therapy was most effective for beta blockers (59 percent), followed by digoxin (58 percent), and then calcium channel blockers (38 percent). At five-year follow-up, adequate rate control increased from approximately 60 to 80 percent of patients. Only 58 percent of patients had adequate rate control with the first drug or combination used. Patients initially treated with a beta blocker were significantly less likely than those treated with calcium channel blockers or digoxin to have their drug regimen changed. Limitations of this study included nonrandom assignment of specific rate-control medication and an inadequate baseline assessment of heart rate. Initial therapy In patients who do require elective management or in those transitioning to long-term therapy, we usually suggest an oral beta blocker or nondihydropyridine calcium channel blocker. Reasons for these preferences are discussed below. Beta blockers We prefer beta blockers in the following groups of patients: Recent myocardial infarction. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 12/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Heart failure due to systolic dysfunction. Inappropriate increase in ventricular rate during exercise. Surges in sympathetic function that trigger AF. Beta blockers may be particularly useful in states of high adrenergic tone (eg, postoperative AF) [27,28]. In the first two settings, beta blockers improve patient survival. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) Oral beta blockers are widely used as primary therapy for rate control in chronic AF. Beta blockers decrease the resting ventricular rate and blunt the ventricular rate response to exercise. Most beta blockers appear to have similar efficacy. For patients with heart failure with systolic dysfunction, the preferred agents for treatment are metoprolol succinate, carvedilol, carvedilol continuous release, and bisoprolol. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, beta-blocker therapy was shown to be effective in achieving goal ventricular rate in 59 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) There is the most supporting evidence for metoprolol, atenolol, and nadolol. Atenolol and nadolol have the advantages of a long half-life and are typically given once daily. Long- acting propranolol can be effective. Bisoprolol and carvedilol are also used ( table 2). It should be noted that beta blockers are contraindicated or relatively contraindicated in some patients, and others cannot tolerate the side effects. (See "Major side effects of beta blockers".) Beta blockers have additional properties that may make them preferred to other rate- control drugs in some AF patients: Patients with systolic dysfunction This is discussed separately. (See "The management of atrial fibrillation in patients with heart failure" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 13/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Patients with AF triggered by sympathetic dysfunction Beta blockers may reduce the incidence of AF recurrence in patients with episodes of AF that are triggered by surges in sympathetic activity [27,28]. Some patients with paroxysmal AF also have sinus node dysfunction, with tachycardia- bradycardia syndrome. In such patients, beta blockers with intrinsic sympathomimetic activity may be useful since they are less likely to worsen bradycardia than standard beta blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Calcium channel blocker A nondihydropyridine calcium channel blocker is preferred in patients with chronic lung disease and in patients who do not tolerate beta blockers. Among the calcium channel blockers, verapamil has a somewhat greater blocking effect on the AV node than diltiazem, and the choice between these drugs is often dictated by side effects ( table 2). In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, calcium channel blocker therapy was shown to be effective in achieving goal ventricular rate in 38 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) Calcium channel blockers have a number of characteristics that need to be considered when they are administered to patients with AF: Variable effect on sinoatrial (SA) nodal function Although both verapamil and diltiazem have an inhibitory effect on the sinus node, their vasodilator effects cause a reflex release of catecholamines that usually maintains or slightly accelerates the SA nodal rate. However, patients with the sinus node dysfunction may be particularly sensitive to the effects of calcium channel blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Negative ionotropic effects Both verapamil and diltiazem have negative inotropic effects, although this is less pronounced with diltiazem. As a result, these drugs should be used with caution in patients with heart failure and in patients taking other negative inotropes, such as beta blockers. They should not be given if the patient is hypotensive. Side effects in older patients With either verapamil or diltiazem, it should be remembered that older patients are more likely to develop side effects, especially those that are cardiac in nature. Although the same maximum doses may be tolerated, it is usually appropriate to titrate more slowly. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 14/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate In summary, diltiazem and verapamil should not be given to patients with severe heart failure (New York Heart Failure class III or IV), preexcitation syndrome, or significant hypotension. In addition, these drugs should be given with caution to patients with sinus node dysfunction, significant liver disease, mild hypotension, marked first-degree heart block, or the concurrent intake of other drugs that inhibit SA nodal function or slow AV nodal conduction. Considerations for patients with heart failure are discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction' and "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with preserved ejection fraction'.) Combination therapy Combination therapy In patients initially tried on a beta blocker or calcium channel

heart rate during 24-hour ambulatory Holter monitoring ECG 100 beats/min (at least 18 hours of interpretable monitoring), and no heart rate >110 percent maximum predicted age-adjusted exercise heart rate. The overall effectiveness (meeting both rest and exertion heart rate goals) of initial monotherapy therapy was most effective for beta blockers (59 percent), followed by digoxin (58 percent), and then calcium channel blockers (38 percent). At five-year follow-up, adequate rate control increased from approximately 60 to 80 percent of patients. Only 58 percent of patients had adequate rate control with the first drug or combination used. Patients initially treated with a beta blocker were significantly less likely than those treated with calcium channel blockers or digoxin to have their drug regimen changed. Limitations of this study included nonrandom assignment of specific rate-control medication and an inadequate baseline assessment of heart rate. Initial therapy In patients who do require elective management or in those transitioning to long-term therapy, we usually suggest an oral beta blocker or nondihydropyridine calcium channel blocker. Reasons for these preferences are discussed below. Beta blockers We prefer beta blockers in the following groups of patients: Recent myocardial infarction. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 12/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Heart failure due to systolic dysfunction. Inappropriate increase in ventricular rate during exercise. Surges in sympathetic function that trigger AF. Beta blockers may be particularly useful in states of high adrenergic tone (eg, postoperative AF) [27,28]. In the first two settings, beta blockers improve patient survival. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) Oral beta blockers are widely used as primary therapy for rate control in chronic AF. Beta blockers decrease the resting ventricular rate and blunt the ventricular rate response to exercise. Most beta blockers appear to have similar efficacy. For patients with heart failure with systolic dysfunction, the preferred agents for treatment are metoprolol succinate, carvedilol, carvedilol continuous release, and bisoprolol. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, beta-blocker therapy was shown to be effective in achieving goal ventricular rate in 59 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) There is the most supporting evidence for metoprolol, atenolol, and nadolol. Atenolol and nadolol have the advantages of a long half-life and are typically given once daily. Long- acting propranolol can be effective. Bisoprolol and carvedilol are also used ( table 2). It should be noted that beta blockers are contraindicated or relatively contraindicated in some patients, and others cannot tolerate the side effects. (See "Major side effects of beta blockers".) Beta blockers have additional properties that may make them preferred to other rate- control drugs in some AF patients: Patients with systolic dysfunction This is discussed separately. (See "The management of atrial fibrillation in patients with heart failure" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 13/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Patients with AF triggered by sympathetic dysfunction Beta blockers may reduce the incidence of AF recurrence in patients with episodes of AF that are triggered by surges in sympathetic activity [27,28]. Some patients with paroxysmal AF also have sinus node dysfunction, with tachycardia- bradycardia syndrome. In such patients, beta blockers with intrinsic sympathomimetic activity may be useful since they are less likely to worsen bradycardia than standard beta blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Calcium channel blocker A nondihydropyridine calcium channel blocker is preferred in patients with chronic lung disease and in patients who do not tolerate beta blockers. Among the calcium channel blockers, verapamil has a somewhat greater blocking effect on the AV node than diltiazem, and the choice between these drugs is often dictated by side effects ( table 2). In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, calcium channel blocker therapy was shown to be effective in achieving goal ventricular rate in 38 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) Calcium channel blockers have a number of characteristics that need to be considered when they are administered to patients with AF: Variable effect on sinoatrial (SA) nodal function Although both verapamil and diltiazem have an inhibitory effect on the sinus node, their vasodilator effects cause a reflex release of catecholamines that usually maintains or slightly accelerates the SA nodal rate. However, patients with the sinus node dysfunction may be particularly sensitive to the effects of calcium channel blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Negative ionotropic effects Both verapamil and diltiazem have negative inotropic effects, although this is less pronounced with diltiazem. As a result, these drugs should be used with caution in patients with heart failure and in patients taking other negative inotropes, such as beta blockers. They should not be given if the patient is hypotensive. Side effects in older patients With either verapamil or diltiazem, it should be remembered that older patients are more likely to develop side effects, especially those that are cardiac in nature. Although the same maximum doses may be tolerated, it is usually appropriate to titrate more slowly. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 14/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate In summary, diltiazem and verapamil should not be given to patients with severe heart failure (New York Heart Failure class III or IV), preexcitation syndrome, or significant hypotension. In addition, these drugs should be given with caution to patients with sinus node dysfunction, significant liver disease, mild hypotension, marked first-degree heart block, or the concurrent intake of other drugs that inhibit SA nodal function or slow AV nodal conduction. Considerations for patients with heart failure are discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction' and "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with preserved ejection fraction'.) Combination therapy Combination therapy In patients initially tried on a beta blocker or calcium channel blocker with persistently high ventricular rates, the combination of a beta blocker and a calcium channel blocker can be tried in most patients. In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, this combination was shown to be effective in achieving goal ventricular rate in 59 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) Adding digoxin In patients who do not achieve adequate rate control on maximum- tolerated doses of a beta blocker and nondihydropyridine calcium channel blocker together, we suggest adding digoxin if AV nodal ablation, pharmacologic rhythm control, or catheter ablation of AF are not being considered. (see "Atrial fibrillation: Atrioventricular node ablation", section on 'Indications'). When digoxin is added to either a beta blocker or calcium channel blocker or to both, patients should be carefully monitored for bradycardia and hypotension. Also, patients with significant left ventricular dysfunction may not tolerate triple therapy ( table 2). Digoxin levels should be obtained periodically for the purpose of detecting potentially high levels. We attempt to keep the level in the lower half of the normal range. Digoxin toxicity is discussed in detail separately. (See "Digitalis (cardiac glycoside) poisoning" and "Cardiac arrhythmias due to digoxin toxicity".) Combination therapy with digoxin was studied in a post-hoc analysis of the AFFIRM rate versus rhythm control trial. The overall effectiveness (meeting both rest and exertion ventricular rate goals) of combination therapy with digoxin was described as follows: Beta blocker plus digoxin 68 percent https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 15/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Calcium channel blocker plus digoxin 60 percent Beta blocker plus calcium channel blocker plus digoxin 76 percent The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) In patients with AF, the following summarizes evidence regarding the efficacy and safety of digoxin as a combination drug for rate control: Three large observational studies of digoxin use among patients with AF have yielded mixed results, with at least two finding an increase in all-cause mortality of about 20 percent [29,30] and one finding no increase [31]. The best available evidence regarding the relationship between digoxin use in AF patients (either alone or in combination with a beta blocker or calcium channel blocker) and mortality comes from a post-hoc subgroup analysis of the ARISTOTLE trial of anticoagulant therapy [32]. The following findings were reported: Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR] 1.09; 95% CI 0.96-1.23) Digoxin concentration 1.2 ng/mL was associated with an increased risk of death (adjusted HR 1.56; 95% CI 1.20-2.04) New digoxin use was associated with a higher risk of death (adjusted HR 1.78; 95% CI 1.37-2.31) Having heart failure versus not having heart failure did not change these effects. The use of digoxin in patients with AF and heart failure is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction'.) Alternative medications Amiodarone For patients with AF, there is a limited role for amiodarone as a long-term agent for rate control. Due to the increased risk of side effects, the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline states that amiodarone can be used as second-line therapy for chronic rate control only when other therapies are unsuccessful or contraindicated [33,34]. We agree with this guideline, and for patients treated with amiodarone for long-term rate control of AF, we require careful follow-up, including monitoring for known medication side effects. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 16/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Data supporting the use of amiodarone as a rate-control agent for AF are more limited compared with evidence supporting its use for pharmacologic rhythm control of AF. In one study, IV amiodarone (7 mg/kg), flecainide, or placebo were given to 98 patients with recent-onset AF (0.5 to 72 hours) [35]. Even when AF did not revert to sinus rhythm, amiodarone promptly slowed the ventricular rate during the eight-hour observation period ( figure 4). In addition, in critically ill patients, amiodarone may be less likely to cause systemic hypotension than IV diltiazem [36]. Digoxin monotherapy In patients without hypotension or severe heart failure, we do not generally use digoxin as a single agent for the following reasons [33,34]: Association with higher mortality in patients with high digoxin levels. It may not be appropriate for use in older patients. There are additional reasons that digoxin should not be used as an initial drug for rate control in most settings Generally less effective rate control compared with beta blockers or calcium channel blockers, particularly during exercise when vagal tone is low and sympathetic tone is high [37]. This is because the drug slows the ventricular rate during AF, primarily by vagotonic inhibition of AV nodal conduction. Digoxin is only rarely effective at terminating AF. One study suggests that digoxin may have a similar efficacy for rate control as bisoprolol [38]. However, the higher toxicity profile and risk of mortality prevent us from using it as monotherapy. Refractory to rate-control medications Some patients will not achieve adequate ventricular rate control with pharmacologic therapy due to poor response to or intolerance of initial, combination, and alternative medications. In such cases, the options are as follows: AV nodal ablation with permanent pacemaker placement If a patient has high refractory ventricular rates despite initial therapy, combination, and other pharmacotherapies, they may be referred for AV nodal ablation with pacemaker placement to achieve adequate rate control of their AF. This is discussed in detail separately. (See "Atrial fibrillation: Atrioventricular node ablation".) Switching to rhythm control In some patients, it is prudent to reconsider a rhythm- control strategy to control the ventricular rate. This is discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Atrioventricular node ablation".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 17/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Monitoring and adjustments These are more important components of successful rate- control strategies than initial drug selection. Once an effective rate control regimen has been developed, it is reasonable to periodically assess adequacy of rate control; monitoring for both bradycardia and tachycardia is important. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Additional cardiac testing' and 'Evaluation and goal ventricular rate' above.) It is also reasonable to monitor left ventricular function in patients treated with a pharmacologic rate-control strategy to make sure that a tachycardia-related cardiomyopathy has not developed. Some experts perform an echocardiogram every two to three years in asymptomatic patients with higher average ventricular rates while others do not. (See "Tests to evaluate left ventricular systolic function".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)") Beyond the Basics topic (See "Patient education: Atrial fibrillation (Beyond the Basics)".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 18/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate SUMMARY AND RECOMMENDATIONS Rationale and rate goal We slow the ventricular rate in patients with atrial fibrillation (AF) to treat symptoms, stabilize hemodynamics symptoms, and/or to avoid tachycardia- mediated cardiomyopathy. (See 'Rationale for rate lowering' above.) We target a mean rate-control goal of <85 beats/min for symptomatic patients with AF. For asymptomatic patients with permanent AF, a more lenient mean rate-control goal of <110 beats/min may be reasonable. (See 'Evaluation and goal ventricular rate' above.) Caution in preexcitation syndrome In these patients, initial therapy is aimed at reversion to sinus rhythm rather than rate control. Amiodarone, digoxin, verapamil, diltiazem, and adenosine are contraindicated with preexcited AF, and beta blockers also should not be used. (See "Treatment of arrhythmias associated with the Wolff-Parkinson- White syndrome", section on 'When to avoid AV nodal blockers'.) Urgent therapy Normotensive patients In these patients, we suggest intravenous nondihydropyridine calcium channel blockers such as diltiazem ( table 2) (Grade 2B). (See 'Urgent therapy' above and 'Normotensive patient' above.) In patients who do not adequately respond to initial therapy with either an IV calcium channel blocker or IV beta blocker, we suggest the addition of IV digoxin as the second drug in combination therapy (Grade 2C). (See 'Combination therapy' above.) Asymptomatic hypotensive patients who do not require vasopressor We typically start oral metoprolol tartrate (short-acting) until the rate is controlled. In patients who do not adequately respond to initial therapy with either IV calcium channel blocker or IV beta blocker, we suggest the addition of IV digoxin as the second drug in combination therapy ( table 2). (See 'Asymptomatic and not on a vasopressor' above.) In patients who do not respond to or are intolerant of IV calcium channel blockers, beta blockers, and/or digoxin, we suggest IV amiodarone as a short-term rate- control strategy ( table 2). Careful attention to anticoagulation is also necessary because there is a small chance of cardioversion with amiodarone. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 19/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate If none of these therapies work, we typically opt for acute cardioversion rather than continued attempts at rate control (with evaluation of the left atrial appendage thrombus if warranted and appropriate anticoagulation strategy). Symptomatic hypotensive patients and/or those requiring vasopressors If the hypotension is symptomatic and requires a vasopressor, we typically opt for acute cardioversion rather than rate control (with evaluation of the left atrial appendage thrombus if warranted and appropriate anticoagulation strategy). (See 'Symptomatic hypotension and/or on a vasopressor' above and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Elective and long-term management We start an oral beta blocker or nondihydropyridine calcium channel blocker. (See 'Choice of nonurgent therapy' above.) Combination therapy We try a combination of oral beta blocker and calcium channel blocker if monotherapy is not effective. (See 'Combination therapy' above.) Alternative short-term therapy In patients who do not respond to or are intolerant of IV calcium channel blockers, beta blockers, and/or digoxin, we suggest IV amiodarone for acute control of the ventricular rate (Grade 2C). (See 'Alternative medications' above.) Refractory to rate control In patients who have a poor response or intolerance to pharmacologic therapy, options are: Atrioventricular (AV) nodal ablation with permanent pacemaker placement. (See "Atrial fibrillation: Atrioventricular node ablation".) Switching to rhythm control. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Atrioventricular node ablation".) Monitoring Careful follow-up for side effects such as bradycardia or persistent tachycardia is imperative. (See 'Monitoring and adjustments' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 20/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate REFERENCES 1. Pritchett EL. Management of atrial fibrillation. N Engl J Med 1992; 326:1264. 2. Atrial fibrillation: current understandings and research imperatives. The National Heart, Lung, and Blood Institute Working Group on Atrial Fibrillation. J Am Coll Cardiol 1993; 22:1830. 3. Mariani MV, Pierucci N, Piro A, et al. Incidence and Determinants of Spontaneous Cardioversion of Early Onset Symptomatic Atrial Fibrillation. Medicina (Kaunas) 2022; 58. 4. Lindberg S, Hansen S, Nielsen T. Spontaneous conversion of first onset atrial fibrillation. Intern Med J 2012; 42:1195. 5. Pluymaekers NAHA, Dudink EAMP, Weijs B, et al. Clinical determinants of early spontaneous conversion to sinus rhythm in patients with atrial fibrillation. Neth Heart J 2021; 29:255. 6. Knight S, Lipoth J, Namvari M, et al. The Accuracy of Wearable Photoplethysmography Sensors for Telehealth Monitoring: A Scoping Review. Telemed J E Health 2023; 29:813. 7. Dorian P. Rate control in atrial fibrillation. N Engl J Med 2010; 362:1439. 8. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 9. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362:1363. 10. Groenveld HF, Tijssen JG, Crijns HJ, et al. Rate control efficacy in permanent atrial fibrillation: successful and failed strict rate control against a background of lenient rate control: data from RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation). J Am Coll Cardiol 2013; 61:741. 11. B hm M, Schwinger RH, Erdmann E. Different cardiodepressant potency of various calcium antagonists in human myocardium. Am J Cardiol 1990; 65:1039. 12. Salerno DM, Dias VC, Kleiger RE, et al. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atrial flutter. The Diltiazem-Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1989; 63:1046. 13. Ellenbogen KA, Dias VC, Plumb VJ, et al. A placebo-controlled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atrial fibrillation and atrial flutter: a multicenter study. J Am Coll Cardiol 1991; 18:891. 14. Ellenbogen KA, Dias VC, Cardello FP, et al. Safety and efficacy of intravenous diltiazem in atrial fibrillation or atrial flutter. Am J Cardiol 1995; 75:45. 15. Steinberg JS, Katz RJ, Bren GB, et al. Efficacy of oral diltiazem to control ventricular response in chronic atrial fibrillation at rest and during exercise. J Am Coll Cardiol 1987; 9:405. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 21/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 16. Roth A, Harrison E, Mitani G, et al. Efficacy and safety of medium- and high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation. Circulation 1986; 73:316. 17. Lan Q, Wu F, Han B, et al. Intravenous diltiazem versus metoprolol for atrial fibrillation with rapid ventricular rate: A meta-analysis. Am J Emerg Med 2022; 51:248. 18. Posen A, Bursua A, Petzel R. DOsing Strategy Effectiveness of Diltiazem in Atrial Fibrillation With Rapid Ventricular Response. Ann Emerg Med 2023; 81:288. 19. Davey MJ, Teubner D. A randomized controlled trial of magnesium sulfate, in addition to usual care, for rate control in atrial fibrillation. Ann Emerg Med 2005; 45:347. 20. Ramesh T, Lee PYK, Mitta M, Allencherril J. Intravenous magnesium in the management of rapid atrial fibrillation: A systematic review and meta-analysis. J Cardiol 2021; 78:375. 21. Chan YH, Hai JJ, Wong CK, et al. Ventricular rate control with ivabradine in patients with permanent atrial fibrillation. J Interv Card Electrophysiol 2022; 65:597. 22. Fontenla A, L pez-Gil M, Tamargo-Men ndez J, et al. Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project. Rev Esp Cardiol (Engl Ed) 2020; 73:368. 23. Sorrentino MJ. Switching from drip to oral diltiazem therapy. Postgrad Med 1998; 104:37. 24. Drug Class Review: Calcium Channel Blockers: Final Report, Oregon Health & Science Univer sity. 25. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 26. Olshansky B, Rosenfeld LE, Warner AL, et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol 2004; 43:1201. 27. Park CS, Lee HY. Clinical utility of sympathetic blockade in cardiovascular disease management. Expert Rev Cardiovasc Ther 2017; 15:277. 28. Dobrev D, Aguilar M, Heijman J, et al. Postoperative atrial fibrillation: mechanisms, manifestations and management. Nat Rev Cardiol 2019; 16:417. 29. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol 2014; 64:660. 30. Washam JB, Stevens SR, Lokhnygina Y, et al. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 22/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Lancet 2015; 385:2363. 31. Allen LA, Fonarow GC, Simon DN, et al. Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort. J Am Coll Cardiol 2015; 65:2691. 32. Lopes RD, Rordorf R, De Ferrari GM, et al. Digoxin and Mortality in Patients With Atrial Fibrillation. J Am Coll Cardiol 2018; 71:1063. 33. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 34. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 35. Donovan KD, Power BM, Hockings BE, et al. Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation. Am J Cardiol 1995; 75:693. 36. Delle Karth G, Geppert A, Neunteufl T, et al. Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias. Crit Care Med 2001; 29:1149. 37. Van Gelder IC, Rienstra M, Crijns HJ, Olshansky B. Rate control in atrial fibrillation. Lancet 2016; 388:818. 38. Kotecha D, Bunting KV, Gill SK, et al. Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial. JAMA 2020; 324:2497. Topic 938 Version 69.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 23/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate GRAPHICS Physiology of the AV node in AF The atrioventricular (AV) node modulates the response between the atrium and the ventricle. In atrial fibrillation, the atrial rate is up to 600 beats per minute while the ventricular rate in response is 90 to 170 beats per minute; this difference in the rate results from several properties of the AV node that impede impulse conduction. The AV node generates a slow action potential (AP) that is mediated by calcium (Ca++) ion currents; the node is therefore slow response tissue. Parasympathetic innervation via the vagus nerve also slows conduction, while activation of the sympathetic nervous system speeds conduction. Graphic 75699 Version 1.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 24/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Effect of drugs on AV function in AF Various drugs can slow conduction through the atrioventricular node in atrial fibrillation by altering its physiology. The calcium (Ca++) channel blockers, primarily diltiazem and verapamil, block the influx of calcium and therefore slow conduction by reducing the upstroke of the action potential; digoxin, carotid massage, Valsalva maneuver, and edrophonium are vagotonic and slow conduction by increasing parasympathetic effects on the node; beta blockers slow conduction by offsetting sympathetic inputs; and adenosine slows conduction only transiently by increasing potassium conduction and decreasing calcium influx. Graphic 51932 Version 1.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 25/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate [2,3] Six-minute walk test technique Flat, straight corridor 30 m (100 feet) in length Turnaround points marked with a cone Patient should wear comfortable clothes and shoes Patient rests in chair for at least 10 minutes prior to test (ie, no warm-up period) Heart rate and pulse oxygen saturation (SpO ) should be monitored throughout the test 2 If the patient is using supplemental oxygen, record the flow rate and type of device [1] Have patient stand and rate baseline dyspnea and overall fatigue using Borg scale* Set lap counter to zero and timer to six minutes Instruct the patient: Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog. Pivot briskly around the cone. Standardized encouragement statements should be provided at one minute intervals, such as "You are doing well. You have _ minutes to go" and "Keep up the good work. You have _ minutes to go." At the end of the test, mark the spot where the patient stopped on the floor If using a pulse oximeter, measure the pulse rate and SpO and record 2 [1] After the test record the Borg* dyspnea and fatigue levels Ask, "What, if anything, kept you from walking farther?" Calculate the distance walked and record Refer to UpToDate table on the modified Borg Scale. Reference: 1. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14:377. 2. American Thoracic Society. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166:111. 3. Holland AE, Spruit MA, Troosters T, et al. An o cial European Respiratory Society/American Thoracic Society technical standard: eld walking tests in chronic respiratory disease. Eur Respir J 2014; 44:1428. Graphic 90285 Version 4.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 26/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Medications and doses for ventricular rate control in adult patients with atrial fibrillation Medication IV dosing Oral dosing* Notes Diltiazem Bolus dosing: IR: 30 mg 4 times daily; increase as needed to IV regimen usually controls the ventricular First bolus: 0.25 achieve ventricular rate control; usual dose: 120 mg/kg (average adult dose: 20 mg) rate within 4 to 5 minutes. to 480 mg/day in 3 or 4 administered over 2 Some experts use a lower bolus dose of 5 divided doses. minutes; if dose is tolerated but does to 15 mg if there is concern for ER: 120 mg once daily or in 2 divided doses not produce desired response (ie, 20% hypotension. depending on formulation ; increase as reduction in baseline heart rate or heart rate 100 beats/min) within 15 minutes, administer a second needed to achieve ventricular rate control; usual dose: 120 to 480 mg/day. bolus. Second bolus: 0.35 mg/kg (average adult dose: 25 mg) administered over 2 minutes. In those who respond to the first or second bolus, initiate a continuous infusion at 5 to 10 mg/hour. May increase in 5 mg/hour increments as needed to a maximum of 15 mg/hour. Esmolol Rapid titration with bolus Not available as oral Due to short half-life, doses: preparation. useful when uncertain if patient will become 500 mcg/kg loading dose administered over 1 minute, hypotensive with a beta blocker. followed by a continuous infusion of 50 mcg/kg/minute. Reassess after 4 minutes. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 27/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate If response is inadequate, administer a second bolus of 500 mcg/kg and increase infusion to 100 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, administer a third and final bolus of 500 mcg/kg and increase infusion to 150 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, may increase infusion to a maximum of 200 mcg/kg/minute. OR Slow titration without bolus doses: Initiate continuous infusion at 50 mcg/kg/minute; if needed based on clinical response, may increase in 50 mcg/kg/minute increments at 30- minute intervals to a maximum of 200 mcg/kg/minute. Verapamil Bolus dosing: 5 to 10 mg administered over 2 to 3 IR: 40 mg 3 to 4 times daily; increase as needed Rate control is often achieved with 1 or 2 minutes; may repeat every 15 to 30 minutes as to achieve ventricular rate control; maximum dose: bolus doses. With IV administration, needed and tolerated. 480 mg/day in 3 to 4 divided doses. onset of effect on AV node is within 2 Once rate control is achieved with bolus doses, minutes and peak https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 28/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate initiate a continuous infusion at 5 mg/hour; ER : 120 or 180 mg once daily; increase as needed effect is in 10 to 15 minutes. titrate based on clinical to achieve ventricular rate Control of the ventricular response is response to a maximum of 20 mg/hour. control; maximum dose: 480 mg/day in 1 to 2 lost in approximately divided doses. 90 minutes if repeated boluses or a maintenance infusion are not given. Metoprolol Bolus dosing: 2.5 to 5 mg IR (metoprolol tartrate): administered over 2 minutes; may repeat at 5- 25 mg twice daily; increase dose gradually minute intervals up to a (eg, by 12.5 mg every 6 total dose of 15 mg. hours) as needed and tolerated to achieve While subsequent doses can be given intravenously, ventricular rate control; maximum dose: 100 mg the optimal regimen is not well defined, and oral twice daily. administration is ER (metoprolol succinate): preferable. 50 mg once daily; increase dose gradually as tolerated to achieve ventricular rate control; maximum dose: 400 mg once daily. Propranolol Bolus dosing: 1 mg IR: 10 mg 3 to 4 times administered over 1 minute; may repeat at 2- daily; increase dose gradually as tolerated to minute intervals for up to 3 achieve ventricular rate doses. control; maximum dose: 40 mg 3 to 4 times daily. ER: 60 mg once daily; increase as needed to achieve ventricular rate control up to 160 mg once daily. Digoxin TDD: 0.25 to 0.5 mg administered over several TDD: 0.5 mg once, followed by 0.25 mg every May use as add-on therapy in patients who minutes, followed by 0.25 mg every 6 hours for a 6 hours for a total loading dose of 0.75 to 1.5 mg.

Effect of drugs on AV function in AF Various drugs can slow conduction through the atrioventricular node in atrial fibrillation by altering its physiology. The calcium (Ca++) channel blockers, primarily diltiazem and verapamil, block the influx of calcium and therefore slow conduction by reducing the upstroke of the action potential; digoxin, carotid massage, Valsalva maneuver, and edrophonium are vagotonic and slow conduction by increasing parasympathetic effects on the node; beta blockers slow conduction by offsetting sympathetic inputs; and adenosine slows conduction only transiently by increasing potassium conduction and decreasing calcium influx. Graphic 51932 Version 1.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 25/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate [2,3] Six-minute walk test technique Flat, straight corridor 30 m (100 feet) in length Turnaround points marked with a cone Patient should wear comfortable clothes and shoes Patient rests in chair for at least 10 minutes prior to test (ie, no warm-up period) Heart rate and pulse oxygen saturation (SpO ) should be monitored throughout the test 2 If the patient is using supplemental oxygen, record the flow rate and type of device [1] Have patient stand and rate baseline dyspnea and overall fatigue using Borg scale* Set lap counter to zero and timer to six minutes Instruct the patient: Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog. Pivot briskly around the cone. Standardized encouragement statements should be provided at one minute intervals, such as "You are doing well. You have _ minutes to go" and "Keep up the good work. You have _ minutes to go." At the end of the test, mark the spot where the patient stopped on the floor If using a pulse oximeter, measure the pulse rate and SpO and record 2 [1] After the test record the Borg* dyspnea and fatigue levels Ask, "What, if anything, kept you from walking farther?" Calculate the distance walked and record Refer to UpToDate table on the modified Borg Scale. Reference: 1. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14:377. 2. American Thoracic Society. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166:111. 3. Holland AE, Spruit MA, Troosters T, et al. An o cial European Respiratory Society/American Thoracic Society technical standard: eld walking tests in chronic respiratory disease. Eur Respir J 2014; 44:1428. Graphic 90285 Version 4.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 26/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Medications and doses for ventricular rate control in adult patients with atrial fibrillation Medication IV dosing Oral dosing* Notes Diltiazem Bolus dosing: IR: 30 mg 4 times daily; increase as needed to IV regimen usually controls the ventricular First bolus: 0.25 achieve ventricular rate control; usual dose: 120 mg/kg (average adult dose: 20 mg) rate within 4 to 5 minutes. to 480 mg/day in 3 or 4 administered over 2 Some experts use a lower bolus dose of 5 divided doses. minutes; if dose is tolerated but does to 15 mg if there is concern for ER: 120 mg once daily or in 2 divided doses not produce desired response (ie, 20% hypotension. depending on formulation ; increase as reduction in baseline heart rate or heart rate 100 beats/min) within 15 minutes, administer a second needed to achieve ventricular rate control; usual dose: 120 to 480 mg/day. bolus. Second bolus: 0.35 mg/kg (average adult dose: 25 mg) administered over 2 minutes. In those who respond to the first or second bolus, initiate a continuous infusion at 5 to 10 mg/hour. May increase in 5 mg/hour increments as needed to a maximum of 15 mg/hour. Esmolol Rapid titration with bolus Not available as oral Due to short half-life, doses: preparation. useful when uncertain if patient will become 500 mcg/kg loading dose administered over 1 minute, hypotensive with a beta blocker. followed by a continuous infusion of 50 mcg/kg/minute. Reassess after 4 minutes. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 27/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate If response is inadequate, administer a second bolus of 500 mcg/kg and increase infusion to 100 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, administer a third and final bolus of 500 mcg/kg and increase infusion to 150 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, may increase infusion to a maximum of 200 mcg/kg/minute. OR Slow titration without bolus doses: Initiate continuous infusion at 50 mcg/kg/minute; if needed based on clinical response, may increase in 50 mcg/kg/minute increments at 30- minute intervals to a maximum of 200 mcg/kg/minute. Verapamil Bolus dosing: 5 to 10 mg administered over 2 to 3 IR: 40 mg 3 to 4 times daily; increase as needed Rate control is often achieved with 1 or 2 minutes; may repeat every 15 to 30 minutes as to achieve ventricular rate control; maximum dose: bolus doses. With IV administration, needed and tolerated. 480 mg/day in 3 to 4 divided doses. onset of effect on AV node is within 2 Once rate control is achieved with bolus doses, minutes and peak https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 28/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate initiate a continuous infusion at 5 mg/hour; ER : 120 or 180 mg once daily; increase as needed effect is in 10 to 15 minutes. titrate based on clinical to achieve ventricular rate Control of the ventricular response is response to a maximum of 20 mg/hour. control; maximum dose: 480 mg/day in 1 to 2 lost in approximately divided doses. 90 minutes if repeated boluses or a maintenance infusion are not given. Metoprolol Bolus dosing: 2.5 to 5 mg IR (metoprolol tartrate): administered over 2 minutes; may repeat at 5- 25 mg twice daily; increase dose gradually minute intervals up to a (eg, by 12.5 mg every 6 total dose of 15 mg. hours) as needed and tolerated to achieve While subsequent doses can be given intravenously, ventricular rate control; maximum dose: 100 mg the optimal regimen is not well defined, and oral twice daily. administration is ER (metoprolol succinate): preferable. 50 mg once daily; increase dose gradually as tolerated to achieve ventricular rate control; maximum dose: 400 mg once daily. Propranolol Bolus dosing: 1 mg IR: 10 mg 3 to 4 times administered over 1 minute; may repeat at 2- daily; increase dose gradually as tolerated to minute intervals for up to 3 achieve ventricular rate doses. control; maximum dose: 40 mg 3 to 4 times daily. ER: 60 mg once daily; increase as needed to achieve ventricular rate control up to 160 mg once daily. Digoxin TDD: 0.25 to 0.5 mg administered over several TDD: 0.5 mg once, followed by 0.25 mg every May use as add-on therapy in patients who minutes, followed by 0.25 mg every 6 hours for a 6 hours for a total loading dose of 0.75 to 1.5 mg. do not adequately respond to a calcium total loading dose of 0.75 to 1.5 mg. channel blocker and/or beta blocker; not Maintenance dose (for use after administration of IV or oral TDD): 0.125 generally used as monotherapy. to 0.25 mg once daily. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 29/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Amiodarone Loading dose: 150 mg over 10 minutes followed by 1 mg/minute for 6 hours, Following IV infusion, administer 400 to 1200 May use in select patients requiring mg/day in divided doses urgent therapy who are intolerant of other then 0.5 mg/minute for 18 hours; may administer to complete a total (IV plus oral) loading dose of preferred agents (ie, repeat boluses of 150 mg over 10 minutes as needed, not to exceed 6 to 8 additional bolus doses approximately 10 grams. Consider overlapping IV calcium channel blockers, beta blockers, and oral therapy for 24 to 48 hours. digoxin). Due to small chance of per 24 hours. cardioversion, careful attention to Usual maintenance dose: 100 to 200 mg once daily. anticoagulation is necessary. This table shows doses of drugs that can be used for ventricular rate control in adult patients with atrial fibrillation who do not have heart failure. It should be used in conjunction with UpToDate content on control of ventricular rate in patients with atrial fibrillation. When initiating or altering therapy, use of a drug interactions database, such as Lexicomp drug interactions, is advised. IV: intravenous; IR: immediate-release; ER: extended-release; AV: atrioventricular; TDD: total digitalizing dose. Oral dosing in this table is initial dosing for patients requiring nonurgent therapy, unless otherwise noted. For patients transitioning from IV to oral therapy, UpToDate authors typically convert the total daily dose of the IV medication to an equivalent divided or long-acting oral dose of a medication in the same class. Refer to UpToDate topic on control of ventricular rate in patients with atrial fibrillation for discussion. Diltiazem extended-release is available in 12- and 24-hour formulations. Refer to a drug information reference, such as Lexicomp drug information included with UpToDate, or local product information for dosing details. Verapamil ER delayed-onset capsules (ie, Verelan PM and generics) are not interchangeable with other ER formulations and are intended for management of hypertension. Digoxin has a narrow therapeutic window and can cause significant toxicity. Individual patient characteristics (eg, kidney function, body habitus, concomitant medications) should be carefully considered when determining loading and maintenance dosing regimens. Dosing in this table does not account for dose adjustments. For discussion of dosing and monitoring, refer to UpToDate content on treatment with digoxin. Amiodarone use is associated with a relatively high incidence of adverse effects. Refer to related UpToDate content for discussion, including monitoring. Graphic 141646 Version 2.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 30/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Dose response to diltiazem for rate control in atrial fibrillation Kaplan-Meier analysis of the percentage of patients maintaining a therapeutic rate control response to each dose level of intravenous diltiazem infusion in patients who initially responded to bolus diltiazem. Maintenance of rate control was greater at doses of 10 to 15 mg/h. Data from Ellenbogen KA, Dias VC, Cardello FP, et al. Am J Cardiol 1995; 75:45. Graphic 80630 Version 3.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 31/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Efficacy of amiodarone in rate control for atrial fibrillation Effect of intravenous placebo, amiodarone, and flecainide on the ventricular response to atrial fibrillation in patients who failed to revert to sinus rhythm after the initiation of therapy. Amiodarone slowed the ventricular response, an effect that was not seen with flecainide or placebo. Although flecainide was less effective for rate control, it was associated with earlier reversion to sinus rhythm than amiodarone or placebo. Note that the time scale is nonlinear. Data from Donovan KD, Power BM, Hockings GE, et al. Am J Cardiol 1995; 75:693. Graphic 81119 Version 3.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 32/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Contributor Disclosures Rachel Kaplan, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 33/33

7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Embolic risk and the role of anticoagulation in atrial flutter : Warren J Manning, MD, Jordan M Prutkin, MD, MHS, FHRS : Bradley P Knight, MD, FACC, Scott E Kasner, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 11, 2022. INTRODUCTION Most patients with atrial flutter should be considered for chronic anticoagulation in a manner similar to those with atrial fibrillation (AF). This recommendation is based not only on the fact atrial flutter carries a risk for systemic embolization but also that these patients usually have episodes of AF. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) Our approach to anticoagulation applies to all types of atrial flutter, whether it is typical or atypical. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) PREVALENCE OF THROMBUS Many patients with atrial flutter have alternating periods of atrial fibrillation (AF) making it difficult to know the exact risk of thrombus formation (and subsequent embolization) specifically attributable to atrial flutter [1]. Atrial mechanical function is not normal in patients with atrial flutter. However, transmitral and left atrial appendage Doppler echocardiography commonly demonstrate more organized atrial and atrial appendage mechanical function with sustained atrial flutter, as opposed to AF, in which organized atrial contraction is absent. One study performed transesophageal https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 1/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate echocardiography (TEE) immediately before and after cardioversion in 19 patients with atrial flutter and 44 patients with AF with the following findings [2]: Prior to cardioversion, patients with atrial flutter had greater left atrial appendage peak ejection velocities and shear rates compared to those with AF. After cardioversion, left atrial appendage peak ejection velocities and shear rates decreased in both groups of patients, but the impaired left atrial appendage function was less pronounced in patients with atrial flutter. New or increased spontaneous echo contrast, a marker of blood stasis, occurred significantly less often in patients with atrial flutter (21 versus 50 percent for AF). Like AF, the vast majority of thrombi among patients with atrial flutter are located in the left atrial appendage. TEE evidence of atrial thrombi has been documented in a number of reports of patients with atrial flutter not receiving chronic anticoagulation [3-8]. As with AF, the thrombi overwhelmingly involve or are exclusively within the left atrial appendage. The frequency with which this occurs may vary with the duration of the arrhythmia and other risk factors (similar to AF) as illustrated by the following observations: Two series evaluated patients with atrial flutter for a mean duration of 33 to 36 days who did not have a history of AF, rheumatic heart disease, or a prosthetic heart valve [3,4]. A left atrial thrombus was found in 1 to 1.6 percent, a right atrial thrombus in 1 percent, and left atrial spontaneous echo contrast in 11 to 13 percent [3,4]. In one of these reports, there was a close correlation between a history of thromboembolism and periods of AF during atrial flutter [4]. Atrial thrombi and spontaneous echo contrast may be more common in patients with atrial flutter of longer duration. In a TEE study of 30 patients with persistent atrial flutter (duration 6.4 months), two patients (7 percent) had thrombus in the left atrial appendage, and 25 percent had spontaneous echo contrast prior to cardioversion [5]. As described below in more depth (see 'Cardioversion' below) and mentioned above, left atrial contractile function (as measured by peak atrial appendage ejection velocity) transiently declines after cardioversion in many patients and is considered a manifestation of atrial "stunning." Left atrial thrombus was present in 5 of 47 consecutive patients (11 percent) with atrial flutter for a mean duration of 28 days who did not have a history of AF or mitral stenosis [6]. https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 2/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate EMBOLIC RISK The risk of embolization in atrial flutter is related to risk factors and the need for cardioversion or ablation. Risk factors and lone atrial flutter Risk factors for clinical thromboembolism include valvular heart disease (eg, rheumatic valve disease, prosthetic valves), increasing age, depressed left ventricular systolic function or heart failure, hypertension, diabetes, vascular disease, and a history of thromboembolism. Atrial flutter without an identifiable risk factor is called lone atrial flutter. It is relatively uncommon, occurring in only 3 of 181 adults with atrial flutter in a population-based study (1.7 percent) [9] and in 8 percent of children and young adults with atrial flutter in a multicenter series [10]. The embolic risk associated with lone atrial flutter was evaluated in a review of 59 mostly elderly patients with lone atrial flutter (mean age at diagnosis 70 years); 75 percent developed recurrent episodes or persistent atrial flutter [11]. At presentation, these patients did not have coronary heart disease, hyperthyroidism, heart failure, valvular heart disease, congenital heart disease, obstructive lung disease, uncontrolled hypertension, or known antecedent atrial fibrillation (AF). At the time of diagnosis, 25 were treated with aspirin and six with warfarin; at last follow-up, 28 were treated with aspirin and 13 with warfarin. The following observations were noted at an average follow-up of 10 years: AF developed in 33 patients (56 percent), which was paroxysmal in 25 and permanent in eight, highlighting the rationale for managing anticoagulation in patients with atrial flutter in a manner similar to AF. One or more ischemic cerebrovascular events occurred in 19 patients (32 percent) at a mean age of 80 years, including six who were in AF at the time of the event. Compared to age- and sex-adjusted expected rates of thromboembolism, the thromboembolic risk was significantly increased in the patients with lone atrial flutter (hazard ratio 5.2 in patients with controlled hypertension and 2.5 in patients without a history of hypertension). When compared with patients with lone AF, the patients with lone atrial flutter had, after adjustment for age and sex, a significantly higher rate of thromboembolism (hazard ratio 2.6). The risk was lower and no longer significant when only patients without a history of hypertension were included (hazard ratio 1.9). (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'.) https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 3/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate Long-term flutter There is an increased risk for clinical thromboembolism in patients with persistent atrial flutter compared to the general population without atrial arrhythmias [1,12-14]. In a systematic review based upon limited data, the long-term embolic risk in patients with sustained atrial flutter (with varying risk factors) was estimated to be approximately 3 percent per year [12]. For comparison, the rate of thromboembolism in patients with AF <1 percent per year in patients with no risk factors, with the rate increasing with increasing CHA DS -VASc score 2 2 ( table 1). One problem with interpreting these data, as mentioned previously, is that many patients with persistent atrial flutter also have episodes of AF (34 percent in the preceding report [13]) also have episodes of AF. In a review of the Medicare database, the risk of stroke was significantly increased in patients with atrial flutter (relative risk 1.41 compared to a control group). In these patients, the relative risk was 1.56 in patients who subsequently had an episode of AF (similar to the risk with AF alone), while those with isolated atrial flutter had a stroke risk not significantly different from the control population (relative risk 1.11) ( figure 1) [1]. Cardioversion Although the risk of clinical thromboembolization at the time of cardioversion is increased compared to individuals not undergoing cardioversion, the absolute thromboembolism risk of cardioversion for pure atrial flutter is not known with a high degree of confidence due to the fact that many patients included in reports of atrial flutter cardioversion related events also had episodes of AF (but happened to be in atrial flutter at the time of cardioversion) [3,13,15-17]. The studies that have attempted to evaluate the risk at the time of cardioversion studied different populations. Some included patients with a prior history of thromboembolism and were thus more likely to report high event rates, while studies in which at least some patients were anticoagulated or underwent precardioversion transesophageal echocardiography (TEE) to assess for thrombus were more likely to report low event rates [3,12-17]. Three early studies found no embolic events in a total of 314 patients with atrial flutter (and without AF) who underwent elective cardioversion for atrial flutter without anticoagulation prior to or after cardioversion [4,18,19]. However, the overall incidence is 0.6 to 1.0 percent [16,17] with a higher risk in patients with a history of AF or underlying heart disease [13,15]. In a meta- analysis of these studies, the rate of short-term emboli ranged from 0 to 7.3 percent [12]. Embolization may be related to a transient reduction in atrial mechanical function leading to post-cardioversion thrombus formation, referred to as atrial "stunning," and is present after successful cardioversion of atrial flutter [2,5,6,20,21]. In one report, left atrial appendage peak ejection velocity fell by 26 percent within 15 minutes of cardioversion and almost 50 percent of https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 4/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate subjects had new or more pronounced spontaneous echo contrast [5]. These changes predispose to de novo thrombus formation [15]. Similar observations have been made in patients with AF. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial stunning'.) The severity of atrial stunning appears to be somewhat less pronounced in atrial flutter than in AF, which could explain the lower embolic risk after cardioversion in atrial flutter. In a report that compared 19 patients with atrial flutter with 44 patients with AF, the left atrial appendage peak ejection velocity was significantly higher in the patients with atrial flutter at baseline (42 versus 28 cm/sec in atrial fibrillation) and after cardioversion (27 versus 15 cm/sec) [2]. In addition, new or more pronounced spontaneous echo contrast was significantly less likely in those with atrial flutter (21 versus 50 percent). Radiofrequency catheter ablation Atrial stunning (see 'Cardioversion' above) also occurs after radiofrequency catheter ablation [21,22]. The likelihood of developing atrial stunning and its duration were assessed in a review of 15 patients with persistent atrial flutter (mean duration 17 months) and seven with paroxysmal atrial flutter who underwent radiofrequency catheter ablation [21]. Significant left atrial appendage stunning and spontaneous echo contrast on TEE were observed after ablation in 80 percent of those with persistent flutter but in none with paroxysmal atrial flutter, suggesting that, like AF, left atrial stunning in atrial flutter is related to the duration of the arrhythmia and not the mode of reversion. These changes resolved after three weeks of sustained sinus rhythm. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.) PREVENTION OF EMBOLIZATION Patients with long-term atrial flutter Patients with persistent or recurrent atrial flutter who also have periods of atrial flutter-fibrillation should be treated in the same manner as those with pure atrial fibrillation (AF) [23,24]. This recommendation also applies to patients with atrial flutter who have a prior history of AF. Though the optimal management of atrial flutter without any history of AF is uncertain and may be more limited ( figure 1) [1], we and others recommend that patients with pure atrial flutter be managed similar to those with AF [25]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) Anticoagulation with warfarin (goal international normalized ratio [INR] between 2.0 and 3.0) has been recommended to prevent embolization in patients with atrial flutter, similar to patients with AF (eg, using CHA DS -VASc criteria for nonvalvular AF). Of the non-vitamin K oral 2 2 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 5/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate anticoagulants tested for stroke prevention in AF, in the large clinical trials, only apixaban enrolled patients with atrial flutter [26]. It is likely, however, that there is similar efficacy of all the non-vitamin K oral anticoagulants (eg, apixaban, dabigatran, edoxaban, and rivaroxaban) for atrial flutter as well as AF. At the time of cardioversion We and others recommend that anticoagulation leading to, at the time of, and after cardioversion of atrial flutter be managed in a manner similar to that for AF [23,24]. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Patients presenting with an initial episode of atrial flutter should be treated in a manner similar to those presenting with their first episode of AF, including a transthoracic echocardiogram (TTE) to evaluate for congenital heart disease, valve disease, and left ventricular systolic function. After radiofrequency catheter ablation Anticoagulation recommendations following catheter ablation of AF are discussed separately. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'Anticoagulation after RF catheter ablation'.) RECOMMENDATIONS OF OTHERS The 2016 European Society of Cardiology guidelines for the management of atrial fibrillation, the 2015 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline on the management of adult patient with supraventricular tachycardia, and the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline on the management of patients with atrial fibrillation (and its 2019 focused update) similarly recommend managing anticoagulation in patients with atrial flutter in a manner similar to those in atrial fibrillation [23,27-31], recognizing that no report has been sufficiently large to accurately define both the risk of embolization and benefit of antithrombotic therapy in a pure atrial flutter population. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 6/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate The risk of embolization in atrial flutter is related to clinical risk factors and underlying cardiac disease (eg, valve disease). However, the exact rates are not known, in part due to the presence of atrial fibrillation (AF) in most cohorts studied and the coexistence of AF and atrial flutter in most individuals. (See 'Long-term flutter' above.) For patients with atrial flutter, with or without AF, we recommend an anticoagulant strategy identical to that used in patients with AF (Grade 1B). (See 'Prevention of embolization' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Biblo LA, Yuan Z, Quan KJ, et al. Risk of stroke in patients with atrial flutter. Am J Cardiol 2001; 87:346. 2. Grimm RA, Stewart WJ, Arheart K, et al. Left atrial appendage "stunning" after electrical cardioversion of atrial flutter: an attenuated response compared with atrial fibrillation as the mechanism for lower susceptibility to thromboembolic events. J Am Coll Cardiol 1997; 29:582. 3. Corrado G, Sgalambro A, Mantero A, et al. Thromboembolic risk in atrial flutter. The FLASIEC (FLutter Atriale Societ Italiana di Ecografia Cardiovascolare) multicentre study. Eur Heart J 2001; 22:1042. 4. Schmidt H, von der Recke G, Illien S, et al. Prevalence of left atrial chamber and appendage thrombi in patients with atrial flutter and its clinical significance. J Am Coll Cardiol 2001; 38:778. 5. Weiss R, Marcovitz P, Knight BP, et al. Acute changes in spontaneous echo contrast and atrial function after cardioversion of persistent atrial flutter. Am J Cardiol 1998; 82:1052. 6. Irani WN, Grayburn PA, Afridi I. Prevalence of thrombus, spontaneous echo contrast, and atrial stunning in patients undergoing cardioversion of atrial flutter. A prospective study using transesophageal echocardiography. Circulation 1997; 95:962. 7. Bikkina M, Alpert MA, Mulekar M, et al. Prevalence of intraatrial thrombus in patients with atrial flutter. Am J Cardiol 1995; 76:186. 8. Orsinelli DA, Pearson AC. Usefulness of transesophageal echocardiography to screen for left atrial thrombus before elective cardioversion for atrial fibrillation. Am J Cardiol 1993; 72:1337. https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 7/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate 9. Granada J, Uribe W, Chyou PH, et al. Incidence and predictors of atrial flutter in the general population. J Am Coll Cardiol 2000; 36:2242. 10. Garson A Jr, Bink-Boelkens M, Hesslein PS, et al. Atrial flutter in the young: a collaborative study of 380 cases. J Am Coll Cardiol 1985; 6:871. 11. Halligan SC, Gersh BJ, Brown RD Jr, et al. The natural history of lone atrial flutter. Ann Intern Med 2004; 140:265. 12. Ghali WA, Wasil BI, Brant R, et al. Atrial flutter and the risk of thromboembolism: a systematic review and meta-analysis. Am J Med 2005; 118:101. 13. Seidl K, Hauer B, Schwick NG, et al. Risk of thromboembolic events in patients with atrial flutter. Am J Cardiol 1998; 82:580. 14. Lanzarotti CJ, Olshansky B. Thromboembolism in chronic atrial flutter: is the risk underestimated? J Am Coll Cardiol 1997; 30:1506. 15. Mehta D, Baruch L. Thromboembolism following cardioversion of "common" atrial flutter. Risk factors and limitations of transesophageal echocardiography. Chest 1996; 110:1001. 16. Elhendy A, Gentile F, Khandheria BK, et al. Thromboembolic complications after electrical cardioversion in patients with atrial flutter. Am J Med 2001; 111:433. 17. Gallagher MM, Hennessy BJ, Edvardsson N, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol 2002; 40:926. 18. Arnold AZ, Mick MJ, Mazurek RP, et al. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992; 19:851. 19. Chalasani P, Cambre S, Silverman ME. Direct-current cardioversion for the conversion of atrial flutter. Am J Cardiol 1996; 77:658. 20. Jordaens L, Missault L, Germonpr E, et al. Delayed restoration of atrial function after conversion of atrial flutter by pacing or electrical cardioversion. Am J Cardiol 1993; 71:63. 21. Sparks PB, Jayaprakash S, Vohra JK, et al. Left atrial "stunning" following radiofrequency catheter ablation of chronic atrial flutter. J Am Coll Cardiol 1998; 32:468. 22. Welch PJ, Afridi I, Joglar JA, et al. Effect of radiofrequency ablation on atrial mechanical function in patients with atrial flutter. Am J Cardiol 1999; 84:420. 23. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e531S. https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 8/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate 24. American College of Cardiology Foundation, American Heart Association, European Society of Cardiology, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Circulation 2013; 127:1916. 25. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:546S. 26. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981. 27. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 28. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 29. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 30. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 31. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2016; 67:e27. Topic 1066 Version 30.0 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 9/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate GRAPHICS Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc 2 2 (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients (n = 73,538) Stroke and thromboembolism event 2 2 rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 10/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate 5 8942 15.26 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 11/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate Stroke risk in atrial flutter is related to concomitant atrial fibrillation Among 395,147 patients over 65 years of age, the risk of stroke in those with chronic atrial flutter is increased when atrial fibrillation (AF) is also present and is equivalent to the risk associated with only AF. The incidence of stroke in those with isolated atrial flutter is the same as the risk in the control patients who have no atrial arrhythmia. Data from Biblo LA, Yuan Z, Quan KJ, et al. Am J Cardiol 2001; 87:346. Graphic 67382 Version 2.0 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 12/13 7/6/23, 3:08 PM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Jordan M Prutkin, MD, MHS, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 13/13

7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Implantable cardioverter-defibrillators: Optimal programming : Martin K Stiles, MB ChB, PhD, FRACP, FHRS : Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 11, 2022. INTRODUCTION Ventricular tachyarrhythmia is a common cause of sudden cardiac arrest (SCA) and sudden cardiac death (SCD). Although cardiopulmonary resuscitation, including chest compressions and assisted ventilation, can provide transient circulatory support for the patient with SCA, the only effective approach for terminating pulseless ventricular tachycardia (VT) or ventricular fibrillation (VF) is electrical defibrillation. Success with external defibrillation led to the development of an implantable defibrillator in the mid-1960s. It was not until 1980 that the first automatic internal defibrillator was implanted in humans [1,2]. (See "Pathophysiology and etiology of sudden cardiac arrest".) Because of its high success rate in terminating VF rapidly, along with the results of multiple clinical trials showing improvement in survival, implantable cardioverter-defibrillator (ICD) implantation is generally considered the first-line treatment option for the secondary prevention of SCD and for primary prevention in certain populations at high risk of SCD due to VT/VF. Alternatives to ICD implantation include antiarrhythmic drugs, ablative surgery, catheter ablation, and, in rare individuals, cardiac transplantation. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation' and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Pharmacologic therapy in survivors of sudden cardiac arrest".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 1/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate This topic will review the approach to optimal ICD programming. The general indications for ICD implantation as well as the components and functionalities of the ICD, the clinical trials documenting the efficacy of an ICD in different clinical settings (including both secondary and primary prevention), complications of ICD placement, and follow-up care of patients with ICDs are discussed separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Cardiac implantable electronic devices: Long-term complications" and "Cardiac implantable electronic devices: Patient follow- up" and "Cardiac implantable electronic devices: Periprocedural complications".) OVERVIEW OF ICD PROGRAMMING AND THERAPIES General approach to programming Our approach to optimal ICD programming seeks to emphasize that, while the decision to implant the ICD and perioperative management are important factors in patient outcome, much of the risk/benefit ratio of these devices is determined by the way they are programmed. When recommending ICD programming settings, we are often guided in our general approach by randomized trials. However, specific patient circumstances may mandate a different approach from that of generic programming recommendations. In particular, evidence for ICD programming is often gleaned from adult populations, and direct translation to pediatric patients may not always be appropriate; this is particularly pertinent for rate cutoff settings in children, teenagers, and young adults. Thus, programming guidelines are simply that: guidelines. They are not always applicable to every patient, and care must be taken to tailor therapy to the individual. Fortunately, most patients do not have such specific requirements, and an empiric approach to programming is reasonable for the majority. Readers who wish for a more comprehensive overview on ICD programming are directed to the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and Testing and the 2019 focused update discussing manufacturer-specific programming [3,4]. Types of ICD programming and therapies As ICD technology has evolved, the number and variety of available programming and therapeutic options have dramatically increased [3]. Contemporary ICDs have a variety of flexible programming and therapeutic options [5]: Bradycardia settings While ICDs are implanted for the treatment of tachyarrhythmias, patients occasionally have a need for bradycardia support also. In addition, the pacemaker settings of an ICD may influence patient outcome even when an indication for bradycardia https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 2/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate pacing does not exist [6,7]. A general principle of ICD bradycardia pacing settings is to minimize the percentage of right ventricular pacing. (See "Overview of pacemakers in heart failure".) Cardiac resynchronization therapy (CRT) The indications for ICD implantation and CRT overlap to a degree. A general principle of ICD bradycardia pacing settings in patients with CRT-defibrillators is to maximize the percentage of biventricular pacing. A detailed discussion of CRT devices is presented separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Arrhythmia detection At their most basic, ICDs detect arrhythmias based on duration criteria (an arrhythmia must be of sufficient length to be significant) and rate criteria (an arrhythmia must exceed a programmed rate cutoff to be significant). Therefore, an episode must be both sufficiently long and sufficiently rapid to trigger therapy. Recommendations for rate criteria and duration have evolved over time and are further refined by the addition of supraventricular tachycardia (SVT) discriminators and algorithms to reduce detection of noise (both physiological and nonphysiological sources of noise). Arrhythmia discrimination The ability to distinguish arrhythmias requiring ICD therapy from other heart rhythms is crucial to appropriate ICD function. ICDs can be programmed to assess heart rate, suddenness of onset, atrioventricular (AV) dissociation, interval stability, QRS templates, and other parameters to help identify ventricular tachyarrhythmias requiring therapy. Noise discrimination Algorithms to avoid signal noise being detected as an arrhythmia have evolved over time. These aim to prevent physiological noise (eg, T-wave oversensing) and nonphysiological noise (eg, electromagnetic interference) from being falsely detected as ventricular arrhythmia and triggering inappropriate therapy. (See "Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment".) Multiple available therapies ICDs can treat ventricular tachyarrhythmias with antitachycardia pacing (ATP) and/or shocks. These therapies have parameters that can be varied and adjusted (eg, the number, rate, and duration of ATP cycles and the delivered energy for cardioversion and defibrillation). In each therapy zone, a sequence of therapies (ATP, cardioversion, or defibrillation) can be delivered. After each therapy, the device reevaluates the rhythm, and if the tachyarrhythmia persists, the next therapy is delivered. These therapies are discussed in detail below. (See 'Tachycardia therapies' below.) Multiple zones ICDs can be programmed to provide different therapies to tachyarrhythmias in up to three heart rate zones. The rationale for this approach is that https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 3/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate relatively slow ventricular tachyarrhythmias (eg, ventricular tachycardia [VT] with a heart rate <180 beats per minute) may not lead to loss of consciousness or other unstable symptoms for at least several minutes. Additionally, VT can often be terminated with ATP, which can be delivered quickly and with no pain and minimal battery drainage. By contrast, faster VTs (eg, heart rate >250 beats per minute) are more likely to be unstable and poorly tolerated; they can require high-energy defibrillation and can become increasingly difficult to terminate if definitive therapy is delayed. Thus, the most successful approach for such fast VTs is high-energy defibrillation. However, there is some evidence that ATP can be effective even for very fast VTs and that self-termination is not uncommon. This has led to strategies employing longer detection times and attempts to terminate VT with ATP before or during capacitor charging. (See 'Duration criteria for ventricular arrhythmia detection' below.) Avoidable therapy A relatively new concept to ICD programming is to recognize therapy as not just appropriate (delivered for ventricular arrhythmia) or inappropriate (delivered for SVT or noise), but to recognize that any given therapy may be avoidable. It is increasingly accepted that self-terminating arrhythmias are common and that programming to treat slower or short duration arrhythmias tends to overtreat patients, often with negative consequences. Thus, eliminating avoidable therapy is one of the aims of modern ICD programming. (See 'Our approach to tachycardia therapies' below.) TACHYCARDIA DETECTION Modern ICD programming for the detection of arrhythmias utilizes higher detection rates, longer detection durations, antitachycardia pacing (ATP), algorithms that discriminate supraventricular tachycardia (SVT) from ventricular tachycardia (VT), and specific electrocardiographic (ECG) features to minimize the sensing of noise. All these strategies combined provide the patient with the security of ICD therapy when needed with the aim of eliminating inappropriate and avoidable therapies. ICDs detect arrhythmias based on two primary criteria (both must be satisfied): Duration criteria An arrhythmia must be of sufficient length to be significant Rate criteria An arrhythmia must exceed a programmed rate cutoff With early generation ICDs in clinical practice, the focus was on rapid detection and treatment of VT/ventricular fibrillation (VF). This was necessary due to the inherent limitations of the devices: long charge times, potential for undersensing, monophasic waveforms, and the knowledge that https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 4/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate defibrillation thresholds increased with VF duration. Therefore, early generation ICDs were programmed to detect and treat arrhythmia rapidly. With subsequent technological improvements in ICDs, resulting in the advent of stored electrograms, improved electrogram sensing, and the move toward primary prevention of sudden cardiac death, there has been a gradual appreciation of the adverse effects of an ICD shock. Initially, the focus was mainly on inappropriate shocks (ie, shocks delivered for nonlife- threatening arrhythmias or because of oversensing). Oversensing is divided into physiological oversensing (eg, T-wave oversensing or double counting of QRS) or nonphysiological oversensing (eg, electromagnetic interference or lead fracture noise). More recently, there has been an appreciation that ventricular arrhythmias may self-terminate without therapy and that slower arrhythmias need not necessarily be treated. Early shock therapies for benign or self- terminating ventricular arrhythmias may appear to be appropriate shocks, but if they were not going to be absolutely necessary, then shocks for these rhythms are avoidable shocks. Our approach to tachycardia detection Our recommendations for tachycardia detection programming in patients with an ICD are generally in agreement with the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter- Defibrillator Programming and Testing and the 2019 focused update discussing manufacturer- specific programming [3,4]. For patients with any ICD (primary or secondary prevention), we recommend that tachyarrhythmia detection duration criteria be programmed to require the tachycardia to continue for at least 6 to 12 seconds (or for 30 intervals), rather than a shorter duration, before completing detection. For patients with a primary prevention ICD (and for secondary prevention patients in whom the VT rate is not known), we recommend that the slowest tachycardia therapy zone limit should be programmed between 185 and 200 beats per minute. For secondary prevention ICD patients for whom the clinical VT rate is known, we program the slowest tachycardia therapy zone at least 10 beats per minute below the documented tachycardia rate but not faster than 200 beats per minute. The aim of the above three recommendations is to reduce the total number of ICD therapies. Faster minimum rates for detection may be appropriate in young patients or those in whom SVT- VT discriminators cannot reliably distinguish SVT from VT, provided no clinical VT exists below this rate. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 5/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Programming multiple tachycardia detection zones can be useful to allow effective use of tiered therapy and/or SVT-VT discriminators. This may allow a shorter delay for faster (and potentially unstable) arrhythmias while allowing slower (and potentially stable) arrhythmias a longer time to self-terminate and/or more attempts at ATP. Discrimination algorithms to distinguish SVT from VT should be programmed to include rhythms with rates faster than 200 beats per minute and potentially up to 230 beats per minute to reduce inappropriate therapies. Discriminator time-out functions should generally be programmed OFF. T-wave oversensing algorithms should usually be ON. Lead-failure alerts should be activated to detect potential lead problems. Duration criteria for ventricular arrhythmia detection For the vast majority of patients with modern ICDs, the devices should be programmed to a longer duration interval. This will allow for a greater number of nonsustained arrhythmias to terminate spontaneously, without any ICD therapy, thereby reducing avoidable shocks ( table 1). Early ICDs used short duration "detection" criteria of up to five seconds (variable depending on manufacturer and tachycardia rate) before either ATP or charging to shock. This time period was comprised of detection time plus duration or number of intervals. More recently, awareness of potential harm from avoidable shocks has led to strategies of prolonged detection settings, with data derived from numerous studies, initially from the nonrandomized PREPARE and RELEVANT studies but subsequently from three randomized trials [8-12]: MADIT-RIT, a randomized trial of three different ICD programming and therapy strategies, assigned 1500 patients receiving an ICD for primary prevention (both ischemic and nonischemic cardiomyopathy) to one of three programming strategies [10]: "Conventional" therapy programming 2.5-second delay at rates of 170 to 199 beats per minute; 1-second delay at rates of 200 or more beats per minute. Delayed therapy programming 60-second delay at rates of 170 to 199 beats per minute; 12-second delay at rates of 200 to 249 beats per minute; 2.5-second delay at rates of 250 or more beats per minute. High-rate therapy programming No therapy at rates of 170 to 199 beats per minutes; 2.5-second delay at rates of 200 or more beats per minute. Patients were followed for an average of 1.4 years, with the primary outcome being the time to first delivery of inappropriate therapy and two prespecified secondary outcomes (all-cause mortality and first syncopal episode). While relatively few patients received https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 6/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate appropriate ICD therapy (242 patients, or 16 percent, with 70 percent of appropriate therapies being ATP), the primary outcome occurred in 152 patients (11 percent). When compared with conventional programming: Inappropriate therapies were lower in both high-rate therapy (hazard ratio [HR] 0.21, 95% CI 0.13-0.34) and the delayed therapy (HR 0.24, 95% CI 0.15-0.40) groups. All-cause mortality was lower in the high-rate therapy group (HR 0.45, 95% CI 0.24-0.85), and there was a trend toward lower mortality in the delayed therapy group that was not statistically significant (HR 0.56, 95% CI 0.30-1.02). The ADVANCE III trial, a randomized, single blind trial of 1902 patients receiving an ICD for primary (1425 patients, 75 percent) or secondary (477 patients, 25 percent) prevention, assigned patients to "standard" detection (18/24) or long detection (30/40) strategies for ventricular rates >187 beats per minute (cycle length 320 milliseconds) [11]. Programming for treatment options of ATP and shocks was the same for all participants. Long detection was associated with a highly significant reduction of overall therapies (appropriate and inappropriate ATP and/or shocks), inappropriate shocks, and all-cause hospitalizations. In the PROVIDE trial, which randomized 1670 patients to experimental programming (two VT and one VF zone requiring 25-, 18-, and 12-beat detections, respectively) or conventional programming (12-beat detection in each of two zones), there was a 36 percent reduction in two-year all-cause shock rate and reduction in mortality with a prolonged detection interval (HR 0.7, 95% CI 0.50-0.98) [12]. These studies (PREPARE, RELEVANT, MADIT-RIT, ADVANCE III, and PROVIDE) consistently showed that programming a prolonged detection algorithm benefited the patient without compromising safety. Importantly, ADVANCE III included a subset of secondary prevention patients (published separately) in whom similar findings were reported [13]. Subsequent meta-analyses of these trials have demonstrated a mortality benefit in the combined therapy-reduction arms without an increased risk of syncope [14,15]. However, there are some limitations to be acknowledged, including that not all ICD manufacturers are represented in these trials [16], there are no data from aging devices in which charge times can be long, and there will always be specific situations in which prolonged detection times may be deleterious (eg, ventricular undersensing). Rate criteria for ventricular arrhythmia detection Ventricular tachyarrhythmia detection by implantable devices is primarily based on rate. For the vast majority of patients with modern ICDs, the devices should be programmed to a higher rate at which therapies should be provided. This will prevent inappropriate shocks for slower supraventricular tachyarrhythmias and allow https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 7/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate for slower nonsustained arrhythmias to terminate spontaneously, thereby reducing avoidable shocks. Heart rates can be extremely rapid during ventricular tachyarrhythmias, and it is less likely that such rates are achieved during supraventricular tachyarrhythmias, thus making rate a powerful component of arrhythmia discrimination. However, VT can also have slower rates in the range of those of supraventricular tachyarrhythmias or even of sinus tachycardia. Therefore, any rate cutoff will always imply a trade-off between maximizing sensitivity for ventricular tachyarrhythmia detection at the expense of inappropriate detection of fast supraventricular tachyarrhythmias and maximizing specificity at the expense of some slow VTs going undetected [17]. The recognition of a significant number of inappropriate therapies in ICD patients, as well as their potentially deleterious consequences, prompted the development of studies that tested if programming faster rate criteria would reduce avoidable ICD therapies and, particularly, shocks. In the MADIT-RIT trial, the primary end point of first occurrence of inappropriate therapy was observed in 20 percent of the conventional group and in 4 percent of the high-rate group over a mean follow-up of 1.4 years. ICD shocks occurred in 4 and 2 percent in the conventional and high-rate groups, respectively. Importantly, all-cause mortality was approximately double in the conventional group (6.6 percent) than in the high-rate group (3.2 percent). Observational studies have demonstrated that even a rate cutoff of 220 beats per minute has been shown to be safe and reduce avoidable shocks [18]. (See 'Duration criteria for ventricular arrhythmia detection' above.) Supraventricular tachyarrhythmia discrimination SVTs are common in patients with ventricular arrhythmias [19-21]. If the ICD interprets an SVT incorrectly as VT, the patient may experience inappropriate shocks, which occur in up to 20 to 25 percent of patients [22-25]. The majority of inappropriate shocks for SVT occur within the range of 181 to 213 beats per minute. Therefore, adjustment of rate criteria and the deployment of SVT discriminators are most likely to be successful at around these rates. Once the duration and rate criteria for VT/VF have been satisfied, SVT discriminators aim to classify the rhythm as SVT (therapies for VT withheld) or VT (therapies delivered). Examples of algorithms used to distinguish SVT from VT include: AV dissociation Identification of different and distinct rhythms in the atrium and the ventricle, particularly when the ventricular rate exceeds the atrial rate, is consistent with AV dissociation seen with VT. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 8/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Atrial rate exceeds ventricular rate In dual-chamber devices (and those with an atrial sensing ring on the ventricular lead), information from the atrial electrode may help differentiate VT from atrial tachyarrhythmias [19-21,26]. The primary discriminator is heart rate; if the atrial rate is greater than the ventricular rate, the arrhythmia is almost certainly SVT, usually atrial fibrillation (AF) or atrial flutter. However, care must be taken not to withhold therapy in the case of a "dual tachycardia" (eg, VT with coexisting AF). QRS templates Many devices record templates of the ventricular electrogram during intrinsic rhythm. During a tachyarrhythmia, the device compares the electrograms during the tachycardia with the baseline recording. Deviations in shape, duration, and polarity all increase the likelihood that the device will categorize the tachycardia as VT or VF. An interval stability criterion detects irregularity in cycle length and can distinguish AF from VT. Obvious pitfalls with this are regularization of AF (perhaps from antiarrhythmic drugs) and irregular VT [27,28]. An onset criterion monitors the cycle length for the sudden or abrupt onset of a high ventricular rate (indicative of a VT) rather than a gradually increasing heart rate (as might be seen in exercise-induced sinus tachycardia). As this discriminator is applied "once only," care should be taken not to allow this discriminator to withhold therapy indefinitely (in case of VT/VF occurring after the rate threshold is crossed gradually). Some dual-chamber devices have "chamber of onset" as a discriminator. Each of these discrimination features is designed to help prevent SVT from being erroneously categorized as VT or VF; therefore, they reduce the likelihood of inappropriate shocks. However, as none of these discriminators are 100 percent specific for SVT, these discriminators can be programmed to "time out" so that the ICD eventually treats the arrhythmia as VT/VF. As discriminator reliability has improved, recommendations have moved away from endorsing the use of the "time out" feature [29]. In addition to discrimination criteria, most contemporary ICDs have a "second look" feature designed to help prevent or limit inappropriate shocks. Once the criteria for delivering a shock are met, the capacitors charge. This takes several seconds (more as the device ages). Following charging, the device reevaluates the heart rhythm to confirm that the tachycardia persists and has not spontaneously terminated. If the tachycardia has resolved, the shock will be diverted. Dual-chamber ICDs can be programmed for mode switching to prevent inappropriate tracking of atrial arrhythmias. In addition, some devices can deliver therapy for atrial tachyarrhythmias such as pace termination of atrial flutter or AF [20,21]. (See "The role of pacemakers in the prevention of atrial fibrillation".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 9/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Therapeutic alternatives for patients who continue to have frequent inappropriate shocks for atrial tachyarrhythmias include antiarrhythmic drugs and catheter ablation. (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Treatment of breakthrough arrhythmias'.) Noise discriminators Noise detected by an ICD can lead to inappropriate shocks. The source of noise may be physiological or nonphysiological. Although less common than inappropriate shocks due to SVT, noise-related therapies can be repetitive and cause serious harm to a patient. Physiological noise can be due to T-wave oversensing, double counting of QRS events, or P wave oversensing. Displacement of the ICD lead into the fibrillating atrium is also possible in the immediate post-implant period. The problem of T-wave oversensing has led to several methods to identify this, including high bandpass filters, altering the sensing bipole, reducing sensitivity, and looking for specific repetitive patterns consistent with T-wave oversensing. Additionally, physiological noise due to T-wave oversensing can often be remedied with reprogramming (eg, adjusting sensitivity, etc). Nonphysiological noise is most commonly related to ICD lead failure. Several high-profile lead recalls have brought this issue to the forefront and led to the development of algorithms designed to alert the clinician early to a potential lead failure and to delay or divert therapy if noise is the likely reason for the episode detected. Generally, the following features are identified when detecting lead noise: Intervals are very short; so short as to be physiologically unlikely Such short intervals are transient and repetitive If noise is present on the lead distal bipole, it is absent on the wide bipole (shock coil electrogram) The first two of these are used to provide alerts (vibratory, audible, or via home monitor). The third may be used to withhold shocks. Many of the algorithms are designed for particular lead failure (eg, Lead Integrity Alert on Medtronic Devices are designed to detect Fidelis fractures, SecureSense on St. Jude Medical Devices to detect Riata failures). Accompanying data, such as a change in lead impedance, sensing, or threshold, are frequently available from remote monitoring and may assist in diagnosing lead failure. TACHYCARDIA THERAPIES https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 10/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Modern ICD programming for the treatment of arrhythmias utilizes antitachycardia pacing (ATP) as the initial therapy for many patients with ventricular tachycardia (VT), given the high rates of successful VT termination following ATP. If ATP is unsuccessful, or if the presenting rhythm is ventricular fibrillation (VF), ICDs can deliver one or more defibrillatory shocks in an effort to terminate VT/VF. Although therapies delivered by the ICD aim to abort sudden cardiac death, both appropriate and inappropriate ICD shocks have been associated with a considerable increase in the risk of mortality [30-35]. In the SCD-HeFT trial, the risk of mortality was fivefold higher in patients who received appropriate ICD shocks and twofold higher in patients who received inappropriate shocks [31]. Likewise, in pooled data from four studies of 2135 ICD patients, shocked VT was associated with a 32 percent increase in the risk of mortality, and patients receiving a shock had lower survival rates than patients treated with ATP only [32]. ICD shocks are likely to be a marker of advanced heart disease, but defibrillation therapies have been associated with troponin release and increased left ventricular dysfunction. Additionally, ICD shocks deplete the battery and are painful for the patient. Our approach to tachycardia therapies Our recommendations for tachycardia therapy programming in patients with an ICD are generally in agreement with the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter- Defibrillator Programming and Testing and the 2019 focused update discussing manufacturer- specific programming [3,4]. For all patients with structural heart disease and ATP-capable devices, ATP therapy should be active for all ventricular tachyarrhythmia detection zones to include arrhythmias up to 230 beats per minute (except when ATP is documented to be ineffective or proarrhythmic). This aims to reduce total shocks. ATP therapy should be programmed to deliver at least one ATP attempt with a minimum of eight stimuli and a cycle length 84 to 88 percent of the tachycardia cycle length for ventricular tachyarrhythmias. Burst ATP therapy is preferred to ramp ATP therapy. We activate shock therapy in all ventricular tachyarrhythmia therapy zones to improve the termination rate of ventricular tachyarrhythmias, except in rare cases where ATP only might be prescribed for hemodynamically stable monomorphic VT. We program the initial shock energy to the maximal available energy in the highest rate detection zone to improve the first shock termination of ventricular arrhythmias, unless specific defibrillation testing demonstrates efficacy at lower energies. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 11/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Antitachycardia pacing VT, particularly reentrant VT associated with scar from a prior myocardial infarction, can often be terminated by pacing the ventricle at a rate slightly faster than the VT. When a paced impulse enters the reentrant circuit during a tachycardia, it can depolarize a segment of the circuit, leaving that segment refractory when the reentrant wave returns, thus terminating the tachycardia. ATP, or overdrive pacing, refers to the delivery of short bursts (eg, eight beats) of rapid ventricular pacing to terminate VT. Although a variety of algorithms exist, ATP is usually programmed to be delivered at a rate that is slightly faster (eg, commencing at a cycle length 10 to 15 percent shorter) than the rate of the detected tachycardia [36-39]. In several studies, as many as 95 percent of episodes of spontaneous VT were successfully terminated with ATP [36,38-41]. Utilization of ATP therapy has evolved from tailored therapy used only if shown to be effective in the electrophysiology (EP) lab to empiric programming as routine therapy. Delivery of ATP has been shown to reduce inappropriate shocks and appropriate shocks and improve quality of life [8-11,42-46]. This programming may improve survival [10]. Indeed, several studies have shown that ATP is effective at terminating slow and fast VT with very low rates of adverse events [41,47- 52]. In the PainFREE Rx II trial, 634 patients with ICDs were randomly assigned to empiric ATP or shock for initial therapy of spontaneous rapid VT (188 to 250 beats per minute) [47]. After a mean follow-up of 11 months, 431 episodes of rapid VT occurred in 98 patients. Pacing was successful in terminating 229 of 284 such episodes in the ATP arm (81 percent). The incidence of VT acceleration, syncope, and sudden death was the same in the ATP and shock arms (seven versus five episodes). The use of ATP during ICD capacitor charging has been clinically validated as safe and effective [51]. It is important to recognize that inappropriate therapies, including inappropriate ATP, delivered primarily in the setting of supraventricular arrhythmias have been associated with increased mortality in the MADIT-RIT and MADIT-CRT trials [33,53]. However, the overall safety of ATP and its value in preventing avoidable ICD shocks are well established. One concern with ATP is that rapid pacing can cause VT to degenerate into VF. For this reason, all ICDs also have high-energy defibrillation, which can be used after ATP as a backup therapy if necessary. However, this theoretical problem associated with ATP appears to be uncommon [23,37,47,48,54,55]. ATP programming Although the ideal number of ATP attempts (ie, bursts) has not been definitively determined, we advocate for two or more attempts, recognizing that a law of https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 12/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate diminishing returns applies as the number of attempts increase, and that as ATP becomes more aggressive, proarrhythmia is more likely. The most effective ATP duration is likewise uncertain; however, most clinicians program eight-pulse bursts of ATP. While one study reported that up to five ATP attempts was safe [56], most data support the use of up to two ATP attempts, as additional attempts yield very little additional efficacy [41,47-52,56,57]. The 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and Testing advocates for "at least one ATP attempt" [3]. In the ADVANCE-D Trial, a prospective randomized clinical trial of 925 patients, eight-pulse ATP was as effective and safe as fifteen-pulse ATP [58]. In the PITAGORA ICD clinical trial, which randomized 206 patients with an ICD to two ATP strategies (interval burst versus interval ramp), burst pacing was more effective for terminating fast VT episodes (between cycle lengths of 240 and 320 milliseconds), although ramp ATP appears more proarrhythmic than burst ATP [59]. In primary prevention ICD patients, the VT cycle length is unknown, so empiric programming is necessary. For secondary prevention patients with recorded VT, the programming can be tailored to the rate of the VT and other clinical features, such as hemodynamic tolerability. Slow monomorphic VT that is well tolerated favors an approach using ATP termination with at least two to three sequences of eight pulses or more. The use of a second burst of ATP has also been shown to increase effectiveness from 64 to 83 percent even in the fast VT range of 188 to 250 beats per minute [57]. Although a second burst has clear value, value beyond two bursts is limited to uncommon clinical situations [42]. However, recent data have shown programming up to six-burst ATP therapies for VTs 150 to 200 beats per minute can avoid ICD shocks in most (88 percent) patients. There is incremental benefit for up to six ATP attempts with a risk of accelerating the VT in nearly 7 percent. Ramp ATP after three failed bursts were shown to be similarly effective [60]. Cardioversion A shock that is synchronized to be delivered at the peak of the R wave is referred to as cardioversion. Because VT is an organized electrical rhythm, the delivery of an electrical shock during the vulnerable period of repolarization can cause VT to degenerate into VF. Synchronized cardioversion prevents shock delivery during the vulnerable period. (See "Basic principles and technique of external electrical cardioversion and defibrillation".) Although ICDs can be programmed to deliver synchronized shocks at a range of energies up to the maximum output of the device (usually 30 to 40 joules), synchronized cardioversion can https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 13/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate often terminate VT with relatively low energy (eg, 10 joules or less). However, low-energy shocks have been shown to be less effective and more arrhythmogenic compared with high-energy shocks [60]. Defibrillation An unsynchronized shock (ie, a shock delivered randomly during the cardiac cycle) is referred to as defibrillation. Because VF is not an organized rhythm, synchronized cardioversion is neither possible nor necessary. Defibrillation can be delivered across a range of energies. Initial shocks are sometimes programmed for lower energies to reduce capacitor charge time and save battery (although all shocks should be at least 10 joules above the defibrillation threshold). Subsequent shocks are usually delivered at higher energies, often at the maximum output of the ICD (eg, 30 to 40 joules), to optimize efficacy. If the defibrillation threshold is determined, the first shock should be 10 joules above this value. In the absence of defibrillation testing, maximum output shocks are programmed. Defibrillation threshold testing was once a routine part of ICD implantation, with the aim of confirming the correct connection of high voltage components and the ability of the system to detect and terminate VF. However, with stepwise technological innovation (eg, biphasic shocks, high-output devices), failure to defibrillate is increasingly rare. Risks of defibrillation testing include hypoperfusion from the VT/VF, failure to defibrillate, the consequences of the shock, and the sedation required to render the patient amnestic of the shock. Therefore, the risk to benefit ratio of routine defibrillation testing is seen by many to be unfavorable. When the defibrillation threshold is not established, defibrillation is programmed to maximum energy from the first shock. The advantages and disadvantages of defibrillation threshold testing are discussed separately. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Defibrillation threshold testing'.) BRADYCARDIA PROGRAMMING While ICDs are implanted primarily for the treatment of tachyarrhythmias, some patients require pacing for bradycardia at the time of implantation, while others will develop a need for

returns, thus terminating the tachycardia. ATP, or overdrive pacing, refers to the delivery of short bursts (eg, eight beats) of rapid ventricular pacing to terminate VT. Although a variety of algorithms exist, ATP is usually programmed to be delivered at a rate that is slightly faster (eg, commencing at a cycle length 10 to 15 percent shorter) than the rate of the detected tachycardia [36-39]. In several studies, as many as 95 percent of episodes of spontaneous VT were successfully terminated with ATP [36,38-41]. Utilization of ATP therapy has evolved from tailored therapy used only if shown to be effective in the electrophysiology (EP) lab to empiric programming as routine therapy. Delivery of ATP has been shown to reduce inappropriate shocks and appropriate shocks and improve quality of life [8-11,42-46]. This programming may improve survival [10]. Indeed, several studies have shown that ATP is effective at terminating slow and fast VT with very low rates of adverse events [41,47- 52]. In the PainFREE Rx II trial, 634 patients with ICDs were randomly assigned to empiric ATP or shock for initial therapy of spontaneous rapid VT (188 to 250 beats per minute) [47]. After a mean follow-up of 11 months, 431 episodes of rapid VT occurred in 98 patients. Pacing was successful in terminating 229 of 284 such episodes in the ATP arm (81 percent). The incidence of VT acceleration, syncope, and sudden death was the same in the ATP and shock arms (seven versus five episodes). The use of ATP during ICD capacitor charging has been clinically validated as safe and effective [51]. It is important to recognize that inappropriate therapies, including inappropriate ATP, delivered primarily in the setting of supraventricular arrhythmias have been associated with increased mortality in the MADIT-RIT and MADIT-CRT trials [33,53]. However, the overall safety of ATP and its value in preventing avoidable ICD shocks are well established. One concern with ATP is that rapid pacing can cause VT to degenerate into VF. For this reason, all ICDs also have high-energy defibrillation, which can be used after ATP as a backup therapy if necessary. However, this theoretical problem associated with ATP appears to be uncommon [23,37,47,48,54,55]. ATP programming Although the ideal number of ATP attempts (ie, bursts) has not been definitively determined, we advocate for two or more attempts, recognizing that a law of https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 12/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate diminishing returns applies as the number of attempts increase, and that as ATP becomes more aggressive, proarrhythmia is more likely. The most effective ATP duration is likewise uncertain; however, most clinicians program eight-pulse bursts of ATP. While one study reported that up to five ATP attempts was safe [56], most data support the use of up to two ATP attempts, as additional attempts yield very little additional efficacy [41,47-52,56,57]. The 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and Testing advocates for "at least one ATP attempt" [3]. In the ADVANCE-D Trial, a prospective randomized clinical trial of 925 patients, eight-pulse ATP was as effective and safe as fifteen-pulse ATP [58]. In the PITAGORA ICD clinical trial, which randomized 206 patients with an ICD to two ATP strategies (interval burst versus interval ramp), burst pacing was more effective for terminating fast VT episodes (between cycle lengths of 240 and 320 milliseconds), although ramp ATP appears more proarrhythmic than burst ATP [59]. In primary prevention ICD patients, the VT cycle length is unknown, so empiric programming is necessary. For secondary prevention patients with recorded VT, the programming can be tailored to the rate of the VT and other clinical features, such as hemodynamic tolerability. Slow monomorphic VT that is well tolerated favors an approach using ATP termination with at least two to three sequences of eight pulses or more. The use of a second burst of ATP has also been shown to increase effectiveness from 64 to 83 percent even in the fast VT range of 188 to 250 beats per minute [57]. Although a second burst has clear value, value beyond two bursts is limited to uncommon clinical situations [42]. However, recent data have shown programming up to six-burst ATP therapies for VTs 150 to 200 beats per minute can avoid ICD shocks in most (88 percent) patients. There is incremental benefit for up to six ATP attempts with a risk of accelerating the VT in nearly 7 percent. Ramp ATP after three failed bursts were shown to be similarly effective [60]. Cardioversion A shock that is synchronized to be delivered at the peak of the R wave is referred to as cardioversion. Because VT is an organized electrical rhythm, the delivery of an electrical shock during the vulnerable period of repolarization can cause VT to degenerate into VF. Synchronized cardioversion prevents shock delivery during the vulnerable period. (See "Basic principles and technique of external electrical cardioversion and defibrillation".) Although ICDs can be programmed to deliver synchronized shocks at a range of energies up to the maximum output of the device (usually 30 to 40 joules), synchronized cardioversion can https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 13/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate often terminate VT with relatively low energy (eg, 10 joules or less). However, low-energy shocks have been shown to be less effective and more arrhythmogenic compared with high-energy shocks [60]. Defibrillation An unsynchronized shock (ie, a shock delivered randomly during the cardiac cycle) is referred to as defibrillation. Because VF is not an organized rhythm, synchronized cardioversion is neither possible nor necessary. Defibrillation can be delivered across a range of energies. Initial shocks are sometimes programmed for lower energies to reduce capacitor charge time and save battery (although all shocks should be at least 10 joules above the defibrillation threshold). Subsequent shocks are usually delivered at higher energies, often at the maximum output of the ICD (eg, 30 to 40 joules), to optimize efficacy. If the defibrillation threshold is determined, the first shock should be 10 joules above this value. In the absence of defibrillation testing, maximum output shocks are programmed. Defibrillation threshold testing was once a routine part of ICD implantation, with the aim of confirming the correct connection of high voltage components and the ability of the system to detect and terminate VF. However, with stepwise technological innovation (eg, biphasic shocks, high-output devices), failure to defibrillate is increasingly rare. Risks of defibrillation testing include hypoperfusion from the VT/VF, failure to defibrillate, the consequences of the shock, and the sedation required to render the patient amnestic of the shock. Therefore, the risk to benefit ratio of routine defibrillation testing is seen by many to be unfavorable. When the defibrillation threshold is not established, defibrillation is programmed to maximum energy from the first shock. The advantages and disadvantages of defibrillation threshold testing are discussed separately. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Defibrillation threshold testing'.) BRADYCARDIA PROGRAMMING While ICDs are implanted primarily for the treatment of tachyarrhythmias, some patients require pacing for bradycardia at the time of implantation, while others will develop a need for bradycardia support at a later time. In addition, the pacemaker settings of an ICD may influence patient outcome even when an indication for bradycardia pacing does not exist [6]. In general, single- and dual-chamber ICDs should be programmed to avoid ventricular pacing, whenever feasible; cardiac resynchronization therapy-defibrillator (CRT-D) devices should be programmed to encourage biventricular pacing. (See "Permanent cardiac pacing: Overview of devices and indications" and "Overview of pacemakers in heart failure".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 14/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Our approach to bradycardia programming Our recommendations for bradycardia programming in patients with an ICD are generally in agreement with the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter- Defibrillator Programming and Testing and the 2019 focused update discussing manufacturer- specific programming [3,4]. For patients who also have sinus node disease and guideline-supported indications for a pacemaker, we provide dual-chamber (right atrial [RA] and right ventricular [RV]) pacing along with the ICD, rather than RV pacing alone, to reduce the risk of atrial fibrillation (AF) and stroke, to avoid pacemaker syndrome, and to improve quality of life. For patients with a single- or dual-chamber ICD without guideline-supported indications for a pacemaker, we adjust the pacing parameters to minimize ventricular stimulation in an effort to improve survival and reduce heart failure (HF) hospitalization. For patients who are in sinus rhythm, with no or only mild left ventricular (LV) dysfunction, and AV block where ventricular pacing is expected, we provide dual-chamber (RA and RV) pacing rather than RV pacing alone, in order to avoid pacemaker syndrome and to improve quality of life. For patients with sinus rhythm, mild to moderate LV dysfunction, and AV block where frequent RV pacing is expected (>50 percent), we suggest biventricular pacing (ie, cardiac resynchronization therapy [CRT]) rather than dual-chamber (RA and RV) pacing in order to improve the combination of HF hospitalization, LV enlargement, and death. For patients who have chronotropic incompetence, we program the ICD to provide sensor augmented physiological rate-responsive pacing, especially if the patient is young and physically active. For patients with a dual-chamber ICD and native PR intervals of 230 milliseconds or less, the mode, automatic mode change, and rate response should be set so that the patient s native AV conduction is favored and minimizes RV pacing. For patients with biventricular pacing, the device should be programmed to produce the highest achievable percentage of ventricular pacing, preferably above 98 percent, in order to improve survival and reduce HF hospitalization. Additionally, the algorithms providing automatic adjustment of AV delay and/or LV-RV offset should be activated, in order to obtain a high percentage of LV synchronized pacing and to reduce the incidence of clinical events. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 15/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Pacing modes and rates for bradycardia in ICD patients The knowledge concerning the most suitable pacing modes and rates for patients with bradycardia is mostly gained from trials involving patients with a pacemaker. Although similar, there are some distinct differences among patients with an ICD that influence best programming practice for bradycardia. In patients with a pacemaker but no ICD, dual-chamber (ie, AV) pacing has been associated with lower rates of atrial fibrillation (AF) and stroke [61]; however, no difference in mortality has been shown between dual-chamber AV pacing and ventricular-only pacing modes. Among ICD recipients in the DAVID trial, patients without symptomatic bradycardia fared worse with DDDR pacing than with back-up VVI pacing, most likely due to unnecessary RV pacing associated with DDDR mode [7]. In patients with persistent sinus bradycardia, atrial pacing (AAI) with back-up ventricular pacing (eg, AAI-DDD) is the mode of choice. This is particularly true for patients with sinus node disease where the greatest benefits in AF reduction and stroke have been seen. In AV node disease, large randomized trials have failed to show superiority of dual- chamber pacing modes for clinical end points [62]. Therefore, the benefit of dual-chamber pacing modes is largely confined to improved exercise capacity and the avoidance of pacemaker syndrome, which occurs when single-chamber ventricular pacing conducts retrogradely to the atria resulting in atrial contraction against closed AV valves. This can cause symptoms such as dyspnea, dizziness, palpitations, and chest pain. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacemaker syndrome'.) Evidence supporting the superiority of dual-chamber pacing modes in exercise capacity and the avoidance of pacemaker syndrome is tempered by the lack of improvement demonstrated in hard clinical end points. Taken together with the increased complication risk and expense of dual-chamber ICDs, patients for whom no indication for bradycardia pacing exists generally undergo implantation of single-chamber ICDs over dual-chamber ICDs. In these patients, care should be taken to avoid ventricular pacing if possible. Further information on algorithms designed to minimize ventricular pacing is presented separately. (See "Overview of pacemakers in heart failure", section on 'Pacing modes to limit RV pacing'.) THE SUBCUTANEOUS ICD The novel subcutaneous ICD (S-ICD) follows many of the same principles as intravascular ICDs but is considered here separately for duration criteria, rate criteria, and discrimination https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 16/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate algorithms. A full discussion of the S-ICD is presented separately. (See "Subcutaneous implantable cardioverter defibrillators".) Programming is simpler with the S-ICD compared with transvenous ICDs. The programming choices in S-ICDs are limited to detection rate, one- or two-zone detection, post-shock pacing, and therapies on or off. Some automatic features may be manually overridden. As the S-ICD does not act as a pacemaker, bradycardia programming recommendations do not apply. Candidates for the S-ICD must initially be screened with a modified trichannel surface ECG that mimics the sensing vectors of the S-ICD system. This test is designed to assess the R wave to T wave ratio for appropriate signal characteristics and relationships. If the screening is not satisfactory for at least one of the three vectors both supine and standing, an S-ICD should not be implanted. Some patients (those with hypertrophic cardiomyopathy in particular) may benefit from additional screening during exercise [63]. At implant, the S-ICD automatically analyzes and selects the optimal sensing vector. Detection of ventricular tachycardia (VT) or ventricular fibrillation (VF) by the S-ICD is programmable utilizing a single or dual zone. In the single-zone configuration, shocks are delivered for detected heart rates above the programmed rate threshold: the "shock zone" [64]. In the dual-zone configuration, arrhythmia discrimination algorithms are active from the lower rate: the "conditional shock zone." In this latter zone, a unique discrimination algorithm is used to classify rhythms as either shockable or nonshockable. If they are classified as supraventricular arrhythmias or nonarrhythmic oversensing, therapy is withheld. The system utilizes an initial 18 of 24 duration criteria (nonprogrammable) prior to capacitor charging commencement; however, this duration is automatically extended following nonsustained ventricular tachyarrhythmia events. A confirmation algorithm is also utilized at the end of capacitor charging to ensure persistence of the ventricular arrhythmia prior to shock delivery. Shocks for spontaneous (noninduced) episodes are delivered at a nonprogrammable 80 joules regardless of the therapy zone of origination. The S-ICD VT detection algorithm, when programmed to include a conditional shock zone, has been demonstrated to be as effective as transvenous ICD system detection algorithms for the prevention of detection of induced supraventricular arrhythmias [65]. Furthermore, in the clinical evaluation of the conditional shock zone, it was strongly associated with a reduction in inappropriate shocks and did not result in prolongation of detection times or increased syncope [66]. The Praetorian trial showed the S-ICD to be noninferior to transvenous ICDs for patients without a pacing indication for the composite endpoint of inappropriate shocks and device-related https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 17/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate complications [67]. However, this trial has come under some criticism for event adjudication and for combining outcomes trending in opposite directions (which favors noninferiority) in the composite endpoint [68]. PRACTICAL PROGRAMMING GUIDANCE With the number of device companies and models available, together with the complexity of programming permutations, attempts have been made to give practical programming guidance. With the publication of the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and Testing and the 2019 focused update, manufacturer-specific programming recommendations were published online with the aim of providing a practical framework within which to optimally program ICDs as per the recommendations of that document [3,4]. The "Manufacturer-Specific Programming Guidelines" are hosted on the Heart Rhythm Society website. It is hoped that this will keep pace with new technology as it is released so as to become a living document of ICD programming best practice. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 18/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Implantable cardioverter-defibrillators (The Basics)" and "Patient education: Sudden cardiac arrest (The Basics)") Beyond the Basics topic (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Background Implantable cardioverter-defibrillator (ICD) implantation is usually the preferred option for the secondary prevention of sudden cardiac death (SCD) and for primary prevention in certain populations at high risk of SCD due to ventricular tachycardia/fibrillation (VT/VF). (See 'Introduction' above.) General approach Our approach to optimal ICD programming seeks to emphasize that much of the risk/benefit ratio of these devices is determined by the way they are programmed. When recommending ICD programming settings, we are often guided in our general approach by randomized trials. However, specific patient circumstances may mandate a different approach from that of generic programming recommendations. (See 'General approach to programming' above.) Tachycardia detection Modern ICD programming utilizes higher arrythmia detection rates, longer detection durations, algorithms that discriminate supraventricular tachycardia (SVT) from VT, and specific electrocardiographic (ECG) features to minimize the sensing of noise. All these strategies combined provide the patient with the security of ICD therapy when needed with the aim of eliminating inappropriate and avoidable therapies. (See 'Tachycardia detection' above and 'Our approach to tachycardia detection' above.) For patients with any ICD (primary or secondary prevention), we recommend that tachyarrhythmia detection duration criteria be programmed to require the tachycardia to continue for at least 6 to 12 seconds (or for 30 intervals), rather than a shorter duration, before completing detection (Grade 1B). For patients with a primary prevention ICD (and for secondary prevention patients in whom the VT rate is not known), we recommend that the slowest tachycardia therapy zone limit should be programmed between 185 and 200 beats per minute (Grade 1B). For secondary prevention ICD patients for whom the clinical VT rate is known, we program the slowest tachycardia therapy zone at least 10 beats per minute below the https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 19/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate documented tachycardia rate but not faster than 200 beats per minute. Tachycardia therapies Modern ICD programming for the treatment of arrhythmias utilizes ATP as the initial therapy for many patients with VT, given the high rates of successful VT termination following ATP. If ATP is unsuccessful, or if the presenting rhythm is VF, ICDs can deliver one or more defibrillatory shocks in an effort to terminate VT/VF. (See 'Tachycardia therapies' above and 'Our approach to tachycardia therapies' above.) Bradycardia programming While ICDs are implanted primarily for the treatment of tachyarrhythmias, some patients require pacing for bradycardia at the time of implantation or at a later time. In general, single- and dual-chamber ICDs should be programmed to avoid ventricular pacing, whenever feasible; cardiac resynchronization therapy-defibrillator (CRT-D) devices should be programmed to encourage biventricular pacing. (See 'Bradycardia programming' above and 'Our approach to bradycardia programming' above.) Subcutaneous ICD Programming is simpler with the subcutaneous ICD (S-ICD). The programming choices in S-ICDs are limited to detection rate, one- or two-zone detection, post-shock pacing, and therapies on or off. Some automatic features may be manually overridden. As the S-ICD does not act as a pacemaker, bradycardia programming recommendations do not apply. (See 'The subcutaneous ICD' above.) Adjunctive therapies These include antiarrhythmic medication and/or catheter ablation and are important in the management of patients treated with an ICD, particularly as an effort to prevent recurrent ICD shocks in patients who have received multiple ICD shocks. Additionally, many other therapies such as those indicated for heart failure or in specific conditions (eg, cervical sympathectomy for long QT syndrome) are complementary to ICD therapy. Thus, a multidisciplinary approach is warranted for the management of ICD patients. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Other treatment options' and "Overview of the management of heart failure with reduced ejection fraction in adults".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Mirowski M, Mower MM, Staewen WS, et al. Standby automatic defibrillator. An approach to prevention of sudden coronary death. Arch Intern Med 1970; 126:158. 2. Mirowski M, Reid PR, Mower MM, et al. Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med 1980; 303:322. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 20/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 3. Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016; 13:e50. 4. Stiles MK, Fauchier L, Morillo CA, Wilkoff BL. 2019 HRS/EHRA/APHRS/LAHRS focused update to 2015 expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2020; 17:e220. 5. Al-Khatib SM, Friedman P, Ellenbogen KA. Defibrillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 6. Wilkoff BL, Kudenchuk PJ, Buxton AE, et al. The DAVID (Dual Chamber and VVI Implantable Defibrillator) II trial. J Am Coll Cardiol 2009; 53:872. 7. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002; 288:3115. 8. Wilkoff BL, Williamson BD, Stern RS, et al. Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol 2008; 52:541. 9. Gasparini M, Menozzi C, Proclemer A, et al. A simplified biventricular defibrillator with fixed long detection intervals reduces implantable cardioverter defibrillator (ICD) interventions and heart failure hospitalizations in patients with non-ischaemic cardiomyopathy implanted for primary prevention: the RELEVANT [Role of long dEtection window programming in patients with LEft VentriculAr dysfunction, Non-ischemic eTiology in primary prevention treated with a biventricular ICD] study. Eur Heart J 2009; 30:2758. 10. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012; 367:2275. 11. Gasparini M, Proclemer A, Klersy C, et al. Effect of long-detection interval vs standard- detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: the ADVANCE III randomized clinical trial. JAMA 2013; 309:1903. 12. Saeed M, Hanna I, Robotis D, et al. Programming implantable cardioverter-defibrillators in patients with primary prevention indication to prolong time to first shock: results from the PROVIDE study. J Cardiovasc Electrophysiol 2014; 25:52. 13. Kloppe A, Proclemer A, Arenal A, et al. Efficacy of long detection interval implantable cardioverter-defibrillator settings in secondary prevention population: data from the Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III (ADVANCE III) trial. Circulation 2014; 130:308. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 21/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 14. Scott PA, Silberbauer J, McDonagh TA, Murgatroyd FD. Impact of prolonged implantable cardioverter-defibrillator arrhythmia detection times on outcomes: a meta-analysis. Heart Rhythm 2014; 11:828. 15. Tan VH, Wilton SB, Kuriachan V, et al. Impact of programming strategies aimed at reducing nonessential implantable cardioverter defibrillator therapies on mortality: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2014; 7:164. 16. Buber J, Luria D, Gurevitz O, et al. Safety and efficacy of strategic implantable cardioverter- defibrillator programming to reduce the shock delivery burden in a primary prevention patient population. Europace 2014; 16:227. 17. B nsch D, Steffgen F, Gr nefeld G, et al. The 1+1 trial: a prospective trial of a dual- versus a single-chamber implantable defibrillator in patients with slow ventricular tachycardias. Circulation 2004; 110:1022. 18. Clementy N, Pierre B, Lallemand B, et al. Long-term follow-up on high-rate cut-off programming for implantable cardioverter defibrillators in primary prevention patients with left ventricular systolic dysfunction. Europace 2012; 14:968. 19. Swerdlow CD, Schsls W, Dijkman B, et al. Detection of atrial fibrillation and flutter by a dual- chamber implantable cardioverter-defibrillator. For the Worldwide Jewel AF Investigators. Circulation 2000; 101:878. 20. Adler SW 2nd, Wolpert C, Warman EN, et al. Efficacy of pacing therapies for treating atrial tachyarrhythmias in patients with ventricular arrhythmias receiving a dual-chamber implantable cardioverter defibrillator. Circulation 2001; 104:887. 21. Friedman PA, Dijkman B, Warman EN, et al. Atrial therapies reduce atrial arrhythmia burden in defibrillator patients. Circulation 2001; 104:1023. 22. Wood MA, Stambler BS, Damiano RJ, et al. Lessons learned from data logging in a multicenter clinical trial using a late-generation implantable cardioverter-defibrillator. The Guardian ATP 4210 Multicenter Investigators Group. J Am Coll Cardiol 1994; 24:1692. 23. Nunain SO, Roelke M, Trouton T, et al. Limitations and late complications of third-generation automatic cardioverter-defibrillators. Circulation 1995; 91:2204. 24. Grimm W, Flores BF, Marchlinski FE. Electrocardiographically documented unnecessary, spontaneous shocks in 241 patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 1992; 15:1667. 25. Klein RC, Raitt MH, Wilkoff BL, et al. Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Cardiovasc Electrophysiol 2003; 14:940. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 22/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 26. Israel CW, Gr nefeld G, Iscolo N, et al. Discrimination between ventricular and supraventricular tachycardia by dual chamber cardioverter defibrillators: importance of the atrial sensing function. Pacing Clin Electrophysiol 2001; 24:183. 27. Swerdlow CD, Chen PS, Kass RM, et al. Discrimination of ventricular tachycardia from sinus tachycardia and atrial fibrillation in a tiered-therapy cardioverter-defibrillator. J Am Coll Cardiol 1994; 23:1342. 28. Le Franc P, Ku T, Vinet A, et al. Underdetection of ventricular tachycardia using a 40 ms stability criterion: effect of antiarrhythmic therapy. Pacing Clin Electrophysiol 1997; 20:2882. 29. Seifert M. Tachycardia discrimination in algorithms in ICDs. In: Cardiac Defibrillation, Erkapic D, Bauernfeind T (Eds), InTech, 2013. 30. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008; 51:1357. 31. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 32. Sweeney MO, Sherfesee L, DeGroot PJ, et al. Differences in effects of electrical therapy type for ventricular arrhythmias on mortality in implantable cardioverter-defibrillator patients. Heart Rhythm 2010; 7:353. 33. Sood N, Ruwald AC, Solomon S, et al. Association between myocardial substrate, implantable cardioverter defibrillator shocks and mortality in MADIT-CRT. Eur Heart J 2014; 35:106. 34. Powell BD, Saxon LA, Boehmer JP, et al. Survival after shock therapy in implantable cardioverter-defibrillator and cardiac resynchronization therapy-defibrillator recipients according to rhythm shocked. The ALTITUDE survival by rhythm study. J Am Coll Cardiol 2013; 62:1674. 35. van Rees JB, Borleffs CJ, de Bie MK, et al. Inappropriate implantable cardioverter-defibrillator shocks: incidence, predictors, and impact on mortality. J Am Coll Cardiol 2011; 57:556. 36. Schaumann A, von zur M hlen F, Herse B, et al. Empirical versus tested antitachycardia pacing in implantable cardioverter defibrillators: a prospective study including 200 patients. Circulation 1998; 97:66. 37. Trappe HJ, Klein H, Kielblock B. Role of antitachycardia pacing in patients with third generation cardioverter defibrillators. Pacing Clin Electrophysiol 1994; 17:506. 38. Saksena S, Chandran P, Shah Y, et al. Comparative efficacy of transvenous cardioversion and pacing in patients with sustained ventricular tachycardia: a prospective, randomized, https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 23/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate crossover study. Circulation 1985; 72:153. 39. Bardy GH, Poole JE, Kudenchuk PJ, et al. A prospective randomized repeat-crossover comparison of antitachycardia pacing with low-energy cardioversion. Circulation 1993; 87:1889. 40. Clinical outcome of patients with malignant ventricular tachyarrhythmias and a multiprogrammable implantable cardioverter-defibrillator implanted with or without thoracotomy: an international multicenter study. PCD Investigator Group. J Am Coll Cardiol 1994; 23:1521. 41. Sullivan RM, Russo AM, Berg KC, et al. Arrhythmia rate distribution and tachyarrhythmia therapy in an ICD population: results from the INTRINSIC RV trial. Heart Rhythm 2012; 9:351. 42. Wilkoff BL, Ousdigian KT, Sterns LD, et al. A comparison of empiric to physician-tailored programming of implantable cardioverter-defibrillators: results from the prospective randomized multicenter EMPIRIC trial. J Am Coll Cardiol 2006; 48:330. 43. Sweeney MO, Wathen MS, Volosin K, et al. Appropriate and inappropriate ventricular therapies, quality of life, and mortality among primary and secondary prevention implantable cardioverter defibrillator patients: results from the Pacing Fast VT REduces Shock ThErapies (PainFREE Rx II) trial. Circulation 2005; 111:2898. 44. Gilliam FR, Hayes DL, Boehmer JP, et al. Real world evaluation of dual-zone ICD and CRT-D programming compared to single-zone programming: the ALTITUDE REDUCES study. J Cardiovasc Electrophysiol 2011; 22:1023. 45. Fischer A, Ousdigian KT, Johnson JW, et al. The impact of atrial fibrillation with rapid ventricular rates and device programming on shocks in 106,513 ICD and CRT-D patients. Heart Rhythm 2012; 9:24. 46. Gonz lez-Enr quez S, Rodr guez-Entem F, Exp sito V, et al. Single-chamber ICD, single-zone therapy in primary and secondary prevention patients: the simpler the better? J Interv Card Electrophysiol 2012; 35:343. 47. Wathen MS, DeGroot PJ, Sweeney MO, et al. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation 2004; 110:2591. 48. Wathen MS, Sweeney MO, DeGroot PJ, et al. Shock reduction using antitachycardia pacing for spontaneous rapid ventricular tachycardia in patients with coronary artery disease. Circulation 2001; 104:796. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 24/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 49. Saeed M, Neason CG, Razavi M, et al. Programming antitachycardia pacing for primary prevention in patients with implantable cardioverter defibrillators: results from the PROVE trial. J Cardiovasc Electrophysiol 2010; 21:1349. 50. Sivagangabalan G, Eshoo S, Eipper VE, et al. Discriminatory therapy for very fast ventricular tachycardia in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2008; 31:1095. 51. Schoels W, Steinhaus D, Johnson WB, et al. Optimizing implantable cardioverter-defibrillator treatment of rapid ventricular tachycardia: antitachycardia pacing therapy during charging. Heart Rhythm 2007; 4:879. 52. Gasparini M, Anselme F, Clementy J, et al. BIVentricular versus right ventricular antitachycardia pacing to terminate ventricular tachyarrhythmias in patients receiving cardiac resynchronization therapy: the ADVANCE CRT-D Trial. Am Heart J 2010; 159:1116. 53. Ruwald AC, Schuger C, Moss AJ, et al. Mortality reduction in relation to implantable cardioverter defibrillator programming in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT). Circ Arrhythm Electrophysiol 2014; 7:785. 54. Nasir N Jr, Pacifico A, Doyle TK, et al. Spontaneous ventricular tachycardia treated by antitachycardia pacing. Cadence Investigators. Am J Cardiol 1997; 79:820. 55. Pinski SL, Fahy GJ. The proarrhythmic potential of implantable cardioverter-defibrillators. Circulation 1995; 92:1651. 56. Martins RP, Blangy H, Muresan L, et al. Safety and efficacy of programming a high number of antitachycardia pacing attempts for fast ventricular tachycardia: a prospective study. Europace 2012; 14:1457. 57. Anguera I, Dallaglio P, Sabat X, et al. The benefit of a second burst antitachycardia sequence for fast ventricular tachycardia in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2014; 37:486. 58. Santini M, Lunati M, Defaye P, et al. Prospective multicenter randomized trial of fast ventricular tachycardia termination by prolonged versus conventional anti-tachyarrhythmia burst pacing in implantable cardioverter-defibrillator patients-Atp DeliVery for pAiNless ICD thErapy (ADVANCE-D) Trial results. J Interv Card Electrophysiol 2010; 27:127. 59. Gulizia MM, Piraino L, Scherillo M, et al. A randomized study to compare ramp versus burst antitachycardia pacing therapies to treat fast ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators: the PITAGORA ICD trial. Circ Arrhythm Electrophysiol 2009; 2:146. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 25/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 60. Strik M, Ramirez FD, Welte N, et al. Progressive implantable cardioverter-defibrillator therapies for ventricular tachycardia: The efficacy and safety of multiple bursts, ramps, and low-energy shocks. Heart Rhythm 2020; 17:2072. 61. Castelnuovo E, Stein K, Pitt M, et al. The effectiveness and cost-effectiveness of dual- chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation. Health Technol Assess 2005; 9:iii, xi. 62. Toff WD, Camm AJ, Skehan JD, United Kingdom Pacing and Cardiovascular Events Trial

Cardiol 2008; 51:1357. 31. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 32. Sweeney MO, Sherfesee L, DeGroot PJ, et al. Differences in effects of electrical therapy type for ventricular arrhythmias on mortality in implantable cardioverter-defibrillator patients. Heart Rhythm 2010; 7:353. 33. Sood N, Ruwald AC, Solomon S, et al. Association between myocardial substrate, implantable cardioverter defibrillator shocks and mortality in MADIT-CRT. Eur Heart J 2014; 35:106. 34. Powell BD, Saxon LA, Boehmer JP, et al. Survival after shock therapy in implantable cardioverter-defibrillator and cardiac resynchronization therapy-defibrillator recipients according to rhythm shocked. The ALTITUDE survival by rhythm study. J Am Coll Cardiol 2013; 62:1674. 35. van Rees JB, Borleffs CJ, de Bie MK, et al. Inappropriate implantable cardioverter-defibrillator shocks: incidence, predictors, and impact on mortality. J Am Coll Cardiol 2011; 57:556. 36. Schaumann A, von zur M hlen F, Herse B, et al. Empirical versus tested antitachycardia pacing in implantable cardioverter defibrillators: a prospective study including 200 patients. Circulation 1998; 97:66. 37. Trappe HJ, Klein H, Kielblock B. Role of antitachycardia pacing in patients with third generation cardioverter defibrillators. Pacing Clin Electrophysiol 1994; 17:506. 38. Saksena S, Chandran P, Shah Y, et al. Comparative efficacy of transvenous cardioversion and pacing in patients with sustained ventricular tachycardia: a prospective, randomized, https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 23/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate crossover study. Circulation 1985; 72:153. 39. Bardy GH, Poole JE, Kudenchuk PJ, et al. A prospective randomized repeat-crossover comparison of antitachycardia pacing with low-energy cardioversion. Circulation 1993; 87:1889. 40. Clinical outcome of patients with malignant ventricular tachyarrhythmias and a multiprogrammable implantable cardioverter-defibrillator implanted with or without thoracotomy: an international multicenter study. PCD Investigator Group. J Am Coll Cardiol 1994; 23:1521. 41. Sullivan RM, Russo AM, Berg KC, et al. Arrhythmia rate distribution and tachyarrhythmia therapy in an ICD population: results from the INTRINSIC RV trial. Heart Rhythm 2012; 9:351. 42. Wilkoff BL, Ousdigian KT, Sterns LD, et al. A comparison of empiric to physician-tailored programming of implantable cardioverter-defibrillators: results from the prospective randomized multicenter EMPIRIC trial. J Am Coll Cardiol 2006; 48:330. 43. Sweeney MO, Wathen MS, Volosin K, et al. Appropriate and inappropriate ventricular therapies, quality of life, and mortality among primary and secondary prevention implantable cardioverter defibrillator patients: results from the Pacing Fast VT REduces Shock ThErapies (PainFREE Rx II) trial. Circulation 2005; 111:2898. 44. Gilliam FR, Hayes DL, Boehmer JP, et al. Real world evaluation of dual-zone ICD and CRT-D programming compared to single-zone programming: the ALTITUDE REDUCES study. J Cardiovasc Electrophysiol 2011; 22:1023. 45. Fischer A, Ousdigian KT, Johnson JW, et al. The impact of atrial fibrillation with rapid ventricular rates and device programming on shocks in 106,513 ICD and CRT-D patients. Heart Rhythm 2012; 9:24. 46. Gonz lez-Enr quez S, Rodr guez-Entem F, Exp sito V, et al. Single-chamber ICD, single-zone therapy in primary and secondary prevention patients: the simpler the better? J Interv Card Electrophysiol 2012; 35:343. 47. Wathen MS, DeGroot PJ, Sweeney MO, et al. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation 2004; 110:2591. 48. Wathen MS, Sweeney MO, DeGroot PJ, et al. Shock reduction using antitachycardia pacing for spontaneous rapid ventricular tachycardia in patients with coronary artery disease. Circulation 2001; 104:796. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 24/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 49. Saeed M, Neason CG, Razavi M, et al. Programming antitachycardia pacing for primary prevention in patients with implantable cardioverter defibrillators: results from the PROVE trial. J Cardiovasc Electrophysiol 2010; 21:1349. 50. Sivagangabalan G, Eshoo S, Eipper VE, et al. Discriminatory therapy for very fast ventricular tachycardia in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2008; 31:1095. 51. Schoels W, Steinhaus D, Johnson WB, et al. Optimizing implantable cardioverter-defibrillator treatment of rapid ventricular tachycardia: antitachycardia pacing therapy during charging. Heart Rhythm 2007; 4:879. 52. Gasparini M, Anselme F, Clementy J, et al. BIVentricular versus right ventricular antitachycardia pacing to terminate ventricular tachyarrhythmias in patients receiving cardiac resynchronization therapy: the ADVANCE CRT-D Trial. Am Heart J 2010; 159:1116. 53. Ruwald AC, Schuger C, Moss AJ, et al. Mortality reduction in relation to implantable cardioverter defibrillator programming in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT). Circ Arrhythm Electrophysiol 2014; 7:785. 54. Nasir N Jr, Pacifico A, Doyle TK, et al. Spontaneous ventricular tachycardia treated by antitachycardia pacing. Cadence Investigators. Am J Cardiol 1997; 79:820. 55. Pinski SL, Fahy GJ. The proarrhythmic potential of implantable cardioverter-defibrillators. Circulation 1995; 92:1651. 56. Martins RP, Blangy H, Muresan L, et al. Safety and efficacy of programming a high number of antitachycardia pacing attempts for fast ventricular tachycardia: a prospective study. Europace 2012; 14:1457. 57. Anguera I, Dallaglio P, Sabat X, et al. The benefit of a second burst antitachycardia sequence for fast ventricular tachycardia in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2014; 37:486. 58. Santini M, Lunati M, Defaye P, et al. Prospective multicenter randomized trial of fast ventricular tachycardia termination by prolonged versus conventional anti-tachyarrhythmia burst pacing in implantable cardioverter-defibrillator patients-Atp DeliVery for pAiNless ICD thErapy (ADVANCE-D) Trial results. J Interv Card Electrophysiol 2010; 27:127. 59. Gulizia MM, Piraino L, Scherillo M, et al. A randomized study to compare ramp versus burst antitachycardia pacing therapies to treat fast ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators: the PITAGORA ICD trial. Circ Arrhythm Electrophysiol 2009; 2:146. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 25/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 60. Strik M, Ramirez FD, Welte N, et al. Progressive implantable cardioverter-defibrillator therapies for ventricular tachycardia: The efficacy and safety of multiple bursts, ramps, and low-energy shocks. Heart Rhythm 2020; 17:2072. 61. Castelnuovo E, Stein K, Pitt M, et al. The effectiveness and cost-effectiveness of dual- chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation. Health Technol Assess 2005; 9:iii, xi. 62. Toff WD, Camm AJ, Skehan JD, United Kingdom Pacing and Cardiovascular Events Trial Investigators. Single-chamber versus dual-chamber pacing for high-grade atrioventricular block. N Engl J Med 2005; 353:145. 63. Francia P, Adduci C, Palano F, et al. Eligibility for the Subcutaneous Implantable Cardioverter-Defibrillator in Patients With Hypertrophic Cardiomyopathy. J Cardiovasc Electrophysiol 2015; 26:893. 64. Weiss R, Knight BP, Gold MR, et al. Safety and efficacy of a totally subcutaneous implantable- cardioverter defibrillator. Circulation 2013; 128:944. 65. Gold MR, Theuns DA, Knight BP, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study. J Cardiovasc Electrophysiol 2012; 23:359. 66. Gold MR, Weiss R, Theuns DA, et al. Use of a discrimination algorithm to reduce inappropriate shocks with a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014; 11:1352. 67. Knops RE, Olde Nordkamp LRA, Delnoy PHM, et al. Subcutaneous or Transvenous Defibrillator Therapy. N Engl J Med 2020; 383:526. 68. Mandrola J, Enache B, Redberg RF. Subcutaneous or Transvenous Defibrillator Therapy. N Engl J Med 2021; 384:676. Topic 113776 Version 15.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 26/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate GRAPHICS Tachycardia detection evidence Short detection controls Prolonged detection intervention Participants (n) Study Findings PREPARE 1391 12 of 16 (58%) 30 of 40 beats Reduction in Nonrandomized beats inappropriate shocks (SVT), Primary prevention 18 of 24 (42%) beats avoidable shocks (VT), and "morbidity index" RELEVANT 324 Nonrandomized 12 of 16 beats 30 of 40 beats Reduction in inappropriate shocks (SVT), Primary prevention avoidable shocks (VT), and HF hospitalizations MADIT-RIT 1500 Randomized 2.5 seconds (170 to 199 bpm) 60 seconds (170 to 199 bpm) Reduction in first inappropriate Primary prevention therapy, first 1 second ( 200 bpm) 12 seconds (200 appropriate therapy, to 249 bpm) 2.5 seconds ( 250 bpm) appropriate ATP, and inappropriate ATP; improved survival ADVANCE-III 1902 Randomized 18 of 24 beats 30 of 40 beats Reduction in overall therapies, inappropriate Primary and secondary shocks, and all- prevention cause hospitalizations PROVIDE 1670 Randomized 12 beats 25 beats (180 to Reduction in all- 214 bpm) cause shock rate; improved survival Primary prevention 18 beats (214 to 250 bpm) 12 beats (>250 bpm) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 27/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate SVT: supraventricular tachycardia; VT: ventricular tachycardia; HF: heart failure; bpm: beats per minute; ATP: antitachycardia pacing. Reproduced from: Wilko BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-de brillator programming and testing. Heart Rhythm 2016; 13:e50. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 115226 Version 1.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 28/29 7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Contributor Disclosures Martin K Stiles, MB ChB, PhD, FRACP, FHRS Consultant/Advisory Boards: Ceryx Medical [Novel pacemaker device]. Speaker's Bureau: Medtronic [AF ablation]. All of the relevant financial relationships listed have been mitigated. Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS Grant/Research/Clinical Trial Support: Abbott [Atrial fibrillation, catheter ablation]; AHA [Atrial fibrillation, cardiovascular disease]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, pacemaker/ICD, atrial fibrillation care]; iRhythm [Atrial fibrillation]; NIA [Atrial fibrillation]; Philips [Lead management]. Consultant/Advisory Boards: Abbott [Atrial fibrillation, catheter ablation]; Abbvie [Atrial fibrillation]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, atrial fibrillation, pacemaker/ICD]; ElectroPhysiology Frontiers [Atrial fibrillation, catheter ablation]; Element Science [DSMB]; Medtronic [Atrial fibrillation, pacemaker/ICDs]; Milestone [Supraventricular tachycardia]; Pacira [Atrial fibrillation]; Philips [Lead extraction]; ReCor [Cardiac arrhythmias]; Sanofi [Atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 29/29

7/6/23, 3:08 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Implantable cardioverter-defibrillators: Overview of indications, components, and functions : Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS, Cara Pellegrini, MD : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 20, 2023. INTRODUCTION Ventricular fibrillation (VF) is a common cause of sudden cardiac death (SCD) and is sometimes preceded by monomorphic or polymorphic ventricular tachycardia (VT). All sustained ventricular arrhythmias have the potential to be lethal arrhythmias. Although cardiopulmonary resuscitation, including chest compressions and assisted ventilation, can provide transient circulatory support for the patient with cardiac arrest, the only effective approach for terminating VF is electrical defibrillation. Implantable cardioverter-defibrillator (ICD) implantation is generally considered the first-line treatment option for the secondary prevention of SCD and for primary prevention in certain populations at high risk of SCD due to VT/VF. This topic will review the general indications for ICD implantation as well as the components and functionalities of the ICD. The clinical trials documenting the efficacy of an ICD in different clinical settings (including both secondary and primary prevention), complications of ICD placement, optimal ICD programming, and follow-up care of patients with ICDs are discussed separately. (See "Implantable cardioverter-defibrillators: Optimal programming".) (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) (See "Cardiac implantable electronic devices: Long-term complications".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 1/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate (See "Cardiac implantable electronic devices: Patient follow-up".) (See "Cardiac implantable electronic devices: Periprocedural complications".) Alternatives and adjunctive therapies to ICD implantation include antiarrhythmic drugs; ablative surgery; catheter ablation; and in advanced cases stellate ganglion resection, noninvasive cardiac radiation, and cardiac transplantation; and are discussed separately. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.) (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) (See "Pharmacologic therapy in survivors of sudden cardiac arrest".) INDICATIONS The main indications for use of an ICD are as follows [1,2]: Secondary prevention of sudden cardiac death (SCD) in patients with prior sustained ventricular tachycardia (VT), ventricular fibrillation (VF), or resuscitated SCD thought to be due to VT/VF. Primary prevention of SCD in patients at increased risk of life-threatening VT/VF. Secondary prevention Implantation of an ICD is recommended for the secondary prevention of SCD due to life-threatening VT/VF in the following settings [2]: Patients with a prior episode of resuscitated VT/VF or sustained hemodynamically unstable VT in whom a completely reversible cause cannot be identified. This includes patients with a variety of underlying heart diseases and those with idiopathic VT/VF and congenital long QT syndrome, but not patients who have VT/VF limited to the first 48 hours after an acute myocardial infarction (MI). (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Secondary prevention of SCD'.) (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".) (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Treatment of associated conditions'.) Patients with episodes of spontaneous sustained VT in the presence of heart disease (valvular, ischemic, hypertrophic, dilated, or infiltrative cardiomyopathies) and other https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 2/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate settings (eg, channelopathies). (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'ICD therapy' and "Catecholaminergic polymorphic ventricular tachycardia".) Patients with unexplained syncope and high suspicion of VT/VF as the etiology. (See "Syncope in adults: Management and prognosis", section on 'Documented, suspected, or induced ventricular tachycardia'.) A key issue is the prevention of total mortality (not arrhythmic or sudden death). Simply correcting VT/VF may not improve overall mortality. Therefore, patient selection for ICD implantation should take into account both the known risk of SCD due to VT/VF for a specific condition and the risk of total mortality from underlying medical conditions as well. Primary prevention Implantation of an ICD is recommended for the primary prevention of SCD due to life-threatening VT/VF in patients who have received optimal guideline-directed medical therapy. While guideline-directed medical therapy used to be relatively simple and included beta-blocker therapy and use of an angiotensin receptor blocker or ACE inhibitor, guideline-directed medical therapy now includes several other medications. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".) Patients on guideline-directed medical therapy who have high risk of SCD include the following groups of patients [2]: Patients with a prior MI (at least 40 days ago) and left ventricular ejection fraction (LVEF) 30 percent. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Patients with a cardiomyopathy, New York Heart Association (NYHA) functional class II to III table 1), and LVEF 35 percent. Patients with a nonischemic cardiomyopathy generally ( require optimal medical therapy for three months with documentation of persistent LVEF 35 percent at that time. However, the DANISH trial calls into question the role of prophylactic ICDs in some patients with nonischemic cardiomyopathy. It is recommended that patients be evaluated at least three months after revascularization (coronary artery bypass graft surgery [CABG] or stent placement). (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Use of an ICD'.) Some patients with heart failure who are candidates for an ICD also have intraventricular conduction delay ( 120 milliseconds) and are candidates for cardiac resynchronization therapy (CRT) with a biventricular pacemaker. Such patients could be treated with a device https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 3/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate with combined ICD and biventricular pacing functions (cardiac resynchronization therapy- defibrillator [CRT-D]). (See 'Cardiac resynchronization therapy' below and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Patients with a prior MI, nonsustained VT, and LVEF 40 percent who have VF or sustained VT-induced during electrophysiology study. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Select patients with certain underlying disorders who are deemed to be at high risk for life- threatening VT/VF. This includes: Patients with congenital long QT syndrome who have recurrent symptoms and/or torsades de pointes despite therapy with beta blockers or other high-risk patients. (See "Congenital long QT syndrome: Treatment", section on 'Implantable cardioverter- defibrillator'.) High-risk patients with hypertrophic cardiomyopathy, arrhythmogenic right ventricular (RV) cardiomyopathy, or cardiac sarcoidosis. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk stratification' and "Management and prognosis of cardiac sarcoidosis", section on 'Implantable cardioverter-defibrillator'.) High-risk patients with Brugada syndrome, catecholaminergic polymorphic VT, and other channelopathies. (See "Catecholaminergic polymorphic ventricular tachycardia", section on 'Implantable cardioverter-defibrillators' and "Brugada syndrome or pattern: Management and approach to screening of relatives".) ICD not recommended ICD therapy is NOT recommended in the following settings [2]: Patients with ventricular tachyarrhythmias due to a completely reversible disorder in the absence of structural heart disease (eg, electrolyte imbalance, drugs, or trauma). Patients who do not have a reasonable expectation of survival with an acceptable functional status for at least one year, even if they otherwise meet ICD implantation criteria. Patients with incessant VT or VF in whom other therapies (eg, catheter ablation) should be considered first. (See "Electrical storm and incessant ventricular tachycardia", section on 'Catheter ablation'.) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 4/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Patients with severe psychiatric illnesses that may be aggravated by device implantation. In clinical practice, this situation is very rarely encountered and may apply more to primary prevention than secondary prevention settings. Patients with NYHA Class IV heart failure that is refractory to optimal medical treatment who are not candidates for cardiac transplantation or CRT. (See "Heart transplantation in adults: Indications and contraindications" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Patients with syncope without inducible ventricular tachyarrhythmias and without structural heart disease. Patients with VF or VT amenable to surgical or catheter ablation in whom the risk of sudden cardiac death is normalized after successful ablation (eg, pre-excited atrial fibrillation and subsequent ventricular arrhythmias associated with the Wolff-Parkinson- White syndrome, RV or LV outflow tract VT, idiopathic VT, or fascicular VT in the absence of structural heart disease). (See "Treatment of arrhythmias associated with the Wolff- Parkinson-White syndrome", section on 'Catheter ablation' and "Ventricular tachycardia in the absence of apparent structural heart disease".) ICD implantation should be delayed in patients with active infections or other acute medical issues. If necessary, the patient can be bridged with a wearable cardioverter- defibrillator (WCD) until ICD implantation can be carried out. (See "Wearable cardioverter- defibrillator".) ELEMENTS OF THE ICD The ICD system is comprised of the following elements [3]: Pacing/sensing electrodes Defibrillation electrodes Pulse generator ( picture 1) In contemporary transvenous ICDs, both the pace/sense electrodes and the defibrillation electrodes are located on a single ventricular lead. Decades ago, ICD systems were implanted epicardially, requiring major surgery to affix separate shocking and sensing electrodes to the epicardial surface of the heart. Generators were typically placed in the upper abdomen. The need for epicardial electrodes and abdominal pulse generators has become vanishingly rare. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 5/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate There is also a subcutaneous ICD (S-ICD) which requires no transvenous leads. (See "Subcutaneous implantable cardioverter defibrillators".) Electrodes Pacing and sensing functions require a pair of electrodes. Contemporary pacemakers and defibrillators usually use leads with two electrodes on the ventricular lead: the distal electrode at the tip of the lead and a second electrode in the shape of a ring, several millimeters back from the tip (ie, true bipolar leads). These bipolar leads provide accurate sensing, with high amplitude, narrow electrograms. Some ICD leads utilize integrated bipolar sensing in which the bipole consists of a single tip electrode and the distal shocking coil electrode. In addition to improved sensing capabilities, bipolar leads reduce the risk of extraneous interference, which could lead to inappropriate device function (eg, inappropriate shocks delivered due to sensing of muscular activity). The defibrillation function of the electrodes requires a relatively large surface area and positioning of the lead to maximize the density of current flow through the ventricular myocardium. Contemporary ICD systems use a "coil" of wire that extends along the ventricular lead as the primary defibrillation electrode. Thus, a single transvenous lead can accomplish all pacing, sensing, and defibrillation functions. In the distant past (and in some unique cases, in persons without vascular access options), epicardial patches were used for defibrillation, but placement required a thoracotomy. Additional defibrillation electrodes improve defibrillation efficacy and reduce the defibrillation threshold. Most contemporary ICD systems have two or three defibrillation electrodes. Along with the distal coil in the right ventricle (RV) on the transvenous lead, some ICD leads have a second defibrillation coil proximal to the RV coil. In addition, with "active can" technology, the metal housing of the ICD serves as one of the shocking electrodes. This configuration requires that the pulse generator be implanted in the pectoral region ( figure 1). The active can and transvenous lead systems can be combined to achieve adequate defibrillation thresholds (minimum energy required for successful defibrillation, which should generally be 10 joules less than the maximum output of the device). (See 'Defibrillation threshold testing' below.) There are three types of pacing offered by current transvenous systems. Single-chamber systems have only an RV lead. Dual-chamber systems have right atrial (RA) and RV leads. Cardiac resynchronization therapy (CRT, also called biventricular) systems have RA, RV, and left ventricular (LV) leads, or in some patients with permanent atrial fibrillation, RV and LV leads. Pulse generator The pulse generator ( picture 1) contains the sensing circuitry as well as the high voltage capacitors and battery. While the initial pulse generators were located in the abdomen, the development of small pulse generators (eg, thickness 15 mm) has permitted https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 6/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate placement in the infraclavicular region of the anterior chest wall in nearly all patients [4]. The majority are placed in a prepectoral (ie, subcutaneous) position, but in some cases, a subpectoral position is advantageous. For most patients with the pulse generator in this location, the impulses generated are transmitted to the myocardium via transvenous leads. Epicardial systems are still available and may be necessary as a result of anatomical limitations to placing a transvenous lead(s). Additionally, a subcutaneous ICD (S-ICD) system is now available in which the pulse generator is placed overlying the left lower lateral ribs. (See 'Choosing the optimal pulse generator location' below.) Battery life in ICD pulse generators has improved over time. For example, devices implanted after 2002 have significantly longer battery lives (5.6 versus 4.9 years) [5]. Single-chamber ICDs implanted since 2002 had the longest battery life (mean 6.7 years). Contemporary ICD devices generally have an expected longevity greater than eight years and CRT- D devices greater than six years, although some ICDs have estimated battery longevity >10 years [6,7]. IMPLANTATION Prior to implanting an ICD, the provider must determine the optimal position for placement of the leads and the pulse generator. Most current ICD systems utilize one or two transvenous leads placed via the axillary, subclavian, or cephalic vein, with attachment to a pulse generator in the subcutaneous tissue in the infraclavicular anterior chest wall. In more recent years, there has been a trend toward single coils rather than dual-coil defibrillation leads. Dual-coil leads were favored earlier in the era of transvenous ICD systems. However, a proximal coil is rarely needed for defibrillation and single-coil leads pose less risk in the future if lead extraction is necessary. An additional defibrillation lead can be placed in the azygos vein, coronary sinus, or subcutaneous tissue if necessary to improve defibrillation. Choosing the optimal pulse generator location Modern devices are small enough to be implanted in the pectoral region of the anterior chest wall; the devices are implanted either subcutaneously or submuscularly, similar to a pacemaker implantation. Although implantation on the left side is preferred, a right-sided implant can be performed [8,9]. The left pectoral position is usually chosen for three reasons: The defibrillation energy requirement is usually lower on the left because of the location of the heart in the left chest Ipsilateral arm movement restrictions shortly after implant are less impactful for the nondominant hand (which for most people is the left) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 7/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate There is a small risk of arm swelling due to venous occlusion; this is less impactful on the nondominant hand (which for most people is the left hand). Additionally, a subcutaneous ICD (S-ICD) system is available that allows for defibrillation (though no backup pacing aside from immediately post-shock or antitachycardia pacing) without the insertion of a transvenous lead. The pulse generator for the S-ICD system ( picture 2) is implanted in a subcutaneous pocket in the left lateral, mid-axillary thoracic position ( picture 3 and picture 4). (See 'Subcutaneous ICD' below and "Subcutaneous implantable cardioverter defibrillators".) Choosing the optimal lead placement In most de novo ICD implantations, the lead with the pace/sense electrodes is placed transvenously, with the distal electrode positioned on the right ventricular (RV) apical endocardium. Defibrillation energy requirement is generally optimized (ie, lowest) with an RV apical lead position. RV septal lead placement is also an option. In rare cases, usually due to limitations of the venous anatomy and/or a high risk of bacteremia and endovascular infection, the pace/sense electrodes are placed on the epicardium during surgery ( image 1). The electrodes should record a ventricular electrogram of at least 5 mV. These signals should be sufficiently large such that detection of lower amplitude ventricular tachycardia (VT) and ventricular fibrillation (VF) is straight-forward. Dual-chamber ICDs have an additional lead with another pair of pace/sense electrodes in the right atrium for atrial sensing and pacing [10]. Not all patients require an atrial lead. Whether use of an atrial lead reduces the risk of inappropriate shocks for supraventricular rhythms is controversial and debated. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacing modes'.) An S-ICD has been developed with no leads placed in the heart. The subcutaneous lead, which toward its terminal end contains an 8 cm shocking coil electrode, is tunneled from a small midline incision and the pulse generator in the left mid axillary line on the lateral chest wall to a position along the left parasternal margin ( image 2). The S-ICD can sense VT/VF and deliver therapeutic shocks but cannot deliver antitachycardia pacing or pacing for bradycardias. (See 'Subcutaneous ICD' below.) Defibrillation threshold testing Defibrillation threshold testing (DFT) has historically been performed at the time of device implantation, although the necessity for this evaluation with modern devices and randomized trials to date has failed to identify clear benefit [11-17]. Among patients who have had DFT testing, only a small fraction need DFT testing. The following 2015 consensus statement on optimal ICD programming and testing counsels that the following groups may be considered for DFT testing [11]: https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 8/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate DFT testing is reasonable to consider in patients undergoing an initial right pectoral ICD implantation or an ICD pulse generator replacement. The rationale for testing right-sided implants is that defibrillation may be more difficult with a right pectoral pulse generator, given the fact that the heart lies in the left chest. For generator changes, there may be concerns about the integrity of the chronic leads. DFT testing should not be performed in patients with a documented nonchronic cardiac thrombus, atrial fibrillation/flutter without adequate anticoagulation, severe aortic stenosis, unstable angina, recent stroke or transient ischemic attack, or hemodynamic instability. Additionally, many centers avoid DFT testing in patients with very low left ventricular ejection fractions (<15 percent) or severe pulmonary hypertension. Furthermore, the 2015 statement counsels that: DFT testing can performed in patients receiving an S-ICD. (See "Subcutaneous implantable cardioverter defibrillators".) DFT testing can be omitted in patients undergoing a left pectoral transvenous ICD implantation with a RV apical lead that is functioning appropriately. Some electrophysiologists feel that universally omitting DFT testing might compromise the safety within certain subsets of patients, especially those patients with high DFTs who would benefit from a higher energy device and/or additional leads. A distinction should be made, however, between DFT testing at initial implantation and at the time of generator replacement. DFT testing at the time of generator replacement is useful in subsets of patients with leads that have a hazard alert or in patients at higher risk of DFT changes (eg, obese patients, patients with heart failure symptoms, patients on amiodarone, etc) [18]. Early ICD systems frequently required lead system adjustment at the time of implantation in order to achieve an adequate safety margin (arbitrarily set at 10 joules or greater). As technology improved, thresholds were substantially reduced [19]. As a result, it is very unusual for defibrillator systems to require modification at the time of implantation ( figure 1). Data regarding DFT testing on the more modern single-coil systems are limited since the available cohort and registry data predate the development of single-coil systems. One paired randomized study of 216 patients with a mix of ICD indications and ICD manufacturers found no difference in first shock efficacy, which was >90 percent for either system [20]. On average, omitting the proximal coil in a single-coil system likely increases the DFT a few joules, which usually does not impact the safety margin but could be significant in some patients [21]. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 9/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Several studies have illustrated the impact of DFT testing at the time of ICD implantation with the current generation of devices, generally showing no significant difference in outcomes [14- 17,22,23]. In the Shockless Implant Evaluation (SIMPLE) trial, a single-blind, multicenter, noninferiority study of 2500 patients receiving an initial ICD in the left pectoral region for standard primary or secondary prevention indications, patients were randomized 1:1 to either have or not have DFT testing at the time of ICD implantation and were followed for an average of 3.1 years [22]. For the composite primary outcome of arrhythmic death or failed appropriate shock, no DFT testing was identified as noninferior to DFT testing (with a trend toward superiority), as patients in the no DFT testing group had a lower incidence of the primary outcome (7 percent per year versus 8 percent per year in the DFT testing group), with no significant differences in the secondary safety outcomes noted between the two groups. Similarly, in the NORDIC ICD trial, which also randomized patients receiving a first ICD to have or not have DFT testing at the time of ICD implantation, no DFT testing was identified as noninferior to DFT testing (also with a trend toward superiority) and was also associated with a trend toward fewer procedure-related adverse events [23]. In a systematic review and meta- analysis of 13 studies involving 9740 patients undergoing initial ICD implantation, there was no significant difference in mortality or adverse outcomes between patients with and without DFT testing [24]. In the absence of randomized data or society guidelines, many electrophysiologists perform DFT for most S-ICD implantations; it is also strongly encouraged for S-ICD generator replacement procedures. However, observational data have not shown that DFT at the time of initial S-ICD implantation is associated with a lower rate of ineffective shocks or cardiovascular mortality [25,26]. Among 566 propensity-matched patients with S-ICDs implanted across 17 European centers, there was no significant difference in the composite of ineffective shocks and cardiovascular mortality in those who underwent or did not undergo defibrillation testing [25]. Similarly, a multi-center Italian study of 650 propensity-matched patients found no significant difference in the composite of all-cause death and ineffective S-ICD therapy, as well as a secondary composite endpoint of all-cause death, ineffective shock, inappropriate shock, and complication [26]. Periprocedural monitoring Nearly all patients who undergo ICD implantation will have the device placed using local anesthesia at the site of the pulse generator insertion, with intravenous sedation provided most commonly by nurse anesthetists and/or anesthesiologists. If patients undergo DFT testing following device implantation, a "deeper" level of sedation may be required, but in most cases DFT testing can be performed without requiring general anesthesia. Following ICD implantation, a posteroanterior (PA) and lateral chest radiograph should be obtained to establish the position of the pulse generator and the associated lead(s) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 10/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate and to exclude any apparent complications, including pneumothorax and lead dislodgment. Patients should also have a 12-lead electrocardiogram (ECG) recorded during pacing to document the ECG appearance of the QRS complex. The monitoring associated with procedural sedation, as well as additional periprocedural observation and timing of discharge post-procedure, is discussed in detail separately. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications", section on 'Monitoring' and "Cardiac implantable electronic devices: Periprocedural complications", section on 'Periprocedural monitoring'.) Complications There are a variety of potential complications associated with ICDs, both at and around the time of implantation as well as long-term over the life of patients and their device(s). Both the periprocedural and long-term complications associated with ICDs are discussed in detail separately. (See "Cardiac implantable electronic devices: Periprocedural complications" and "Cardiac implantable electronic devices: Long-term complications".) ICD FUNCTIONS ECG monitoring and storage Contemporary ICDs have more extensive storage and monitoring capacities, thereby allowing more expedient patient management, often without requiring a face-to-face visit. Some examples: Recording and display of stored electrograms from tachyarrhythmia events. This can be very helpful for the detection of "silent" or asymptomatic arrhythmias where management of the patient is likely to change (eg, brief episodes of rate-controlled atrial fibrillation). Telemetry capabilities that permit easier analysis when patients receive shocks. Remote monitoring capabilities via telephone or internet that allow clinicians to review ICD parameters and events without requiring the patient to come to the office or hospital. (See "Cardiac implantable electronic devices: Patient follow-up".) Antitachycardia pacing Ventricular tachycardia (VT), particularly reentrant VT associated with scar from a prior myocardial infarction, can sometimes be terminated by pacing the ventricle. When a paced impulse enters the reentrant circuit during a tachycardia, it can depolarize a segment of the circuit, leaving that segment refractory when the reentrant wave returns, thus terminating the tachycardia. Antitachycardia pacing, or overdrive pacing, refers to the delivery of short bursts (eg, eight beats) of rapid ventricular pacing to terminate VT ( waveform 1). Although a variety of https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 11/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate algorithms exist, antitachycardia pacing is usually programmed to be delivered at a rate that is slightly faster (eg, at a cycle length 10 to 12 percent shorter) than the rate of the detected tachycardia. Subcutaneous ICDs (S-ICDs) cannot deliver antitachycardic pacing. (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Antitachycardia pacing'.) Though employed substantially less frequently, antitachycardia pacing can also terminate some atrial tachyarrhythmias, and these features have been incorporated in some contemporary ICD systems. Cardioversion/defibrillation A shock that is synchronized to be delivered at the peak of the R wave is referred to as cardioversion. Because VT is an organized electrical rhythm, the delivery of an electrical shock during the vulnerable period of repolarization can cause VT to degenerate into ventricular fibrillation (VF). Synchronized cardioversion prevents shock delivery during the vulnerable period. Although ICDs can be programmed to deliver synchronized shocks at a range of energies up to the maximum output of the device (usually 30 to 40 joules), synchronized cardioversion can often terminate VT with relatively low energy (eg, 10 joules or less). (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Cardioversion'.) An unsynchronized shock (ie, a shock delivered randomly during the cardiac cycle) is referred to as defibrillation. Clinicians can program ICDs to deliver unsynchronized shocks for very rapid ventricular arrhythmias (eg, heart rate greater than 200 beats/min). Because VF is not an organized rhythm, synchronized cardioversion is neither possible nor necessary. Similarly, it can be difficult to synchronize with very rapid VTs, and such rapid rhythms are unlikely to be hemodynamically tolerated. ICDs are typically programmed to deliver synchronized shocks at energies approaching the maximum output of the device (usually 30 to 40 joules) ( waveform 2). (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Defibrillation'.) Bradycardia pacing All contemporary transvenous ICDs are capable of pacing; however, current S-ICDs can deliver pacing for only 30 seconds post shock delivery and not standard bradycardia pacing. Many patients with an ICD have a conventional indication for cardiac pacing [27]. Separate ICDs and pacemakers can lead to device-to-device interactions, particularly with older models, potentially resulting in inappropriate shocks and underdetection of VT/VF [28-31]. With rare exceptions, patients should have only one transvenous or epicardial device, although the combined use of a leadless pacemaker with an S-ICD is under investigation. Generally, however, when a patient with a pacemaker develops an indication for ICD implantation, the pacemaker is removed and replaced with an ICD. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 12/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate For patients with known atrioventricular (AV) block or sinus node dysfunction, or those who are receiving left ventricular (LV) pacing as part of cardiac resynchronization therapy (CRT), the device will be programmed accordingly. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacing modes'.) For those without pre-existing AV block or sinus node dysfunction and who presumably do not require regular ventricular pacing, the ICD will typically be programmed to minimize the amount of pacing provided (eg, pace only for intrinsic rates less than 40 beats/min). (See "Overview of pacemakers in heart failure" and "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing'.) In addition to the usual indications for pacing, the ability to provide pacing also protects against bradyarrhythmias that can follow a tachycardia or shock, and also against ventricular arrhythmias that are bradycardia-dependent [32]. Because of the unique physiology following a ventricular tachyarrhythmia and device shock, ICDs allow for distinct post-shock pacing programming (usually at higher outputs). S-ICDs are able to provide this brief pacing function. Cardiac resynchronization therapy CRT, which utilizes biventricular pacing, is an effective treatment for symptomatic heart failure in some patients with LV dyssynchrony. CRT is currently recommended in patients with advanced heart failure (usually NYHA class III or IV), severe systolic dysfunction (LV ejection fraction 35 percent), and intraventricular conduction delay (QRS >120 milliseconds). The evidence of benefit is greatest in patients with left bundle branch block and a QRS duration >150 milliseconds. Pacing of the LV is most frequently achieved by transvenous insertion of an electrode into a cardiac vein via the coronary sinus. Surgical placement of an epicardial lead is also an option in patients following failed efforts at transvenous lead placement, or in patients undergoing cardiac surgery for another reason. Conduction system pacing is another means of synchronizing ventricular stimulation; its impact, compared with traditional CRT with an coronary sinus lead, is being actively investigated. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: System implantation and programming" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Improvement in heart failure can reduce the frequency of ventricular arrhythmias, raising the possibility that biventricular pacing may have an adjunctive role with an ICD by reducing the need for ICD therapy. Although an initial series of 32 patients found such an effect [33], this benefit was not confirmed in the much larger MIRACLE ICD trial of 369 patients [34]. Although the addition of biventricular pacing to ICD therapy was associated with significant improvements https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 13/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate in symptoms and quality of life, there was no reduction in the number of appropriate or inappropriate shocks. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Perioperative ICD functioning During surgical procedures, the function of ICDs may be affected by electromagnetic interference (EMI), most commonly due to use of an electrosurgery unit (ESU). ICDs with integrated bipolar sensing configuration may be more susceptible to EMI than those with true bipolar sensing. Very rarely, direct damage from cautery to the ICD may alter its ability to deliver pacing or shocks or reset the ICD to an alternate or backup mode. The much more common concern is that the device might misinterpret the cautery as tachyarrhythmia, leading to withholding of bradycardia pacing and perhaps inappropriate ICD shocks. A full discussion regarding the perioperative management of patients with an ICD, including optimal monitoring and cardiac implantable electronic device programming, is presented separately. (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator".) NONVASCULAR CARDIOVERTER-DEFIBRILLATOR Transvenous ICDs have a number of short- and long-term complications that may potentially be avoided with nonvascular systems. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Transvenous lead systems' and "Cardiac implantable electronic devices: Long-term complications".) Wearable cardioverter-defibrillator Some patients who are at risk for sudden cardiac death do not meet established criteria for implantation of an ICD or may require only short-term protection (such as patients awaiting subsequent ICD insertion or cardiac transplantation). In

atrial tachyarrhythmias, and these features have been incorporated in some contemporary ICD systems. Cardioversion/defibrillation A shock that is synchronized to be delivered at the peak of the R wave is referred to as cardioversion. Because VT is an organized electrical rhythm, the delivery of an electrical shock during the vulnerable period of repolarization can cause VT to degenerate into ventricular fibrillation (VF). Synchronized cardioversion prevents shock delivery during the vulnerable period. Although ICDs can be programmed to deliver synchronized shocks at a range of energies up to the maximum output of the device (usually 30 to 40 joules), synchronized cardioversion can often terminate VT with relatively low energy (eg, 10 joules or less). (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Cardioversion'.) An unsynchronized shock (ie, a shock delivered randomly during the cardiac cycle) is referred to as defibrillation. Clinicians can program ICDs to deliver unsynchronized shocks for very rapid ventricular arrhythmias (eg, heart rate greater than 200 beats/min). Because VF is not an organized rhythm, synchronized cardioversion is neither possible nor necessary. Similarly, it can be difficult to synchronize with very rapid VTs, and such rapid rhythms are unlikely to be hemodynamically tolerated. ICDs are typically programmed to deliver synchronized shocks at energies approaching the maximum output of the device (usually 30 to 40 joules) ( waveform 2). (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Defibrillation'.) Bradycardia pacing All contemporary transvenous ICDs are capable of pacing; however, current S-ICDs can deliver pacing for only 30 seconds post shock delivery and not standard bradycardia pacing. Many patients with an ICD have a conventional indication for cardiac pacing [27]. Separate ICDs and pacemakers can lead to device-to-device interactions, particularly with older models, potentially resulting in inappropriate shocks and underdetection of VT/VF [28-31]. With rare exceptions, patients should have only one transvenous or epicardial device, although the combined use of a leadless pacemaker with an S-ICD is under investigation. Generally, however, when a patient with a pacemaker develops an indication for ICD implantation, the pacemaker is removed and replaced with an ICD. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 12/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate For patients with known atrioventricular (AV) block or sinus node dysfunction, or those who are receiving left ventricular (LV) pacing as part of cardiac resynchronization therapy (CRT), the device will be programmed accordingly. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacing modes'.) For those without pre-existing AV block or sinus node dysfunction and who presumably do not require regular ventricular pacing, the ICD will typically be programmed to minimize the amount of pacing provided (eg, pace only for intrinsic rates less than 40 beats/min). (See "Overview of pacemakers in heart failure" and "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing'.) In addition to the usual indications for pacing, the ability to provide pacing also protects against bradyarrhythmias that can follow a tachycardia or shock, and also against ventricular arrhythmias that are bradycardia-dependent [32]. Because of the unique physiology following a ventricular tachyarrhythmia and device shock, ICDs allow for distinct post-shock pacing programming (usually at higher outputs). S-ICDs are able to provide this brief pacing function. Cardiac resynchronization therapy CRT, which utilizes biventricular pacing, is an effective treatment for symptomatic heart failure in some patients with LV dyssynchrony. CRT is currently recommended in patients with advanced heart failure (usually NYHA class III or IV), severe systolic dysfunction (LV ejection fraction 35 percent), and intraventricular conduction delay (QRS >120 milliseconds). The evidence of benefit is greatest in patients with left bundle branch block and a QRS duration >150 milliseconds. Pacing of the LV is most frequently achieved by transvenous insertion of an electrode into a cardiac vein via the coronary sinus. Surgical placement of an epicardial lead is also an option in patients following failed efforts at transvenous lead placement, or in patients undergoing cardiac surgery for another reason. Conduction system pacing is another means of synchronizing ventricular stimulation; its impact, compared with traditional CRT with an coronary sinus lead, is being actively investigated. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: System implantation and programming" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Improvement in heart failure can reduce the frequency of ventricular arrhythmias, raising the possibility that biventricular pacing may have an adjunctive role with an ICD by reducing the need for ICD therapy. Although an initial series of 32 patients found such an effect [33], this benefit was not confirmed in the much larger MIRACLE ICD trial of 369 patients [34]. Although the addition of biventricular pacing to ICD therapy was associated with significant improvements https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 13/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate in symptoms and quality of life, there was no reduction in the number of appropriate or inappropriate shocks. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Perioperative ICD functioning During surgical procedures, the function of ICDs may be affected by electromagnetic interference (EMI), most commonly due to use of an electrosurgery unit (ESU). ICDs with integrated bipolar sensing configuration may be more susceptible to EMI than those with true bipolar sensing. Very rarely, direct damage from cautery to the ICD may alter its ability to deliver pacing or shocks or reset the ICD to an alternate or backup mode. The much more common concern is that the device might misinterpret the cautery as tachyarrhythmia, leading to withholding of bradycardia pacing and perhaps inappropriate ICD shocks. A full discussion regarding the perioperative management of patients with an ICD, including optimal monitoring and cardiac implantable electronic device programming, is presented separately. (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator".) NONVASCULAR CARDIOVERTER-DEFIBRILLATOR Transvenous ICDs have a number of short- and long-term complications that may potentially be avoided with nonvascular systems. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Transvenous lead systems' and "Cardiac implantable electronic devices: Long-term complications".) Wearable cardioverter-defibrillator Some patients who are at risk for sudden cardiac death do not meet established criteria for implantation of an ICD or may require only short-term protection (such as patients awaiting subsequent ICD insertion or cardiac transplantation). In such settings, a wearable cardioverter-defibrillator (WCD) may be preferable to either ICD insertion or bystander resuscitation. The indications for use, efficacy, and limitations of the WCD are discussed separately. (See "Wearable cardioverter-defibrillator".) Subcutaneous ICD Some patients who are at risk for sudden cardiac death and require an ICD will have compelling reasons for avoiding the indwelling transvenous leads associated with a standard ICD (eg, other indwelling leads or catheters, high risk for systemic infection, relatively young age at implant with numerous device implants anticipated over a lifetime, high risk for lead fracture, etc). An entirely subcutaneous ICD (S-ICD) can provide an effective alternative means of defibrillation. The S-ICD is discussed separately. (See "Subcutaneous implantable cardioverter defibrillators".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 14/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Extravascular ICD The extravascular ICD is not yet approved for use in the United States but if found to be safe and efficacious may provide benefits of antitachycardia pacing that are lacking in S-ICDs. The extravascular ICD has a single lead implanted substernally, and in addition to defibrillation it can deliver pause-prevention and antitachycardia pacing. A preliminary single- arm study in 316 selected patients with indications for an ICD suggests the extravascular ICD can be successfully implanted (in 94.6 percent) and can detect and terminate ventricular arrythmia (98.7 percent) at the time of implantation; there was a moderate but comparable rate of major complications up to six months post-implantation (7.3 percent) with lead dislodgement and wound infection necessitating system removal being the most common [35]. SUMMARY AND RECOMMENDATIONS Indications Because of its high success rate in terminating ventricular tachycardia (VT) and ventricular fibrillation (VF) rapidly, along with the results of multiple clinical trials showing improvement in survival, implantable cardioverter-defibrillator (ICD) implantation is generally considered the first-line treatment option for the secondary prevention of sudden cardiac death (SCD) and for primary prevention in certain populations at high risk of SCD due to VT/VF. However, there are some situations in which ICD therapy is not recommended, including but not limited to patients with VT/VF from a completely reversible disorder and patients without a reasonable expectation of survival with an acceptable functional status for at least one year. (See 'Introduction' above and 'Indications' above and 'ICD not recommended' above.) Components of the ICD The ICD system is comprised of pacing/sensing electrodes, defibrillation electrodes, and a pulse generator ( picture 1). Contemporary ICDs use leads with pace-sense electrodes and shock coils on a single ventricular lead. Most current ICD systems utilize one, two, or three transvenous leads placed via the axillary, subclavian, or cephalic vein, with attachment to a pulse generator in the subcutaneous tissue in the infraclavicular anterior chest wall. Subcutaneous ICD (S-ICD) systems are an effective alternative that avoid indwelling transvenous lead(s) but lack some of the standard capabilities of a traditional transvenous ICD. (See 'Elements of the ICD' above.) Defibrillation threshold (DFT) While DFT used to be very common, in contemporary EP practice, it is infrequently performed due to the results of randomized trials and the performance of contemporary ICD systems. However, DFT testing is generally performed at the time of device implantation in patients receiving an S-ICD and is reasonable in patients undergoing a right pectoral ICD implantation or ICD pulse generator replacement or those with multiple high-risk features for an elevated DFT (ie, patient with high body mass index https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 15/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate on amiodarone with a nonischemic cardiomyopathy). However, DFT testing is commonly omitted in patients undergoing a left pectoral transvenous ICD implantation with a right ventricular apical lead that is functioning appropriately. (See 'Defibrillation threshold testing' above.) ICD functions Contemporary ICDs have extensive storage and monitoring capacities, the ability to deliver antitachycardia pacing (ie, overdrive pacing) to terminate VT, the ability to deliver synchronized and unsynchronized shocks for VT/VF, and the option of bradycardia pacing. (See 'ICD functions' above.) Nonvascular cardioverter defibrillators Transvenous ICDs have a number of short- and long-term complications that may potentially be avoided with nonvascular systems (including wearable cardioverter-defibrillators, subcutaneous, and extravascular ICDs). (See 'Nonvascular cardioverter-defibrillator' above.) The optimal approach to programming of modern ICDs is discussed in detail separately. (See "Implantable cardioverter-defibrillators: Optimal programming".) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Russo AM, Stainback RF, Bailey SR, et al. ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation appropriate use criteria task force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2013; 61:1318. 2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 16/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 3. DiMarco JP. Implantable cardioverter-defibrillators. N Engl J Med 2003; 349:1836. 4. Fenelon G, Huvelle E, Brugada P. Initial clinical experience with a new small sized third- generation implantable cardioverter defibrillator: results of a multicenter study. European Ventak Mini Investigator Group. Pacing Clin Electrophysiol 1997; 20:2967. 5. Thijssen J, Borleffs CJ, van Rees JB, et al. Implantable cardioverter-defibrillator longevity under clinical circumstances: an analysis according to device type, generation, and manufacturer. Heart Rhythm 2012; 9:513. 6. Boriani G, Merino J, Wright DJ, et al. Battery longevity of implantable cardioverter- defibrillators and cardiac resynchronization therapy defibrillators: technical, clinical and economic aspects. An expert review paper from EHRA. Europace 2018; 20:1882. 7. Zanon F, Martignani C, Ammendola E, et al. Device Longevity in a Contemporary Cohort of ICD/CRT-D Patients Undergoing Device Replacement. J Cardiovasc Electrophysiol 2016; 27:840. 8. Flaker GC, Tummala R, Wilson J. Comparison of right- and left-sided pectoral implantation parameters with the Jewel active can cardiodefibrillator. The World Wide Jewel Investigators. Pacing Clin Electrophysiol 1998; 21:447. 9. Gold MR, Shih HT, Herre J, et al. Comparison of defibrillation efficacy and survival associated with right versus left pectoral placement for implantable defibrillators. Am J Cardiol 2007; 100:243. 10. Israel CW, Gr nefeld G, Iscolo N, et al. Discrimination between ventricular and supraventricular tachycardia by dual chamber cardioverter defibrillators: importance of the atrial sensing function. Pacing Clin Electrophysiol 2001; 24:183. 11. Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016; 13:e50. 12. Strickberger SA, Klein GJ. Is defibrillation testing required for defibrillator implantation? J Am Coll Cardiol 2004; 44:88. 13. Day JD, Doshi RN, Belott P, et al. Inductionless or limited shock testing is possible in most patients with implantable cardioverter- defibrillators/cardiac resynchronization therapy defibrillators: results of the multicenter ASSURE Study (Arrhythmia Single Shock Defibrillation Threshold Testing Versus Upper Limit of Vulnerability: Risk Reduction Evaluation With Implantable Cardioverter-Defibrillator Implantations). Circulation 2007; 115:2382. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 17/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate 14. Healey JS, Gula LJ, Birnie DH, et al. A randomized-controlled pilot study comparing ICD implantation with and without intraoperative defibrillation testing in patients with heart failure and severe left ventricular dysfunction: a substudy of the RAFT trial. J Cardiovasc Electrophysiol 2012; 23:1313. 15. Guenther M, Rauwolf T, Br ggemann B, et al. Pre-hospital discharge testing after implantable cardioverter defibrillator implantation: a measure of safety or out of date? A retrospective analysis of 975 patients. Europace 2012; 14:217. 16. Brignole M, Occhetta E, Bongiorni MG, et al. Clinical evaluation of defibrillation testing in an unselected population of 2,120 consecutive patients undergoing first implantable cardioverter-defibrillator implant. J Am Coll Cardiol 2012; 60:981. 17. Arnson Y, Suleiman M, Glikson M, et al. Role of defibrillation threshold testing during implantable cardioverter-defibrillator placement: data from the Israeli ICD Registry. Heart Rhythm 2014; 11:814. 18. Phan K, Kabunga P, Kilborn MJ, Sy RW. Defibrillator Threshold Testing at Generator Replacement: Is it Time to Abandon the Practice? Pacing Clin Electrophysiol 2015; 38:777. 19. Kopp DE, Blakeman BP, Kall JG, et al. Predictors of defibrillation energy requirements with nonepicardial lead systems. Pacing Clin Electrophysiol 1995; 18:253. 20. Larsen JM, Heath FP, Riahi S, et al. Single and dual coil shock efficacy and predictors of shock failure in patients with modern implantable cardioverter defibrillators-a single-center paired randomized study. J Interv Card Electrophysiol 2019; 54:65. 21. Sunderland N, Kaura A, Murgatroyd F, et al. Outcomes with single-coil versus dual-coil implantable cardioverter defibrillators: a meta-analysis. Europace 2018; 20:e21. 22. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015; 385:785. 23. B nsch D, Bonnemeier H, Brandt J, et al. Intra-operative defibrillation testing and clinical shock efficacy in patients with implantable cardioverter-defibrillators: the NORDIC ICD randomized clinical trial. Eur Heart J 2015; 36:2500. 24. Phan K, Ha H, Kabunga P, et al. Systematic Review of Defibrillation Threshold Testing at De Novo Implantation. Circ Arrhythm Electrophysiol 2016; 9:e003357. 25. Forleo GB, Gasperetti A, Breitenstein A, et al. Subcutaneous implantable cardioverter- defibrillator and defibrillation testing: A propensity-matched pilot study. Heart Rhythm 2021; 18:2072. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 18/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate 26. Bianchi V, Bisignani G, Migliore F, et al. Safety of Omitting Defibrillation Efficacy Testing With Subcutaneous Defibrillators: A Propensity-Matched Case-Control Study. Circ Arrhythm Electrophysiol 2021; 14:e010381. 27. Best PJ, Hayes DL, Stanton MS. The potential usage of dual chamber pacing in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 1999; 22:79. 28. Calkins H, Brinker J, Veltri EP, et al. Clinical interactions between pacemakers and automatic implantable cardioverter-defibrillators. J Am Coll Cardiol 1990; 16:666. 29. Ellenbogen KA, Edel T, Moore S, et al. A prospective randomized-controlled trial of ventricular fibrillation detection time in a DDDR ventricular defibrillator. Ventak AV II DR Study Investigators. Pacing Clin Electrophysiol 2000; 23:1268. 30. Glikson M, Trusty JM, Grice SK, et al. A stepwise testing protocol for modern implantable cardioverter-defibrillator systems to prevent pacemaker-implantable cardioverter- defibrillator interactions. Am J Cardiol 1999; 83:360. 31. Mattke S, Markewitz A, M ller D, et al. The combined transvenous implantation of cardioverter defibrillators and permanent pacemakers. Pacing Clin Electrophysiol 1997; 20:2775. 32. Fisher JD, Teichman SL, Ferrick A, et al. Antiarrhythmic effects of VVI pacing at physiologic rates: a crossover controlled evaluation. Pacing Clin Electrophysiol 1987; 10:822. 33. Higgins SL, Yong P, Sheck D, et al. Biventricular pacing diminishes the need for implantable cardioverter defibrillator therapy. Ventak CHF Investigators. J Am Coll Cardiol 2000; 36:824. 34. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003; 289:2685. 35. Friedman P, Murgatroyd F, Boersma LVA, et al. Efficacy and Safety of an Extravascular Implantable Cardioverter-Defibrillator. N Engl J Med 2022; 387:1292. Topic 921 Version 53.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 19/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate GRAPHICS NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac Ordinary physical Patients can perform to disease but without activity, such as completion any activity requiring 7 metabolic equivalents (ie, can resulting limitations of physical activity. walking and climbing stairs, does not cause Ordinary physical angina. Angina with carry 24 lb up 8 steps; activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. strenuous or rapid prolonged exertion at work or recreation. do outdoor work [shovel snow, spade soil]; do recreational activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair- Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. climbing after meals, in cold, in wind, or when under emotional stress, or only during the few hours after without stopping, garden, rake, weed, roller skate, dance foxtrot, walk at 4 mph on level ground) but awakening. Walking more than 2 blocks on cannot and do not perform to completion activities requiring 7 metabolic equivalents. the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac Marked limitation of Patients can perform to disease resulting in marked limitation of ordinary physical activity. Walking 1 to 2 completion any activity requiring 2 metabolic equivalents (eg, shower physical activity. They blocks on the level and are comfortable at rest. Less-than-ordinary climbing 1 flight in normal conditions. without stopping, strip and make bed, clean https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 20/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate physical activity causes windows, walk 2.5 fatigue, palpitation, mph, bowl, play golf, dyspnea, or anginal pain. dress without stopping) but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac disease resulting in Inability to carry on any physical activity Patients cannot or do not perform to inability to carry on any physical activity without discomfort. Anginal syndrome may completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac be present at rest. equivalents. Cannot carry out activities insufficiency or of the listed above (specific anginal syndrome may be present even at rest. If any physical activity activity scale III). is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 21/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Examples of transvenous ICD pulse generators Examples of implantable cardioverter-defibrillator pulse generators commonly used in practice in 2015. ICD: implantable cardioverter-defibrillator. Graphic 104721 Version 2.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 22/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Transvenous ICD shock lead configurations With the active can electrode, current flows between the coil(s) right ventricular (RV) electrode and the housing (active can) of the pulse generator. For transvenous leads with two coils, current also flows between two transvenous coils (RV and superior vena cava). ICD: implantable cardioverter-defibrillator. Graphic 113994 Version 1.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 23/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Subcutaneous ICD pulse generator Example of subcutaneous implantable cardioverter-defibrillator pulse generator commonly used in practice in 2015. ICD: implantable cardioverter-defibrillator. Graphic 104722 Version 3.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 24/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Subcutaneous implantable cardioverter-defibrillator Modi ed from: 1. Al-Khatib SM, Friedman P, Ellenbogen KA. De brillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 2. Mayo Clinic. Subcutaneous implantable cardioverter-de brillator (S-ICD). https://www.mayoclinic.org/diseases-conditions/ventricular-tachycardia/multimedia/img- 20303862 (Accessed on March 31, 2021). Graphic 130973 Version 1.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 25/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Lateral view of a patient with a subcutaneous implantable cardioverter-defibrillator (S-ICD) Lateral view of a patient with an S-ICD. S-ICD: subcutaneous implantable cardioverter-defibrillator. Reproduced with permission from: Magnusson P, Pergolizzi JV, LeQuang JA. The Subcutaneous Implantable Cardioverter-De brillator. In: Cardiac Pacing and Monitoring, Min M (Ed), IntechOpen, 2019. Copyright Peter Magnusson, MD, PhD. Graphic 131058 Version 2.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 26/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Different ICD lead systems Chest radiographs of two different implantable cardioverter-defibrillator (ICD) systems. Left panel shows an ICD epicardial lead system. Epicardial sensing electrodes are located on the left ventricle (arrow) and the three epicardial patch electrodes are located on the right atrium, and the inferior and lateral walls of the left ventricle. Right panel shows a dual coil transvenous ICD lead system with a pulse generator in the pectoral region. Courtesy of Douglas Kopp, MD. Graphic 56923 Version 3.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 27/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Posteroanterior (PA) and lateral chest radiographs of a subcutaneous implantable cardioverter-defibrillator (S-ICD) Posteroanterior (PA) and lateral chest radiographs of a subcutaneous implantable cardioverter-defibrillator (S-ICD) with the defibrillation lead visible adjacent to the sternum and the pulse generator in the axilla. Graphic 97372 Version 2.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 28/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Implantable cardioverter-defibrillator (ICD) electrogram anti-tachycardia pacin monomorphic ventricular tachycardia (VT) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 29/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Stored intracardiac electrogram from an ICD showing the development of monomorphic ventricular tachycar which is successfully terminated by a burst of anti-tachycardia pacing delivered by the ICD. This tachycardia i monomorphic VT, but is labeled VF by the device because it was detected in the VF zone due to the rapid rate RA: right atrial; RV: right ventricular; VT: ventricular tachycardia; VF: ventricular fibrillation; ATP: anti-tachycar pacing; AS: atrium sensed; VS: ventricle sensed. Graphic 114829 Version 2.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 30/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Implantable cardioverter-defibrillator (ICD) electrogram shock for ventricular f (VF) Stored intracardiac electrogram from an ICD showing the development of ventricular fibrillation, which is suc terminated by a single shock from the ICD. RA: right atrium; RV: right ventricle; AS: atrium sensed; AP: atrium paced; A pacing: atrial pacing; VF: ventricu fibrillation; PVC: premature ventricular contraction; VPB: ventricular premature beats. Graphic 114831 Version 1.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 31/32 7/6/23, 3:09 PM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Contributor Disclosures Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS Grant/Research/Clinical Trial Support: Abbott [Atrial fibrillation, catheter ablation]; AHA [Atrial fibrillation, cardiovascular disease]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, pacemaker/ICD, atrial fibrillation care]; iRhythm [Atrial fibrillation]; NIA [Atrial fibrillation]; Philips [Lead management]. Consultant/Advisory Boards: Abbott [Atrial fibrillation, catheter ablation]; Abbvie [Atrial fibrillation]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, atrial fibrillation, pacemaker/ICD]; ElectroPhysiology Frontiers [Atrial fibrillation, catheter ablation]; Element Science [DSMB]; Medtronic [Atrial fibrillation, pacemaker/ICDs]; Milestone [Supraventricular tachycardia]; Pacira [Atrial fibrillation]; Philips [Lead extraction]; ReCor [Cardiac arrhythmias]; Sanofi [Atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Cara Pellegrini, MD Consultant/Advisory Boards: Abbott [Atrial fibrillation and supraventricular tachycardia]; Biosense Webster [Ablation]; Cook Medical [Lead extraction tools and techniques]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 32/32

7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 25, 2023. INTRODUCTION For patients with atrial fibrillation (AF), the two principal goals of long-term therapy are to improve quality of life (eg, symptom control) and to prevent associated morbidity and mortality (principally the prevention of thromboembolism). (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Adverse hemodynamics in AF' and "Atrial fibrillation in adults: Use of oral anticoagulants".) In asymptomatic or minimally symptomatic patients with AF, there is often no need to pursue aggressive measures to maintain sinus rhythm. For those patients who might feel better in sinus rhythm, rate- and rhythm-control strategies improve symptoms, but neither has been conclusively shown to improve survival compared to the other. The factors determining the choice between these two strategies are discussed elsewhere. (See "Management of atrial fibrillation: Rhythm control versus rate control".) For those patients in whom a rhythm control strategy is chosen, catheter ablation or antiarrhythmic drugs are the two principle therapeutic options. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) This topic will compare the efficacy and safety of these two options for rhythm control and provide recommendations for choosing one or the other. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 1/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate CLASSIFICATION The following terms are used in the classification of patients with atrial fibrillation (AF). In the studies discussed in this topic, some, but not all, of these groups have been included (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'): Paroxysmal (ie, self-terminating or intermittent) AF Paroxysmal AF is defined as recurrent AF ( 2 episodes) that terminates spontaneously in seven days or less, usually less than 24 hours. (See "Paroxysmal atrial fibrillation".) Persistent AF Persistent AF is defined as AF that fails to self-terminate within seven days. Episodes often require pharmacologic or electrical cardioversion to restore sinus rhythm. While a patient who has had persistent AF can have later episodes of paroxysmal AF, AF is generally considered a progressive disease. In individuals with paroxysmal AF, progression to persistent and permanent AF occurs in >50 percent beyond 10 years despite antiarrhythmic therapy [1]. Long-standing persistent AF Long-standing persistent AF refers to persistent AF that has lasted for one year or more [2]. Permanent AF Permanent AF is a term used to identify individuals with persistent AF where a decision has been made to no longer pursue a rhythm control strategy. CATHETER ABLATION AND ANTIARRHYTHMIC DRUG THERAPY General considerations Catheter ablation uses either cryoablation (cryotherapy) or radiofrequency ablation (RFA). AF will recur in one year in approximately 20 to 40 percent of patients who have a catheter ablation, although overall AF burden is often markedly decreased [3]; a recurrence is defined as an AF episode >30 seconds in duration on routine monitoring. Important complications from catheter ablation include cardiac tamponade, pulmonary vein stenosis (<1 percent), phrenic nerve paralysis (about 3 percent with cryoballoon), and rare instances of stroke and atrioesophageal fistula [4,5]. These and other complications are described in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) A 2017 randomized comparison between cryoablation and RFA showed similar success rates, as did a meta-analysis of observational studies [6,7]. (See "Atrial fibrillation: Catheter ablation" and https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 2/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non- electrophysiologists".) Commonly employed drugs to maintain sinus rhythm are amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone. Approximately 25 to 50 percent of people who receive antiarrhythmic medications will have recurrent AF within one year. Important side effects of antiarrhythmics include proarrhythmia, bradyarrhythmia, and organ toxicity in the case of amiodarone. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Approach For patients with symptomatic paroxysmal AF, in whom rhythm rather than a rate control is pursued, we suggest catheter ablation as first-line therapy in some patients as an alternative to antiarrhythmic drugs (AADs); this is particularly true for younger patients or patients who are poor candidates for AAD therapy or are concerned about the potential complications of AADs. Other factors that may impact the safety and efficacy of catheter ablation also need to be considered when deciding between catheter ablation and AAD. For patients with symptomatic paroxysmal or persistent AF who have failed or become intolerant to one or more AADs, we recommend catheter ablation. For patients with symptomatic persistent or longstanding persistent AF who have failed or become intolerant of one or more AADs or who choose not to start antiarrhythmic therapy, we suggest catheter ablation. Initial treatment of paroxysmal AF with catheter cryoballoon ablation was associated with a lower incidence of persistent AF or recurrent atrial tachyarrhythmia over three years of follow-up than initial use of AADs. Three hundred and three patients were assigned to undergo initial rhythm-control therapy with catheter ablation or to receive antiarrhythmic therapy. Over 36 months of follow-up the following findings were noted: Patients assigned catheter ablation had less persistent AF compared with patients assigned to AADs (1.9 versus 7.4 percent; hazard ratio [HR] 0.25 95% CI 0.09-0.70). Patients assigned catheter ablation had less recurrent atrial tachyarrhythmia, which occurred in 87 patients in the ablation group (56.5 percent) and in 115 in the AAD group (77.2 percent; 56.5 versus 77.2 percent; HR 0.51 95% CI 0.38-0.67). Serious adverse events occurred in seven patients (4.5 percent) in the ablation group and in 15 (10.1 percent) in the AAD group. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 3/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate PATIENTS WITHOUT PRIOR ANTIARRHYTHMIC DRUG TREATMENT Some patients with paroxysmal or persistent atrial fibrillation (AF) (see 'Classification' above) prefer a rhythm as opposed to a rate control strategy in order to decrease symptoms (see "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'). For patients who have chosen rhythm control and who have not previously received antiarrhythmic drug (AAD) therapy, we usually start with AAD rather than CA. On occasion, initial treatment with CA may be appropriate. All patients need to be informed of the possibility of recurrence of symptoms and adverse events with both therapies. Recurrence rates and side effects are discussed in detail elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Atrial fibrillation: Catheter ablation", section on 'Complications' and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Drug-related arrhythmias and mortality'.) Prior to 2020, catheter ablation (CA) was generally not offered as first-line therapy given the complexity of the procedure and the potential for complications. It was typically offered to patients who had failed AAD therapy. However, evidence suggests that CA is superior to AAD for control of symptoms. While CA appears superior to AAD for the prevention of AF recurrence, there is no evidence that the rates of cardiovascular death, myocardial infarction, or stroke differ between the two interventions. In addition, in the studies demonstrating superiority of CA, the procedure was performed by highly expert electrophysiologists. Thus, for most patients, we start with AAD. CA by an experienced operator may be considered as first-line therapy for symptomatic patients who, after a full discussion of the benefits and risks of both approaches, prefer an invasive approach. In a meta-analysis of six studies in 1200 patients comparing CA with AAD as first-line treatment for paroxysmal AF, CA was associated with [8]: Lower rates of recurrent atrial arrhythmias (35 versus 53 percent; risk ratio [RR] 0.64, 95% CI 0.51-0.80) [8]. Similar risks of serious adverse events (18 versus 21 percent; RR 0.87, 95% CI 0.58-1.30). Adverse events were defined differently across studies and included stroke, tamponade, and death. Lower rates of symptomatic atrial arrhythmias. Lower healthcare resource utilization. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 4/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate Lower rates of crossover to alternative treatment (RR 0.21, 95% CI 0.13-0.32). Limitations of this study include a moderate degree of heterogeneity among the included studies; one study in particular accounted for most of the heterogeneity (the RAAFT 2 trial) [9]. PATIENTS WITH PRIOR ANTIARRHYTHMIC DRUG TREATMENT For patients with either paroxysmal or persistent (see 'Classification' above) AF who are interested in decreasing their symptom burden and have received treatment with at least one antiarrhythmic drug, either catheter ablation or long-term antiarrhythmic drug therapy is a reasonable approach. The patient's choice will be guided by advantages and burdens of each approach. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) This section will review the studies that have directly compared the two approaches. These studies suggest that although catheter ablation and antiarrhythmic drug therapy lead to similar rates of all-cause mortality and other serious morbidities, there may be a greater improvement in quality of life with the former. This topic is not intended to address management in patients who have failed rhythm control with two or more antiarrhythmic drugs or those who have already received catheter ablation. Failure of an antiarrhythmic drug is defined as a drug trial that results in a reduction in AF burden that is not satisfactory to the patient, or results in side effects that are intolerable to the patient, proarrhythmia, or organ toxicity. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Long-term issues'.) Three early meta-analyses of studies comparing catheter ablation and antiarrhythmic drug therapy found that recurrence of AF occurred less often in patients who received catheter ablation in the 12 months after initiation of therapy [10-12]. The following three randomized trials directly compared catheter ablation with antiarrhythmic drug therapy: The ThermoCool AF study randomly assigned 167 symptomatic patients with paroxysmal AF (no episodes lasting more than 30 days) who did not respond to at least one AAD and who experienced at least three episodes of paroxysmal AF within six months before randomization to either catheter ablation (with RFA) or AAD therapy in a 2:1 fashion [13]. Patients with significant left ventricular dysfunction, persistent AF, and advanced heart failure were excluded. Catheter ablation included pulmonary vein isolation with confirmation of entrance block, and AAD therapy included flecainide (36 percent), https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 5/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate propafenone (41 percent), dofetilide, sotalol, or quinidine at the investigator's discretion. After nine months, there were significantly fewer patients with documented symptomatic paroxysmal AF in the catheter ablation group (16 versus 66 percent; hazard ratio 0.30, 95% CI 0.19-0.47). In addition, major treatment-related adverse events occurred more often with AAD therapy (9 versus 5 percent) at 30 days. Mean quality-of-life scores improved significantly with catheter ablation compared to AAD therapy. The STOP AF trial randomly assigned 245 paroxysmal AF patients (in a 2:1 manner) to cryoballoon ablation or drug therapy [14]. Patients had previously failed drug therapy; paroxysmal and early persistent AF were present in 78 and 22 percent, respectively. Treatment success was defined as freedom from chronic treatment failure, as defined by the absence of: any detectable AF after the blanking period; use of a non-study antiarrhythmic drug; and any non-protocol intervention for AF. At 12 months, the primary end point was present in 69.9 and 7.3 percent of the two groups (p<0.001). Serious adverse procedure-related events occurred in 3.1 percent. Phrenic nerve palsy occurred in 11.2 percent, but resolved in the majority. The Catheter ABlation vs ANtiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) trial randomly assigned 2204 patients with paroxysmal (43 percent) or persistent AF (57 percent) to catheter ablation or antiarrhythmic drug therapy [15]. Patients were excluded if they had a prior catheter ablation or had failed two or more antiarrhythmic drugs. The following findings were noted: Among the patients who received antiarrhythmic drug therapy, 27.5 percent crossed over to the ablation group. The primary composite end point (death, disabling stroke, serous bleeding, or cardiac arrest) occurred in 8.0 and 9.2 percent of the two groups, respectively (hazard ratio [HR] 0.86, 95% CI 0.65-1.15), during a median follow-up of about four years. There was no difference in all-cause mortality (5.2 versus 6.1 percent; HR 0.85, 95% CI 0.60-1.21). The end point of death or cardiovascular hospitalization occurred less often with catheter ablation (51.7 versus 58.1 percent; HR 0.83, 95% CI 0.74-0.93), as did the rate for AF recurrence (49.9 versus 69.5 percent; HR 0.52, 95% CI 0.45-0.60). Both patient groups achieved significant improvement in quality-of-life scores, and the improvement in the catheter ablation group was significantly greater than in the drug therapy group. Using one quality-of-life tool, the mean score at baseline was approximately 63 points. At 12 months, the scores were 80.9 and 86.4 points, respectively [16]. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 6/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate The Catheter Ablation compared with optimized Pharmacological Therapy for Atrial Fibrillation (CAPTAF) trial randomly assigned 155 patients with symptomatic persistent or paroxysmal AF to catheter ablation or antiarrhythmic drug therapy [17]. The primary end point, SF-36 General Health score, improved more in the ablation group than the drug therapy group from baseline to 12 months (mean baseline score, 61.8 versus 62.7; mean change 11.9 versus 3.1, respectively; p = 0.003). Patients with heart failure Mortality and morbidity are higher among patients with atrial fibrillation and heart failure than among those with heart failure alone. Catheter ablation for atrial fibrillation has been proposed as a means of improving outcomes among patients with heart failure who are otherwise receiving appropriate treatment. This issue is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of catheter ablation are available in societal guidelines. The 2016 European Society of Cardiology guideline recommends catheter ablation for patients with symptomatic, paroxysmal, persistent, and probably long-standing persistent atrial fibrillation who have failed (or are intolerant to) treatment with at least one antiarrhythmic drug [18]. The 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation makes the following recommendations regarding catheter ablation (CA) to maintain sinus rhythm [19] CA is useful for symptomatic paroxysmal AF refractory or intolerant to at least one class I or III antiarrhythmic medication when a rhythm control strategy is desired. CA is reasonable for selected patients with symptomatic persistent AF refractory or intolerant to at least one class I or III antiarrhythmic medication. CA may be considered for symptomatic long-standing (>12 months) persistent AF refractory or intolerant to at least one class I or III antiarrhythmic medication, when a rhythm control strategy is desired. CA may be considered prior to initiation of antiarrhythmic drug therapy with a class I or III antiarrhythmic medication for symptomatic paroxysmal AF when a rhythm control strategy is desired. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 7/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS For most patients with new-onset symptomatic paroxysmal atrial fibrillation (AF) who have chosen a rhythm rather than a rate control strategy, we suggest antiarrhythmic drug (AAD) therapy rather than catheter ablation (CA) as initial therapy (Grade 2C). Patients who may reasonably prefer CA as initial therapy include those who are concerned about the potential complications of AAD or the higher rate of AF recurrence with it. (See 'Patients without prior antiarrhythmic drug treatment' above.) For patients with symptomatic paroxysmal or persistent AF and who have failed or become intolerant to one or more AAD, we recommend CA (Grade 1A). (See 'Patients with prior antiarrhythmic drug treatment' above.) For patients with symptomatic persistent or longstanding persistent AF who have failed or become intolerant of one or more AAD or who choose not to start antiarrhythmic therapy, we suggest CA (Grade 2B). (See 'Patients with prior antiarrhythmic drug treatment' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wilber DJ. Pursuing sinus rhythm in patients with persistent atrial fibrillation: when is it too late? J Am Coll Cardiol 2009; 54:796. 2. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. 3. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or Radiofrequency Ablation for Atrial Fibrillation Assessed by Continuous Monitoring: A Randomized Clinical Trial. Circulation 2019; 140:1779. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 8/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate 4. Teunissen C, Velthuis BK, Hassink RJ, et al. Incidence of Pulmonary Vein Stenosis After Radiofrequency Catheter Ablation of Atrial Fibrillation. JACC Clin Electrophysiol 2017; 3:589. 5. Samuel M, Almohammadi M, Tsadok MA, et al. Population-Based Evaluation of Major Adverse Events After Catheter Ablation for Atrial Fibrillation. JACC Clin Electrophysiol 2017; 3:1425. 6. Kuck KH, F rnkranz A, Chun KR, et al. Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of- life outcomes in the FIRE AND ICE trial. Eur Heart J 2016; 37:2858. 7. Buiatti A, von Olshausen G, Barthel P, et al. Cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: an updated meta-analysis of randomized and observational studies. Europace 2017; 19:378. 8. Imberti JF, Ding WY, Kotalczyk A, et al. Catheter ablation as first-line treatment for paroxysmal atrial fibrillation: a systematic review and meta-analysis. Heart 2021; 107:1630. 9. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. JAMA 2014; 311:692. 10. Noheria A, Kumar A, Wylie JV Jr, Josephson ME. Catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation: a systematic review. Arch Intern Med 2008; 168:581. 11. Terasawa T, Balk EM, Chung M, et al. Systematic review: comparative effectiveness of radiofrequency catheter ablation for atrial fibrillation. Ann Intern Med 2009; 151:191. 12. Chen HS, Wen JM, Wu SN, Liu JP. Catheter ablation for paroxysmal and persistent atrial fibrillation. Cochrane Database Syst Rev 2012; :CD007101. 13. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010; 303:333. 14. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013; 61:1713. 15. Packer DL, Mark DB, Robb RA, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1261. 16. Mark DB, Anstrom KJ, Sheng S, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1275. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 9/10 7/6/23, 3:08 PM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate 17. Blomstr m-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial. JAMA 2019; 321:1059. 18. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 19. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:e275. Topic 93920 Version 30.0 Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 10/10

7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Management of cardiac implantable electronic devices in patients receiving palliative care : Kapil Kumar, MD : R Sean Morrison, MD, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 22, 2023. INTRODUCTION Discontinuation of cardiac implantable electronic device (CIED) therapy, including both permanent pacemakers (PPMs) and implantable cardioverter-defibrillators (ICDs), is a complicated issue. For many patients, these are often life-sustaining therapies, with many ethical, legal, and religious principles that underlie the decision-making process to withdraw CIEDs. The issues related to changes in CIED therapy, including specific issues related to palliative care, will be discussed here. A more extensive discussion of palliative care planning and ethical issues which arise in palliative care are presented separately. (See "Palliative care: The last hours and days of life".) (See "Overview of comprehensive patient assessment in palliative care".) (See "Ethical issues in palliative care".) KEY CONCEPTS IN PALLIATIVE CARE A few key concepts specifically relevant to the management of CIEDs in patients receiving palliative care will be reviewed here ( algorithm 1). Advance care planning Patients at any stage of health or illness should be encouraged to engage in advance care planning to identify their goals of care, articulate wishes in the setting of serious illness, and name a surrogate decision maker. Advance care plans should also https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 1/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate specifically address CIED management when the patient has one. Advance care plans and proxy designations can always be subsequently modified in the event of a change in clinical status or change in the patient's goals of care. (See "Advance care planning and advance directives" and "Discussing goals of care".) Patients and advance directives Advance care planning should be an important part of every patient's care plan regardless of underlying illness, but such advance directives take on additional importance for patients with significant medical comorbidities who are being considered for palliative care. Advance-care planning for patients with CIEDs however, still needs improvement, as evidenced by the following observational data [1-4]. In a retrospective study of the prevalence of an advanced directive among 420 patients with an implantable cardioverter-defibrillator (ICD), only 28 percent had an advance directive in place at the time of ICD implantation, with only 1 percent specifically addressing the issue of ICD deactivation at end of life [1]. In a survey of 278 patients with an ICD, more than half of the patients had executed an advance directive, but only 1 percent had included a plan for the management of the ICD [2]. In a nationwide survey of 3067 participants with CIEDs from the Swedish ICD and Pacemaker Registry which asked patients 11 questions (true or false type questions) about their knowledge of the ICD and its function in relation to end-of-life issues, 29 percent of patients were able to answer only five or fewer questions correctly, indicating a significant lack of understanding of the ICD and how it might impact quality of life in an end-of-life situation [3]. Clinicians and advance care planning Advance care plans should be an integral part of the clinical care plan for all patients, especially when caring for patients who are being considered for palliative care. However, patient and clinician understandings regarding the role of advanced directives and the capabilities of CIED programming can be vastly different [5-10]. As examples: In a survey of United States clinicians, one-third of internists and two-thirds of electrophysiologists who responded believed patients knew they could deactivate the shocking function of an ICD [5]. However, in a separate survey, nearly 50 percent of patients indicated that they had never considered ICD deactivation in the context of end-of- life situations [6]. Clinicians who believe that patients know the options for device management at the end of life may be less likely to discuss deactivation [5]. https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 2/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate In a survey of 294 patients in the Netherlands, 68 percent believed that it is possible to turn the ICD off [7]. In contrast, in a 54 patient study in the United States, only 3 percent recalled receiving information about deactivation when providing consent for implantation, and 38 percent became aware later [8]. In one chart review of 150 patients who underwent device deactivation at a tertiary care center, 42 percent of patients with device deactivation had a palliative care consultation, and of those, 68 percent specifically addressed device deactivation, indicating the potential value of a palliative care consult regarding goals of care [9]. A separate study revealed that only 10 percent of hospice providers have a device deactivation policy [10]. When differing opinions or beliefs are present Although patients have the right to request withdrawal of therapy, it is possible that the personal and professional values of the provider and the patient may differ. Various professional society guidelines stipulate that clinicians in this position have an obligation to arrange for alternative provisions of care in cases of conscientious objection that cannot be resolved by ethics or clerical consultation [11-13]. Additionally, while ethicists are not routinely involved in decisions regarding withdrawal of CIED therapy, there are select occasions in which an ethics committee may be helpful, namely when the patient is unable to provide consent and there is a difference of opinion among family members and/or health care providers. Separate topic reviews on discussing goals of care and handling requests for potentially futile or inappropriate therapies are available. (See "Discussing goals of care" and "Palliative care: Medically futile and potentially inappropriate therapies of questionable benefit".) Withholding versus withdrawing therapy Withholding therapy refers to not providing a therapy that may be indicated, in contrast to withdrawing therapy which generally refers to removal of a previously instituted and indicated therapy. Withholding a life-sustaining therapy is sometimes seen as emotionally easier for clinicians and families to accept compared with withdrawing a previously instituted life-sustaining therapy, probably because there is a perception of less involvement in the patient's death. However, in multiple countries, including the United States and United Kingdom, there is no ethically meaningful distinction between withholding and withdrawing life-sustaining treatments. A more extensive discussion of the ethical issues in palliative care as well as the distinction between withholding and withdrawing therapy is presented separately. (See "Withholding and withdrawing ventilatory support in adults in the intensive care unit", section on 'Ethical misperceptions about foregoing ventilatory support' and "Ethical issues in palliative care".) FREQUENCY OF LATE-LIFE ICD THERAPIES https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 3/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate Patients and providers should engage in early and frequent discussions regarding how the CIED fits in with the patient s goals of care and advance care planning. Patient opinions regarding their end-of-life implantable cardioverter-defibrillator (ICD) therapy can vary widely. Some patients choose to deactivate their ICD when nearing end of life. Others wish to have all possible efforts at prolonging life; they may choose to maintain ICD therapies and accept the potentially negative side effects (eg, shock-related pain, anxiety, etc). For these patients, receiving ICD shocks near the end of life can have a profoundly negative impact on quality of life and may also negatively impact family and friends. Unfortunately, patient and provider discussions regarding ICD deactivation occur much less frequently than do discussions regarding living wills and health care proxy assignment. In a prospective study of 51 patients with ICDs and significant medical comorbidities who were followed for up to 18 months, living wills and health care proxy assignment were completed 88 and 98 percent of the time, whereas communication about patient prognosis and ICD deactivation occurred only 10 and 23 percent of the time [14]. These low rates of discussions regarding ICD deactivation likely result in low rates of ICD deactivation near the end of life. A retrospective chart review of 98 patients with ICDs from the MADIT II who later died found that 15 percent chose to have their ICDs deactivated [15]. This is consistent with studies from other countries. In a study from Sweden, 52 percent of the patients had a do-not-resuscitate order, yet 65 percent of them still had the ICD activated 24 hours before death [16]. Unfortunately, ICD shocks are common at the end of life. Last month of life Interviews with family members of deceased patients in a single practice found that approximately 20 percent of patients with ICDs had the device discharge in the last month of life [5]. A separate clinical cohort study from Japan studied 27 patients with do-not-resuscitate orders. Twenty-seven percent of patients experienced an ICD shock, and 24 percent experienced electrical storm [17]. Last 24 hours of life In the MADIT II trial, 83 patients had terminal illnesses and active ICDs; 12 percent of these patients had a device discharge within 24 hours of death [15]. In an autopsy study from Sweden, 125 ICDs were explanted from patients who had died. The study showed that 31 percent of patients received shock treatment during the last 24 hours of their lives. However, arrhythmic death was the primary cause of death in only 13 percent [16]. Most notably, 52 percent of the patients had a do-not-resuscitate order, yet 65 percent of them still had the ICD activated 24 hours before death [16]. https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 4/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate INDICATIONS FOR DISCONTINUING CIED THERAPY The discussion around discontinuation of CIED therapy is different depending on whether the device in question is a permanent pacemaker (PPM) or an ICD ( algorithm 1). In general, however, a discussion regarding the discontinuation of CIED therapy typically arises in one or more of the following settings: The goals of care have changed As examples: The patient and/or the healthcare proxy have decided (patient preference) that a patient with an advanced serious life-threatening illness should not be resuscitated by either external or internal (ie, ICD) defibrillation. The patient and/or the healthcare proxy have decided (patient preference) to withdraw treatments in a patient who is pacemaker-dependent. A CIED complication has occurred Most commonly due to infection or device component malfunction necessitating CIED removal. Patient-directed change in goals of care The concept of patient autonomy underlies both the ethical and legal principles surrounding CIED deactivation, with these ethical and legal principles having been well established. Patients with capacity (or the patient's legally designated surrogate) can request discontinuation of any medical or device treatment, including therapies such as pacemaker treatment in a pacemaker-dependent patient. When made by a patient with capacity or the relevant surrogate, such a decision falls within the spectrum of "withdrawal of treatment", is ethically sound, and should be distinguished from an act of euthanasia or physician-assisted suicide. No patient is committed to therapy that he or she no longer wishes to receive [18]. In addition, it is not necessary for patients to be terminally ill to make these requests. (See "Ethical issues in palliative care".) Device complications necessitating CIED removal Occasionally, it becomes necessary to remove a CIED system, the generator, and accompanying lead(s) due to a complication, most commonly CIED system infection or structural failure of a CIED component such as lead fracture. When a pacemaker is removed, the indication for pacing versus the risks of reimplantation should be addressed. When an ICD is removed, the patient is no longer protected from sudden cardiac death, and a decision must be made about if and when to place a new ICD. (See "Cardiac implantable electronic devices: Long-term complications" and "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".) https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 5/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate WHAT TO EXPECT AFTER DEVICE DISCONTINUATION Discontinuation of ICD therapy All modern ICD systems have the ability to treat ventricular tachyarrhythmias and provide for backup pacing functionality (ie, serve as a pacemaker). Each of these functions can be turned off individually. For most patients with an ICD, discontinuing antitachycardia therapies (including antitachycardia pacing and shocks) by reprogramming the device will not have any immediate impact on comfort or quality of life ( algorithm 1). The only exception would be in a patient who is receiving, or has recently received, one or more ICD shocks. In this case, quality of life may improve by reducing painful shocks, but a recurrent ventricular arrhythmia would be untreated and potentially fatal. When discontinuation of ICD therapy is requested because of a change in the goals of care, the role of the clinician is to fully explain the implications of the decision. Some issues that may be important include: Shock-related pain and anxiety Among patients with a terminal illness and a poor prognosis, the pain from an ICD shock, or the anxiety of potentially receiving an ICD shock, can be contrary to a primary goal of maintaining the patient's comfort [19]. When a patient with a preexisting ICD has a new diagnosis of a terminal illness, the option of disabling ICD therapies should be included in broader discussions of end-of-life care. Many patients will choose to disable ICD therapies, resulting in fewer shocks (and greater comfort) in the final days of a terminal illness [20]. Long-term recovery Patients in all states of health, ranging from those with a terminal- illness to active and healthy patients without an advanced life-threatening illness, may request that they not be resuscitated due to a fear of recovery to an incapacitated state requiring long-term mechanical support. Because an ICD treats potentially lethal arrhythmias quite rapidly, patients may recover to their baseline condition after the device has discharged. However, it should be noted that recurrence of ventricular arrhythmias is high, and their presence may not only be a manifestation but also a driver of worsening cardiac status. Discontinuing pacemaker therapy in the nonpacemaker-dependent patient For patients who are not pacemaker-dependent, discontinuing pacemaker therapy (either by reprogramming or removing the device) would not be expected to immediately result in death ( algorithm 1). In nearly all cases, the device may be noninvasively reprogrammed such that device removal is not typically required to accomplish withdrawal of therapy. https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 6/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate While potentially controversial to some patients and providers, the discontinuation of a permanent pacemaker (PPM) in patients who are not PPM-dependent is generally considered reasonable if desired by the patient; this decision amounts to withholding rather than withdrawing therapy. Among 658 respondents to a survey regarding the withdrawal of PPM therapy at the end of life, legal professionals (89 percent), medical professionals (87 percent), and patients (79 percent) were consistent in their opinion that withdrawal of PPM therapy in a patient who was not PPM-dependent was appropriate if requested by the patient [21]. Discontinuing pacemaker therapy in the pacemaker-dependent patient More challenging and controversial is the decision to withdraw PPM therapy in a patient who is PPM- dependent, which would generally be considered a withdrawal of therapy. For patients who are pacemaker-dependent, discontinuing pacemaker therapy (either by reprogramming or removing the device) will almost certainly result in symptomatic bradycardia or asystole ( algorithm 1). Clinicians should notify the patient (or the patient's proxy) of the likelihood of loss of consciousness related to bradycardia or asystole and may wish to consider administering additional sedation to the patient at the time the pacemaker is reprogrammed should that decision ultimately be made. The 2018 American College of Cardiology/American Heart Association/Heart Rhythm Society Guidelines support shared decision-making regarding discontinuation of PPM therapy; these guidelines state patients with decision-making capacity or his/her/their legally defined surrogate have the right to refuse or request withdrawal of pacemaker therapy, even if the patient is pacemaker dependent [22]. It should be noted that turning off the pacing function of a pacemaker may not lead to the immediate demise of the patient. Many patients have an underlying junctional or ventricular escape rhythm that may sustain life for several hours, days, or even longer. During this time, a patient may have worse quality of life due to syncope or significant lightheadedness. For patients who have cardiac resynchronization therapy (biventricular pacemaker), their underlying heart failure symptoms may also worsen after withdrawal of pacing. Among the same 658 respondents to the survey discussed above regarding the withdrawal of PPM therapy at the end of life, greater numbers of legal professionals (85 percent) than patients (66 percent) and medical professionals (63 percent) thought that a pacemaker could be turned off in a pacemaker-dependent patient [21]. In a separate survey, an even larger proportion of electrophysiologists (318 of 384 respondents; 83 percent) responded that deactivation of antitachycardia therapies in an ICD was ethically and morally different than discontinuing pacemaker therapy in a pacemaker-dependent patient [23]. However, given the competent patient's ultimate autonomous right to medical decision-making, the patient retains an absolute right to request turning off a PPM in a pacemaker-dependent https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 7/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate patient if an informed discussion has taken place between the patient (or proxy) and clinician. In the context of an ethical discussion, regardless of the fact that a patient is pacemaker dependent, the pacemaker still represents an artificial life-sustaining treatment that the patient has the right to refuse at any time [12,18]. Patient autonomy as well as the clinician's ability to withdraw or withhold treatment considered to be futile or otherwise inappropriate are highly important components of any discussion regarding the withdrawal of PPM therapy in a PPM- dependent patient. (See "Ethical issues in palliative care".) On occasion, the clinician who is asked to withdraw pacemaker therapy in a pacemaker- dependent patient may disagree with the decision to withdraw pacemaker therapy or may have a conscientious objection to performing this function. In this situation, the patient should be referred for another opinion to a clinician with expertise in pacemakers, or a consultation with the hospital ethics committee may be requested. LOGISTICS OF CIED DEACTIVATION Important logistic considerations include documentation of the care plan, choice of the appropriate environment for CIED reprogramming, and the appropriate CIED settings. Discussion and documentation Prior to any changes in CIED programming, there should be adequate discussion between the patient (or proxy) and clinician regarding the process and expected clinical progression with or without device deactivation, along with documentation of the discussion and the wishes of the patient (or proxy) [24,25]. With the exception of urgent or emergent situations (ie, recurrent ICD shocks delivered to the patient), reprogramming of the CIED, particularly in hospitalized patients, should not occur until an order and/or a note documenting the discussion has been placed in the patient's record. Choosing the proper location Choice of the most appropriate location for device deactivation is most relevant for pacemaker-dependent patients, as in most instances these are the only patients likely to experience an abrupt change in clinical status. Because of the high likelihood of symptomatic bradycardia or asystole following PPM deactivation in a pacemaker-dependent patient, these patients should have their device deactivated in a setting in which additional sedation can be administered prior to the PPM being reprogrammed. Typically, this occurs in a health care environment (eg, hospital, nursing home) or at home with hospice care. Since most non-pacemaker-dependent patients and patients with an ICD typically experience few, if any, immediate consequences following device deactivation, these https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 8/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate patients can have their devices reprogrammed anywhere that is feasible for the patient and the clinician. Device reprogramming Typically, the reprogramming of the CIED can be handled by the clinician who routinely follows the patient for CIED-related issues, but any clinician who is trained in the management of CIEDs can reprogram the device. The following are examples of the types of reprogramming: For patients with an ICD, tachycardia therapies (ie, antitachycardia pacing and ICD shocks) can be disabled. If pacemaker support is necessary and remains consistent with the goals of care, contemporary ICDs can be programmed to maintain functionality as a pacemaker. If planned ICD inactivation has not yet been performed, emergent deactivation of antitachycardia therapies, including antitachycardia pacing and shocks, can be accomplished for most devices by placing a magnet over the ICD generator. While the magnet is in place, the ICD will withhold antitachycardia therapy while continuing with pacing functions. When the magnet is removed, the original parameters are restored. For patients with a permanent pacemaker (PPM), some devices may be programmed to an OOO mode. Alternatively, the lower rate limit or output may be reprogrammed so that the device is functionally programmed "off." SUMMARY AND RECOMMENDATIONS Discontinuing therapy Discontinuation of cardiac implantable electronic device (CIED) therapy, including both permanent pacemakers (PPMs) and implantable cardioverter- defibrillators (ICDs), is a complicated issue. Patients at any stage of health or illness should be encouraged to engage in advance care planning to identify their goals of care, specifically addressing CIED management when the patient has an active device. (See "Advance care planning and advance directives" and "Discussing goals of care".) Key concepts in palliative care The utility of late-life ICD therapies will be viewed differently according to the wishes of the patient or proxy. Patients who wish to have all possible efforts at prolonging life will likely desire to maintain ICD therapies and accept the potentially negative side effects (eg, shock-related pain, anxiety, etc). However, for those patients who decline life-prolonging therapies, receiving ICD shocks near the end of life can have a profoundly negative impact on quality of life and may also impact family and friends. (See 'Key concepts in palliative care' above.) https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 9/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate Indications for discontinuation A discussion regarding the discontinuation of CIED therapy should typically arise when the goals of care have changed or a CIED complication has occurred. Patients with capacity (or the patient's legally designated surrogate) can request discontinuation of any medical or device treatment, including therapies such as pacemaker treatment in a pacemaker-dependent patient. (See 'Indications for discontinuing CIED therapy' above.) What the patient and family should expect following CIED discontinuation varies depending on the device and clinical scenario ( algorithm 1). (See 'What to expect after device discontinuation' above.) For most patients with an ICD, discontinuing antitachycardia therapies (including antitachycardia pacing and shocks) by reprogramming the device will not have any immediate impact on comfort or quality of life. The only exception would be in a patient who is receiving, or has recently received, one or more ICD shocks. In this case, quality of life may improve by reducing painful shocks, but a recurrent ventricular arrhythmia would be untreated and potentially fatal. For patients who are not pacemaker-dependent, discontinuing pacemaker therapy (either by reprogramming or removing the device) would not be expected to immediately result in death or have an immediate impact on comfort or quality of life. For patients who are pacemaker-dependent, discontinuing pacemaker therapy (either by reprogramming or removing the device) will almost certainly result in symptomatic bradycardia or asystole. Clinicians should notify the patient (or the patient's proxy) of the likelihood of loss of consciousness related to bradycardia or asystole and may wish to consider administering additional sedation to the patient at the time the pacemaker is reprogrammed. Logistics of deactivation Following discussion between the patient (and/or the patient's healthcare proxy) and the clinician and decision-making regarding deactivation of cardiac implantable electronic device (CIED) therapies, the CIED can usually be reprogrammed to provide or withhold the desired therapies. Important logistic considerations including documentation of the care plan, choice of the appropriate setting for CIED reprogramming, and the appropriate environs in which to make the programming changes. (See 'Logistics of CIED deactivation' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 10/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate The UpToDate editorial staff acknowledges Ann Garlitski, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Tajouri TH, Ottenberg AL, Hayes DL, Mueller PS. The use of advance directives among patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2012; 35:567. 2. Kirkpatrick JN, Gottlieb M, Sehgal P, et al. Deactivation of implantable cardioverter defibrillators in terminal illness and end of life care. Am J Cardiol 2012; 109:91. 3. Str mberg A, Fluur C, Miller J, et al. ICD recipients' understanding of ethical issues, ICD function, and practical consequences of withdrawing the ICD in the end-of-life. Pacing Clin Electrophysiol 2014; 37:834. 4. Stoevelaar R, Brinkman-Stoppelenburg A, van Driel AG, et al. Implantable cardioverter defibrillator deactivation and advance care planning: a focus group study. Heart 2020; 106:190. 5. Goldstein N, Bradley E, Zeidman J, et al. Barriers to conversations about deactivation of implantable defibrillators in seriously ill patients: results of a nationwide survey comparing cardiology specialists to primary care physicians. J Am Coll Cardiol 2009; 54:371. 6. Herman D, Stros P, Curila K, et al. Deactivation of implantable cardioverter-defibrillators: results of patient surveys. Europace 2013; 15:963. 7. Pedersen SS, Chaitsing R, Szili-Torok T, et al. Patients' perspective on deactivation of the implantable cardioverter-defibrillator near the end of life. Am J Cardiol 2013; 111:1443. 8. Raphael CE, Koa-Wing M, Stain N, et al. Implantable cardioverter-defibrillator recipient attitudes towards device deactivation: how much do patients want to know? Pacing Clin Electrophysiol 2011; 34:1628. 9. Pasalic D, Gazelka HM, Topazian RJ, et al. Palliative Care Consultation and Associated End-of- Life Care After Pacemaker or Implantable Cardioverter-Defibrillator Deactivation. Am J Hosp Palliat Care 2016; 33:966. 10. Goldstein N, Carlson M, Livote E, Kutner JS. Brief communication: Management of implantable cardioverter-defibrillators in hospice: A nationwide survey. Ann Intern Med 2010; 152:296. 11. Pitcher D, Soar J, Hogg K, et al. Cardiovascular implanted electronic devices in people towards the end of life, during cardiopulmonary resuscitation and after death: guidance https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 11/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate from the Resuscitation Council (UK), British Cardiovascular Society and National Council for Palliative Care. Heart 2016; 102 Suppl 7:A1. 12. Lampert R, Hayes DL, Annas GJ, et al. HRS Expert Consensus Statement on the Management of Cardiovascular Implantable Electronic Devices (CIEDs) in patients nearing end of life or requesting withdrawal of therapy. Heart Rhythm 2010; 7:1008. 13. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, personnel, frequency and ethical considerations. Heart Rhythm 2008; 5:907. 14. Kramer DB, Habtemariam D, Adjei-Poku Y, et al. The Decisions, Interventions, and Goals in ImplaNtable Cardioverter-DefIbrillator TherapY (DIGNITY) Pilot Study. J Am Heart Assoc 2017; 6. 15. Sherazi S, McNitt S, Aktas MK, et al. End-of-life care in patients with implantable cardioverter defibrillators: a MADIT-II substudy. Pacing Clin Electrophysiol 2013; 36:1273. 16. Kinch Westerdahl A, Sj blom J, Mattiasson AC, et al. Implantable cardioverter-defibrillator therapy before death: high risk for painful shocks at end of life. Circulation 2014; 129:422. 17. Nakazawa M, Suzuki T, Shiga T, et al. Deactivation of implantable cardioverter defibrillator in Japanese patients with end-stage heart failure. J Arrhythm 2021; 37:196. 18. Kramer DB, Mitchell SL, Brock DW. Deactivation of pacemakers and implantable cardioverter-defibrillators. Prog Cardiovasc Dis 2012; 55:290. 19. Palacios-Ce a D, Losa-Iglesias ME, Alvarez-L pez C, et al. Patients, intimate partners and family experiences of implantable cardioverter defibrillators: qualitative systematic review. J Adv Nurs 2011; 67:2537. 20. Lewis WR, Luebke DL, Johnson NJ, et al. Withdrawing implantable defibrillator shock therapy in terminally ill patients. Am J Med 2006; 119:892. 21. Kapa S, Mueller PS, Hayes DL, Asirvatham SJ. Perspectives on withdrawing pacemaker and implantable cardioverter-defibrillator therapies at end of life: results of a survey of medical and legal professionals and patients. Mayo Clin Proc 2010; 85:981. 22. Writing Committee Members, Kusumoto FM, Schoenfeld MH, et al. 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2019; 16:e128. 23. Daeschler M, Verdino RJ, Caplan AL, Kirkpatrick JN. Defibrillator Deactivation against a Patient's Wishes: Perspectives of Electrophysiology Practitioners. Pacing Clin Electrophysiol https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 12/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate 2015; 38:917. 24. Hadler RA, Goldstein NE, Bekelman DB, et al. "Why Would I Choose Death?": A Qualitative Study of Patient Understanding of the Role and Limitations of Cardiac Devices. J Cardiovasc Nurs 2019; 34:275. 25. Goldstein NE, Mehta D, Siddiqui S, et al. "That's like an act of suicide" patients' attitudes toward deactivation of implantable defibrillators. J Gen Intern Med 2008; 23 Suppl 1:7. Topic 91204 Version 22.0 https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 13/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate GRAPHICS Approach to cardiac implantable electronic device management (permanent pacemakers and implantable cardioverter-defibrillators) in patients receiving palliative care* CIED: cardiac implantable electronic device; ICD: implantable cardioverter-defibrillator; PPM: permanent pacemaker. There is no inherent code status among patients receiving palliative care. Patients may opt for a status of do not resuscitate (DNR), but may continue to choose active CIED therapies. Clarification of code status and the establishment of advanced directives, including CIED management, is an important component of the care plan. in patients without a health care proxy, decisions regarding capacity may require evaluation by psychiatric experts, legal review for determining guardianship, etc. In general, CIED reprogramming occurs in a controlled setting on an elective basis. The one exception may be for a patient who is receiving repetitive ICD shocks in whom placing a magnet over the ICD will terminate the delivery of shocks. https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 14/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate On occasion, the clinician who is asked to withdraw pacemaker therapy in a pacemaker- dependent patient may disagree with the decision to withdraw pacemaker therapy or may have a conscientious objection to performing this. In this situation, the patient should be referred for another opinion by a clinician with expertise in pacemakers, or a consultation with the hospital ethics committee may be requested. Expected clinical course will vary based on type of CIED. In most cases, deactivation of an ICD or a PPM in a non-pacemaker dependent patient will not immediately impact the patient's clinical condition. Deactivating a PPM in a patient who is pacemaker dependent may lead to an immediate deterioration of clinical condition and/or fairly rapid demise depending upon the patient's underlying cardiac rhythm and overall hemodynamic status. Graphic 126133 Version 1.0 https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 15/16 7/6/23, 3:09 PM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. R Sean Morrison, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 16/16

7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Modes of cardiac pacing: Nomenclature and selection : Mark S Link, MD : N A Mark Estes, III, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 07, 2022. INTRODUCTION Once it has been established that bradycardia or a conduction disorder warrants permanent pacing, the most appropriate pacing mode for the patient must be selected. The choice depends upon the specific abnormality that is present, since a wide range of pacemaker functions have been developed to accommodate specific clinical needs ( table 1). (See "Permanent cardiac pacing: Overview of devices and indications".) To facilitate the use and understanding of pacemakers, a standardized classification code has been developed. Most patients can be managed with one of two or three common modes (AAI, VVI, or DDD), with or without rate responsiveness. Contemporary pacemakers are versatile and capable of the most commonly used pacing modes and basic functions (ie, mode switching and rate responsiveness). Some advanced features are available in selected devices. Pacemaker nomenclature and the clinical application of common pacing modes and functions will be reviewed here. NOMENCLATURE Five position code A three-letter code describing the basic function of the various pacing systems was first proposed in 1974 by a combined task force from the American Heart Association and the American College of Cardiology and subsequently updated by a committee from the North American Society of Pacing and Electrophysiology (NASPE) and the British Pacing https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 1/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate and Electrophysiology Group (BPEG). The code, which has five positions, is designated the NBG code for pacing nomenclature ( table 2) [1]. The code is generic and does not describe specific or unique functional characteristics for each device. When a code includes only three or four characters, it can be assumed that the positions not mentioned are "O" or absent. Position I The first position reflects the chamber(s) paced. "A" indicates the atrium, "V" indicates the ventricle, and "D" means dual chamber (ie, both the atrium and the ventricle). Position II The second position refers to the chamber(s) sensed. The letters are the same as those for the first position: "A" for atrium, "V" for ventricle, "D" for dual. An additional option "O" indicates an absence of sensing. Programmed in this mode, a device will pace automatically at a specified rate, ignoring any intrinsic rhythm. (See 'Asynchronous pacing' below.) Manufacturers sometimes use "S" in the first and second positions to indicate that the device is capable of pacing only a single cardiac chamber. Once the device is implanted and connected to a lead in either the atrium or the ventricle, "S" should be changed to "A" or "V" in the clinical record to reflect the chamber in which pacing and sensing are occurring. Position III The third position refers to how the pacemaker responds to a sensed event. "I" indicates that a sensed event inhibits the output pulse and causes the pacemaker to recycle for one or more timing cycles. "T" indicates that an output pulse is triggered in response to a sensed event. "D" indicates that there are dual modes of response. This designation is restricted to dual- chamber systems. An event sensed in the atrium inhibits the atrial output but triggers a ventricular output. There is a programmable delay between the sensed atrial event and the triggered ventricular output to mimic the normal PR interval. If the ventricular lead senses a native ventricular signal during the programmed delay, it will inhibit the ventricular output. "O" indicates no response to sensed input; it is most commonly used in conjunction with an "O" in the second position. Position IV The fourth position reflects rate modulation, also referred to as rate responsive or rate adaptive pacing. (See 'Rate responsiveness' below.) "R" in the fourth position indicates that the pacemaker has rate modulation and incorporates a sensor to adjust its programmed paced heart rate in response to patient https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 2/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate activity. From a practical standpoint, "R" is the only indicator commonly used in the fourth position. "O" indicates that rate modulation is either unavailable or disabled. "O" is often omitted from the fourth position (ie, DDD is the same as DDDO). Position V The fifth position is rarely ever utilized but specifies the location or absence of multisite pacing, defined as stimulation sites in both atria, both ventricles, more than one stimulation site in any single chamber, or a combination of these. The fifth position of the code is rarely used. "O" means no multisite pacing "A" indicates multisite pacing in the atrium or atria "V" indicates multisite pacing in the ventricle or ventricles "D" indicates dual multisite pacing in both atrium and ventricle The most common application of multisite pacing is biventricular pacing for the management of heart failure. This issue is discussed in detail separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) ADDITIONAL FEATURES In addition to the above basic pacing modes, modern pacemakers have additional features to improve performance in a variety of specific clinical settings. Mode switching and rate responsiveness are available in all contemporary pacemakers. Some features are available in select devices and can be utilized as specific clinical situations demand. Mode switching In dual-chamber pacing systems (DDD/DDDR or less commonly, VDD/VDDR), the ventricle will be paced following every sensed atrial event, up to a programmed maximum ventricular rate. If the patient develops a paroxysmal atrial tachyarrhythmia (eg, atrial fibrillation [AF]), the ventricle would then be paced at this maximum programmed rate for the duration of the arrhythmia, which is obviously undesirable. Mode switching refers to automatic reprogramming of a pacemaker to a mode that no longer tracks the intrinsic atrial rate, usually VVI, DDI, or DVI with or without rate responsiveness. When the sensed atrial rate again falls below the mode switching cutoff and the device assumes that a physiologic rhythm has been restored (ie, with termination of the arrhythmia), the pacing mode automatically reverts to the original programming. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 3/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate All contemporary dual-chamber pacemakers have mode switching capabilities. This feature can be activated or disabled, depending upon the clinical situation. Rate responsiveness As described above, rate responsiveness, also referred to as rate modulation or rate adaptation, refers to the ability of a pacemaker to adjust its programmed paced rate based upon patient activity. A variety of sensors have been designed to determine when a patient is physically active (eg, vibration, minute ventilation, change in right ventricular impedance). The range of heart rates, the pace of acceleration and deceleration, and the degree of activity required to initiate this response are all programmable in rate-adaptive pacing modes. Modes to minimize ventricular pacing Right ventricular (RV) pacing causes the right ventricle to contract before the left ventricle (LV), and causes the septum to contract before the lateral wall of the LV, simulating the effects of left bundle branch block. This phenomenon is referred to as ventricular dyssynchrony or asynchrony. Whether due to RV pacing or intrinsic conduction abnormalities, dyssynchrony can cause or exacerbate heart failure in some patients and increase the frequency of AF. (See "Overview of pacemakers in heart failure" and "The role of pacemakers in the prevention of atrial fibrillation".) Native atrioventricular (AV) conduction is hemodynamically preferable to RV pacing. With an increased understanding of the detrimental effects of RV pacing, efforts have been made to develop pacing modes that minimize ventricular pacing [2-7]. Examples of novel pacing strategies for this purpose include the following: Ventricular avoidance pacing algorithms A dual-chamber device can be programmed to pace AAI (allowing native conduction), but if specific criteria are met that signify a loss of AV conduction, the pacemaker will automatically switch to DDD pacing for some period of time until the algorithm once again determines the presence of intrinsic AV conduction. This approach has been associated with a markedly lower rate of frequency of ventricular pacing compared with conventional dual-chamber pacing (9 versus 99 percent and 4 versus 74 percent in two studies) [3,4,7]. AV search hysteresis Algorithms exist that will prolong the programmed AV delay in a dual-chamber device to allow native conduction when present. The mechanism and frequency with which the algorithm allows AV prolongation to determine the presence of intrinsic AV conduction and the degree to which the AV delay can be extended are variable depending on manufacturer and model [5]. If native conduction with a long PR or AR is present, the device will allow this to continue until the allowed interval is exceeded and there is no intrinsic QRS. This will generally reset the algorithm to the original programmed AV interval. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 4/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Biventricular pacing In some patients, ventricular dyssynchrony is unavoidable due to intrinsic conduction disease or inevitable ventricular pacing. If such a patient also has heart failure and LV dysfunction, synchrony may be restored with biventricular pacing, or cardiac resynchronization therapy (CRT), which improves outcomes in selected patients. Cardiac resynchronization therapy is discussed in detail elsewhere. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Patients with LV dysfunction and a mildly reduced ejection fraction (EF; eg, 36 to 49 percent) who have an indication for permanent pacing have traditionally received a standard dual-chamber pacemaker. However, given the potential for ventricular pacing (especially RV apical pacing) to cause or exacerbate LV dysfunction, it is believed that patients might have better outcomes if cardiac resynchronization therapy (ie, biventricular pacing) was the initially implanted device. One trial, BLOCK-HF, demonstrated that in patients with AV block and LV systolic dysfunction (LVEF <50 percent) with NYHA class I, II, or III heart failure, biventricular pacing was superior to conventional RV pacing for the primary outcome of time to death from any cause, urgent IV therapy for heart failure, or 15 percent or greater increase in LV end-systolic volume index [8]. In a post hoc analysis of the BLOCK-HF trial, patients in the biventricular pacing arm were more likely to have improvement in NYHA functional status and in a clinical composite score incorporating various clinical outcomes [9]. Additional randomized clinical trials are needed to assess conventional pacing versus biventricular stimulation in patients with mildly reduced LV function. His bundle pacing His bundle pacing is an alternative approach to reduce the risk of dyssynchrony, as discussed separately. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'His bundle pacing'.) PACING MODES In selecting the ideal pacing mode, the patient's overall physical condition, associated medical problems, exercise capacity, left ventricular function, and chronotropic response to exercise must be considered along with the underlying rhythm disturbance. Some of the various ventricular and atrial pacing systems available and their NBG codes are shown in the table ( table 3). Single-chamber pacing Early pacemakers were designed to sense and pace in a single chamber. Ventricular pacing can prevent ventricular bradyarrhythmias or asystole of any etiology. Atrial pacing can be used in patients with isolated sinus node dysfunction (SND) and intact AV conduction. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 5/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate VVI or VVIR pacing Ventricular demand pacing (ventricle paced, ventricle sensed, and pacemaker inhibited in response to a sensed beat) remains the most commonly used pacing mode. Advantages of ventricular demand pacing include the requirement for only a single lead and the ability to protect the patient from dangerous bradycardias of any etiology. However, ventricular demand pacing cannot maintain AV synchrony, and lack of AV synchrony can result in pacemaker syndrome. (See 'Pacemaker syndrome' below.) Virtually all devices currently in use are capable of VVIR pacing. VVIR pacing is primarily indicated in patients with chronic atrial fibrillation with a slow ventricular response. By contrast, in a patient with normal sinus rhythm, VVIR pacing should not be used as an excuse to forego attempts at placing an atrial lead. If sinus node function is intact, dual-chamber (DDD) pacing preserves AV synchrony and maintains the patient's natural heart rate response to activity. This approach is optimal and should be used whenever possible. (See 'Physiologic pacing' below.) AAI or AAIR pacing Atrial demand pacing (atrium paced, atrium sensed, and pacemaker inhibited in response to sensed atrial beat) is appropriate for patients with SND who have intact AV nodal function. Patients with symptomatic sinus bradycardia or sinus pauses, but with an intact ability to accelerate their heart rate with exertion, can be programmed in an AAI mode. Those who cannot adequately accelerate their heart rate should have rate responsive capability available (ie, AAIR). As with ventricular demand pacemakers, these devices have the benefit of requiring only a single lead. However, unlike ventricular single-chamber pacemakers, they will not protect patients from ventricular bradyarrhythmias due to AV conduction block. Due to this limitation, atrial demand pacemakers are infrequently used. Many clinicians are concerned that a patient who already has sinus node disease will later develop AV conduction disease. Although it would be uncommon for AV block to develop precipitously and result in a catastrophic event, gradual development of AV conduction system disease may require upgrade of the pacemaker to a dual- chamber device. Pacemaker upgrade can be technically more difficult than original placement of a dual-chamber pacemaker, and the second procedure obviously entails additional cost and patient risk. However, if the patient with SND is assessed carefully and does not have AV node disease at the time of pacemaker implant, the occurrence of clinically significant AV nodal disease is very low (less than 2 percent per year) [10]. Assessment prior to use of an AAI system should include incremental atrial pacing at the time of pacemaker implant. Although criteria vary among https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 6/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate institutions and implanting clinicians, the adult patient should be capable of 1:1 AV nodal conduction to rates of 120 to 140 beats/minute. Dual-chamber pacing DDD or DDDR pacing The dual-chamber (DDD) pacing system provides physiologic pacing (see 'Physiologic pacing' below), with sensing and pacing capabilities in both the atrium and the ventricle. The pacemaker will be totally inhibited in the presence of sinus rhythm with normal AV conduction if the sinus rate is faster than the programmed lower rate of the pacemaker and the intrinsic AV conduction is faster than the programmed AV interval. If there is sinus bradycardia but normal AV conduction with the intrinsic QRS occurring before the end of the programmed AV interval, there will be atrial pacing with a native QRS complex following each paced atrial beat. Both the atrium and ventricle will be paced if there is sinus bradycardia and delayed or absent AV conduction. The ventricle will be paced synchronously with the atrium if there is normal sinus rhythm with delayed or absent AV conduction. As a result, there are four different rhythms that can be seen with normal pacemaker function ( waveform 1): Normal sinus rhythm Atrial pacing, normally conducted to the ventricle with a native QRS AV sequential pacing Atrial sensing and ventricular pacing The DDD pacing mode is appropriate for patients with AV block who have normal sinus node function. DDD pacing is also considered by some to be the mode of choice in carotid sinus hypersensitivity with symptomatic cardioinhibition. However, most patients should receive a pacemaker capable of DDDR pacing, even if rate response is not initially programmed "on." The ideal patient for DDDR pacing is one with combined sinus nodal and AV nodal dysfunction in whom DDDR pacing would restore rate responsiveness and AV synchrony. DDDR pacing is also appropriate for patients with SND and normal AV conduction. As noted above, many practitioners are not comfortable with AAIR pacing. Use of DDDR pacing mode with an algorithm that will minimize ventricular pacing is often preferred. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 7/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate DDI or DDIR pacing In the DDI pacing mode, there is atrial sensing and pacing, and ventricular sensing and pacing; however, the pacemaker will not track intrinsic atrial activity. When there is a sensed native atrial rate, the pacemaker will inhibit both atrial and ventricular output, thereby allowing native conduction to the ventricle. If AV block develops, ventricular pacing will occur at a programmed rate, but will not be synchronized with the atrium. As an example, if a device is programmed DDI at 50 beats per minute, and the patient has sinus rhythm at 60 with 1:1 AV conduction, the device will be fully inhibited. If AV block develops, the pacemaker will pace the ventricle at 50 beats per minute. If sinus bradycardia develops, the pacemaker will pace the atrium and ventricle synchronously at 50 beats per minute. In the DDI mode, if the sinus rate is below the programmed rate, the pacemaker will pace the atrium and ventricle sequentially. There are few, if any, advantages of DDI or DDIR pacing at this time. At one time, this mode was helpful for the patient with atrial tachyarrhythmias. Since DDI does not "track," this mode would alleviate the concern of fast ventricular rates in response to the atrial tachyarrhythmia. However, this has become much less important since essentially all dual-chamber devices now have mode switching capability. (See 'Mode switching' above.) Less common modes VDD and DVI mode remain programmable options in most pacemakers but are rarely used. VDD pacing VDD pacing (ventricle paced, atrium and ventricle sensed, and either inhibition or tracking of the pacemaker in response to a sensed beat) may be appropriate for the patient with normal sinus node function and conduction disease of the AV node. Dual-chamber (two lead) VDD pacing systems have largely been supplanted by DDD pacemakers. However, a single-lead VDD pacing system, now available for many years, has increased interest in the use of VDD as the initial pacing mode in patients with AV block but normal sinus node function [11-13]. In these systems, atrial sensing is accomplished from "floating" sensing electrodes on the atrial portion of the ventricular pacing lead. One limitation to the use of a single-lead VDD pacemaker is that patients with initially normal SA node function may develop SND. This would then require a second procedure to place an atrial lead capable of pacing in order to maintain AV synchrony and chronotropic competence. However, this is an infrequent occurrence [14,15]. DVI pacing DVI pacemakers (atrium and ventricle paced, ventricular sensing only, and inhibition of pacemaker in response to sensed ventricular beat) are now of historical interest only. DVI pacing is, by definition, limited by the absence of atrial sensing, which prevents the https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 8/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate restoration of rate responsiveness in the chronotropically competent patient. In addition, lack of atrial sensing may lead to competitive atrial pacing and initiation of atrial rhythm disturbances. Asynchronous pacing Pacemakers may be programmed to pace at a fixed rate, without attempting to sense or react to native cardiac activity. These modes are referred to as asynchronous pacing. AOO, VOO, or DOO mode In these modes, the atrium, ventricle, or both are paced, but the pacemaker has no sensing capability and hence there is no sensing response of the pacemaker. Asynchronous pacing modes are rarely used long-term. These modes, however, may be temporarily necessary for patients who are undergoing a surgical procedure, especially if the patient is pacemaker-dependent. Electrocautery could be sensed by the pacemaker and misinterpreted as native cardiac activity, thereby inhibiting pacing output. This could produce significant bradycardia or asystole in a pacemaker-dependent patient. Thus, prior to surgery, the pacemaker could be reprogrammed to an asynchronous mode that turns off its sensing capability. After surgery, the pacemaker should be reprogrammed to its prior mode. Alternatively, a magnet placed over the pacemaker will deactivate its ability to sense and, while left in place, will result in asynchronous pacing. Although this approach has been used for many years there are some concerns that are likely more theoretical than real. Pacing in an asynchronous mode can be associated with competition between the native and the paced rhythms, with the possibility that a paced impulse will occur during a native T wave (or the vulnerable period). To reduce this risk, asynchronous pacing could be programmed to a relatively higher rate ( 80 beats/minute). PHYSIOLOGIC PACING Physiologic pacing is a term that has been used to describe pacing systems that most closely approximate normal cardiac behavior. It most commonly refers to systems that maintain AV synchrony (eg, AAI or DDD systems, in contrast to VVI systems), but has also been applied to rate responsive pacemakers. (See 'AAI or AAIR pacing' above and 'Dual-chamber pacing' above and 'Rate responsiveness' above.) Potential advantages Physiologic pacing has several potential hemodynamic and clinical advantages compared with VVI pacing [16]. These include: Reduced incidence of atrial fibrillation (AF) The incidence of atrial tachyarrhythmias, particularly AF, is reduced by physiologic compared with VVI pacing. (See "The role of https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 9/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate pacemakers in the prevention of atrial fibrillation".) Reduced incidence of thromboembolic events A lower rate of thromboembolic events is suggested in the meta-analysis of physiologic pacing discussed below, and may be secondary to the lower incidence of AF [17]. Improved hemodynamics The maintenance of AV synchrony and "atrial kick" is hemodynamically favorable and physiologic pacing improves cardiac output, arterial pressure, and coronary blood flow [18-21]. The magnitude of these improvements is small, and their clinical significance is not clear but, in some studies, physiologic pacing has resulted in a lower incidence of heart failure [22]. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial systole'.) Avoidance of pacemaker syndrome VVI pacing is associated with the development of "pacemaker syndrome." This syndrome is due to AV dyssynchrony or retrograde ventricular-to-atrial conduction. It is prevented by physiologic pacing [23,24]. (See 'Pacemaker syndrome' below.) Effects on outcomes Several trials and a meta-analysis have compared physiologic and VVI pacing [17,24-29]. In the aggregate, these reports demonstrate that across the spectrum of patients with bradycardic indications for pacemakers, physiologic pacing does not improve survival or the incidence of heart failure, but does reduce the incidence of AF and may reduce the incidence of stroke. The meta-analysis included data from five randomized trials [17]: A Danish trial of 225 patients with sinus node dysfunction (SND) and normal AV conduction [22,25,30]. The MOST trial of 2010 patients with SND, 20 percent of whom also had AV conduction disease [26,31]. The CTOPP trial of 2568 patients with both SND and AV conduction disease (42 percent with SND) [27,29,32,33]. The PASE trial of 407 patients, 43 percent with SND [24,34]. The UKPACE trial of 2021 older adult patients, all of whom had AV conduction disease [28]. The meta-analysis included 7231 patients and over 35,000 patient-years of follow-up. The average patient age was 76. Most patients randomly assigned to physiologic pacing received a https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 10/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate dual-chamber (DDD) pacemaker, while all of those in the Danish trial and some in CTOPP received an AAI pacemaker. The following findings were noted: There was no difference in the incidence of heart failure or in all-cause mortality between physiologic and VVI pacing (31 versus 33 percent all-cause mortality). Physiologic pacing significantly reduced the incidence of AF (17 versus 22 percent). Physiologic pacing appeared to reduce the incidence of stroke (5.2 versus 6.3 percent). However, the authors suggested cautious interpretation of this finding, due to borderline statistical significance (95% CI 0.67-0.99, p = 0.035) and the lack of adjustment for multiple hypothesis testing. Subgroup analysis suggested that physiologic pacing may be more beneficial in patients with SND than those with AV block. Among patients with SND, physiologic pacing appeared to reduce the combined endpoint of stroke or cardiovascular death. However, the authors suggested caution in the interpretation of this subgroup analysis, because of heterogeneity in the populations of the included trials (ie, different percentages of patients with SND). Issues specifically related to physiologic pacing and SND are discussed separately. There was no additional advantage in several other subgroups that are often considered to derive a greater benefit from physiologic pacing (eg, those with left ventricular dysfunction or heart failure). Patients appear to prefer physiologic pacing, suggested by relatively high crossover rates from VVI to dual-chamber pacing in the two trials in which this was easy to do. (See 'Patient preference' below.) The results of the meta-analysis are broadly consistent with those of the individual trials. However, due to some differences in the patient populations (eg, SND versus AV block, older adult patients), and the pacemakers used (eg, AAI versus DDD), some points from individual studies are worth consideration: As in the subgroup analysis, results from the Danish trial suggested a greater benefit of physiologic pacing in patients with SND than in those with AV block, which we now understand to be a function of maintaining intrinsic AV conduction in the SND group [30]. In adults with advanced age, the rates of AF and stroke are high regardless of pacing mode. The value of physiologic pacing may be less significant in this group, particularly those with AV block [28,35]. This was best illustrated in the UKPACE trial of 2021 older adult https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 11/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate patients (average age 80), all of whom had AV block [28]. In this population, physiologic pacing did not reduce the rates of mortality, AF, or thromboembolism. Pacemaker syndrome Pacemaker syndrome is a phenomenon associated with the loss of AV synchrony and is seen most commonly with single-chamber VVI pacing. It is defined as the adverse hemodynamics associated with a normally functioning pacing system, resulting in overt symptoms or limitation of the patient's ability to achieve optimal functional status [23]. The development of the pacemaker syndrome with VVI pacing may require upgrade from a VVI pacemaker to a dual-chamber system in some patients. Symptoms most commonly include general malaise, easy fatigability, dyspnea, orthopnea, cough, dizziness, atypical chest discomfort, and a sensation of throat fullness and, less commonly, may result in pre-syncope or syncope. Physical examination may reveal hypotension, rales, increased jugular venous pressure with cannon A waves, peripheral edema, and murmurs of tricuspid and/or mitral regurgitation [23,36]. Patient preference Although no consistent mortality benefit has been identified in randomized clinical trials with physiologic pacing, patients seem to prefer physiologic pacing as illustrated by the following observations: In a double-blind crossover study of different pacing modes, 86 percent of patients preferred physiologic pacing [37]. In PASE and MOST, quality of life scores were higher in patients with SND randomly assigned to physiologic pacing [24,26]. In the clinical trials comparing physiologic and VVI pacing, when crossing over from VVI to physiologic pacing was easy, up to 38 percent of patients chose to cross over. In PASE and MOST, all patients received dual-chamber pacemakers, and randomization to physiologic or VVI pacing occurred after implantation [24,26]. Thus, crossover required only device reprogramming (as opposed to a second procedure). The crossover rates in these two trials were 26 and 38 percent (compared with less than 5 percent in the other trials). The high crossover rate in MOST led to questions about the validity of the results. However, in a later study, the results of intention-to-treat and on-treatment analyses were similar [31]. As in the original report from MOST [26], the on-treatment analysis showed no difference in the primary endpoint between the two pacing modes, but there was a significant reduction in the incidence of AF with physiologic pacing. Based upon the reduced incidence of AF and patient preference, we suggest that physiologic pacing should be used in most patients who require a pacemaker. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 12/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate MODE SELECTION ALGORITHMS A number of guidelines and algorithms are available for determining the appropriate pacing mode for patients with sinus node disease and AV node disease [38]. The indications and contraindications for the various types of pacing modes are listed in the accompanying tables ( table 4) [38]. In this listing, chronotropically competent refers to the ability of a patient to achieve an appropriate heart rate for a given physiologic activity. Several algorithms are also available: General algorithms for all bradycardic indications ( algorithm 1 and figure 1) An algorithm for sick sinus syndrome ( algorithm 2) An algorithm for AV block ( algorithm 3) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Pacemakers (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 13/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate SUMMARY AND RECOMMENDATIONS Nomenclature For permanent cardiac pacing, the five position NBG code indicates the chamber(s) paced, the chamber(s) sensed, the response to sensing, presence or absence of rate modulation, and location or absence of multisite pacing ( table 2). (See 'Nomenclature' above.) Selection of pacing mode In selecting a pacing mode, the patient's overall physical condition, associated medical problems, exercise capacity, left ventricular (LV) function, and chronotropic response to exercise must be considered along with the underlying rhythm disturbance. Some commonly used pacing modes are shown in the table ( table 3). (See 'Pacing modes' above.) Most patients with a standard bradycardic indication for pacing can be managed with one of three common pacing modes (with or without rate responsive pacing): AAI(R), VVI(R), or DDD(R). At the time of implantation, one should consider how many leads will be necessary and which additional features, if any, will be of potential value. Choice of single- or dual-chamber pacemaker The most important choice in most patients with a bradycardic indication for pacing is whether to place a single- or dual- chamber pacemaker (see "Permanent cardiac pacing: Overview of devices and indications" and 'Pacing modes' above). The choice varies with the clinical setting: Atrial fibrillation In patients with chronic atrial fibrillation (AF) who require a pacemaker due to slow ventricular response, we recommend a single-chamber ventricular pacemaker (VVI or VVIR) (Grade 1B). (See 'VVI or VVIR pacing' above.) Sinus rhythm In patients in sinus rhythm with conditions that could be managed with either a single- or a dual-chamber pacemaker (eg, atrioventricular [AV] block, sinus node dysfunction [SND]), we suggest a dual-chamber pacemaker (Grade 2B). (See 'Physiologic pacing' above and 'Dual-chamber pacing' above.) Exception for advanced age or difficult two lead implantation A single- chamber pacemaker is a reasonable alternative in patients who are adults with advanced age or whose anatomy and physical condition make the implantation of two leads more difficult than usual. In such cases, the additional costs and risks of a dual-chamber physiologic pacemaker may outweigh the potential benefits of the reduced risk of AF and patient preference. VVI(R) pacing will be effective in all such patients. (See 'VVI or VVIR pacing' above.) https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 14/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Possible exception for SND with intact AV conduction An AAI(R) pacemaker is a reasonable alternative to VVI(R) pacing in the subset of patients with SND in whom AV conduction is intact and meets intra-implant testing criteria (see "Sinus node dysfunction: Treatment"). However, effective AAIR pacing is more commonly accomplished with a dual-chamber pacemaker with a ventricular pacing avoidance option. (See 'AAI or AAIR pacing' above and 'Modes to minimize ventricular pacing' above.) Additional features The following additional features are appropriate for selected patients: Rate responsiveness This feature can be programmed for patients who are active, but not chronotropically competent. (See 'Rate responsiveness' above.) Mode switching This feature can be programmed for patients with paroxysmal atrial arrhythmias. (See 'Mode switching' above.) Ventricular pacing avoidance Algorithms to avoid ventricular pacing are appropriate for most patients with PR prolongation or type II AV block. Some parameter to minimize ventricular pacing is available in most contemporary devices. (See 'Modes to minimize ventricular pacing' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bernstein AD, Daubert JC, Fletcher RD, et al. The revised NASPE/BPEG generic code for antibradycardia, adaptive-rate, and multisite pacing. North American Society of Pacing and Electrophysiology/British Pacing and Electrophysiology Group. Pacing Clin Electrophysiol 2002; 25:260. 2. Sweeney MO, Prinzen FW. A new paradigm for physiologic ventricular pacing. J Am Coll Cardiol 2006; 47:282. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 15/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate 3. Sweeney MO, Bank AJ, Nsah E, et al. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007; 357:1000. 4. Sweeney MO, Ellenbogen KA, Casavant D, et al. Multicenter, prospective, randomized safety and efficacy study of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol 2005; 16:811. 5. Olshansky B, Day JD, Moore S, et al. Is dual-chamber programming inferior to single- chamber programming in an implantable cardioverter-defibrillator? Results of the INTRINSIC RV (Inhibition of Unnecessary RV Pacing With AVSH in ICDs) study. Circulation 2007; 115:9. 6. Ricci RP, Botto GL, B n zet JM, et al. Association between ventricular pacing and persistent atrial fibrillation in patients indicated to elective pacemaker replacement: Results of the Prefer for Elective Replacement MVP (PreFER MVP) randomized study. Heart Rhythm 2015; 12:2239.

https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 12/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate MODE SELECTION ALGORITHMS A number of guidelines and algorithms are available for determining the appropriate pacing mode for patients with sinus node disease and AV node disease [38]. The indications and contraindications for the various types of pacing modes are listed in the accompanying tables ( table 4) [38]. In this listing, chronotropically competent refers to the ability of a patient to achieve an appropriate heart rate for a given physiologic activity. Several algorithms are also available: General algorithms for all bradycardic indications ( algorithm 1 and figure 1) An algorithm for sick sinus syndrome ( algorithm 2) An algorithm for AV block ( algorithm 3) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Pacemakers (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 13/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate SUMMARY AND RECOMMENDATIONS Nomenclature For permanent cardiac pacing, the five position NBG code indicates the chamber(s) paced, the chamber(s) sensed, the response to sensing, presence or absence of rate modulation, and location or absence of multisite pacing ( table 2). (See 'Nomenclature' above.) Selection of pacing mode In selecting a pacing mode, the patient's overall physical condition, associated medical problems, exercise capacity, left ventricular (LV) function, and chronotropic response to exercise must be considered along with the underlying rhythm disturbance. Some commonly used pacing modes are shown in the table ( table 3). (See 'Pacing modes' above.) Most patients with a standard bradycardic indication for pacing can be managed with one of three common pacing modes (with or without rate responsive pacing): AAI(R), VVI(R), or DDD(R). At the time of implantation, one should consider how many leads will be necessary and which additional features, if any, will be of potential value. Choice of single- or dual-chamber pacemaker The most important choice in most patients with a bradycardic indication for pacing is whether to place a single- or dual- chamber pacemaker (see "Permanent cardiac pacing: Overview of devices and indications" and 'Pacing modes' above). The choice varies with the clinical setting: Atrial fibrillation In patients with chronic atrial fibrillation (AF) who require a pacemaker due to slow ventricular response, we recommend a single-chamber ventricular pacemaker (VVI or VVIR) (Grade 1B). (See 'VVI or VVIR pacing' above.) Sinus rhythm In patients in sinus rhythm with conditions that could be managed with either a single- or a dual-chamber pacemaker (eg, atrioventricular [AV] block, sinus node dysfunction [SND]), we suggest a dual-chamber pacemaker (Grade 2B). (See 'Physiologic pacing' above and 'Dual-chamber pacing' above.) Exception for advanced age or difficult two lead implantation A single- chamber pacemaker is a reasonable alternative in patients who are adults with advanced age or whose anatomy and physical condition make the implantation of two leads more difficult than usual. In such cases, the additional costs and risks of a dual-chamber physiologic pacemaker may outweigh the potential benefits of the reduced risk of AF and patient preference. VVI(R) pacing will be effective in all such patients. (See 'VVI or VVIR pacing' above.) https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 14/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Possible exception for SND with intact AV conduction An AAI(R) pacemaker is a reasonable alternative to VVI(R) pacing in the subset of patients with SND in whom AV conduction is intact and meets intra-implant testing criteria (see "Sinus node dysfunction: Treatment"). However, effective AAIR pacing is more commonly accomplished with a dual-chamber pacemaker with a ventricular pacing avoidance option. (See 'AAI or AAIR pacing' above and 'Modes to minimize ventricular pacing' above.) Additional features The following additional features are appropriate for selected patients: Rate responsiveness This feature can be programmed for patients who are active, but not chronotropically competent. (See 'Rate responsiveness' above.) Mode switching This feature can be programmed for patients with paroxysmal atrial arrhythmias. (See 'Mode switching' above.) Ventricular pacing avoidance Algorithms to avoid ventricular pacing are appropriate for most patients with PR prolongation or type II AV block. Some parameter to minimize ventricular pacing is available in most contemporary devices. (See 'Modes to minimize ventricular pacing' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bernstein AD, Daubert JC, Fletcher RD, et al. The revised NASPE/BPEG generic code for antibradycardia, adaptive-rate, and multisite pacing. North American Society of Pacing and Electrophysiology/British Pacing and Electrophysiology Group. Pacing Clin Electrophysiol 2002; 25:260. 2. Sweeney MO, Prinzen FW. A new paradigm for physiologic ventricular pacing. J Am Coll Cardiol 2006; 47:282. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 15/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate 3. Sweeney MO, Bank AJ, Nsah E, et al. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007; 357:1000. 4. Sweeney MO, Ellenbogen KA, Casavant D, et al. Multicenter, prospective, randomized safety and efficacy study of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol 2005; 16:811. 5. Olshansky B, Day JD, Moore S, et al. Is dual-chamber programming inferior to single- chamber programming in an implantable cardioverter-defibrillator? Results of the INTRINSIC RV (Inhibition of Unnecessary RV Pacing With AVSH in ICDs) study. Circulation 2007; 115:9. 6. Ricci RP, Botto GL, B n zet JM, et al. Association between ventricular pacing and persistent atrial fibrillation in patients indicated to elective pacemaker replacement: Results of the Prefer for Elective Replacement MVP (PreFER MVP) randomized study. Heart Rhythm 2015; 12:2239. 7. Stockburger M, Boveda S, Moreno J, et al. Long-term clinical effects of ventricular pacing reduction with a changeover mode to minimize ventricular pacing in a general pacemaker population. Eur Heart J 2015; 36:151. 8. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013; 368:1585. 9. Curtis AB, Worley SJ, Chung ES, et al. Improvement in Clinical Outcomes With Biventricular Versus Right Ventricular Pacing: The BLOCK HF Study. J Am Coll Cardiol 2016; 67:2148. 10. Hayes DL, Furman S. Stability of AV conduction in sick sinus node syndrome patients with implanted atrial pacemakers. Am Heart J 1984; 107:644. 11. Antonioli, G, Ansani, et al. Single-Lead VDD Pacing. In: New Perspectives in Cardiac Pacing, 3, Barold, S, Mugica, J (Eds), Futura Publishing, Mount Kisco 1993. 12. Rey JL, Tribouilloy C, Elghelbazouri F, Otmani A. Single-lead VDD pacing: long-term experience with four different systems. Am Heart J 1998; 135:1036. 13. Huang M, Krahn AD, Yee R, et al. Optimal pacing for symptomatic AV block: a comparison of VDD and DDD pacing. Pacing Clin Electrophysiol 2004; 27:19. 14. Wiegand UK, Bode F, Schneider R, et al. Development of sinus node disease in patients with AV block: implications for single lead VDD pacing. Heart 1999; 81:580. 15. Morsi A, Lau C, Nishimura S, Goldman BS. The development of sinoatrial dysfunction in pacemaker patients with isolated atrioventricular block. Pacing Clin Electrophysiol 1998; 21:1430. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 16/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate 16. Lamas GA, Ellenbogen KA. Evidence base for pacemaker mode selection: from physiology to randomized trials. Circulation 2004; 109:443. 17. Healey JS, Toff WD, Lamas GA, et al. Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data. Circulation 2006; 114:11. 18. Stewart WJ, Dicola VC, Harthorne JW, et al. Doppler ultrasound measurement of cardiac output in patients with physiologic pacemakers. Effects of left ventricular function and retrograde ventriculoatrial conduction. Am J Cardiol 1984; 54:308. 19. Rediker DE, Eagle KA, Homma S, et al. Clinical and hemodynamic comparison of VVI versus DDD pacing in patients with DDD pacemakers. Am J Cardiol 1988; 61:323. 20. Boon NA, Frew AJ, Johnston JA, Cobbe SM. A comparison of symptoms and intra-arterial ambulatory blood pressure during long term dual chamber atrioventricular synchronous (DDD) and ventricular demand (VVI) pacing. Br Heart J 1987; 58:34. 21. Takeuchi M, Nohtomi Y, Kuroiwa A. Effect of ventricular pacing on coronary blood flow in patients with normal coronary arteries. Pacing Clin Electrophysiol 1997; 20:2463. 22. Nielsen JC, Andersen HR, Thomsen PE, et al. Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single- chamber atrial or ventricular pacing. Circulation 1998; 97:987. 23. Ausubel K, Furman S. The pacemaker syndrome. Ann Intern Med 1985; 103:420. 24. Lamas GA, Orav EJ, Stambler BS, et al. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. Pacemaker Selection in the Elderly Investigators. N Engl J Med 1998; 338:1097. 25. Andersen HR, Thuesen L, Bagger JP, et al. Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet 1994; 344:1523. 26. Lamas GA, Lee KL, Sweeney MO, et al. Ventricular pacing or dual-chamber pacing for sinus- node dysfunction. N Engl J Med 2002; 346:1854. 27. Connolly SJ, Kerr CR, Gent M, et al. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med 2000; 342:1385. 28. Toff WD, Camm AJ, Skehan JD, United Kingdom Pacing and Cardiovascular Events Trial Investigators. Single-chamber versus dual-chamber pacing for high-grade atrioventricular block. N Engl J Med 2005; 353:145. 29. Kerr CR, Connolly SJ, Abdollah H, et al. Canadian Trial of Physiological Pacing: Effects of physiological pacing during long-term follow-up. Circulation 2004; 109:357. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 17/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate 30. Andersen HR, Nielsen JC, Thomsen PE, et al. Long-term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet 1997; 350:1210. 31. Hellkamp AS, Lee KL, Sweeney MO, et al. Treatment crossovers did not affect randomized treatment comparisons in the Mode Selection Trial (MOST). J Am Coll Cardiol 2006; 47:2260. 32. Skanes AC, Krahn AD, Yee R, et al. Progression to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing. CTOPP Investigators. J Am Coll Cardiol 2001; 38:167. 33. Tang AS, Roberts RS, Kerr C, et al. Relationship between pacemaker dependency and the effect of pacing mode on cardiovascular outcomes. Circulation 2001; 103:3081. 34. Ellenbogen KA, Stambler BS, Orav EJ, et al. Clinical characteristics of patients intolerant to VVIR pacing. Am J Cardiol 2000; 86:59. 35. Jahangir A, Shen WK, Neubauer SA, et al. Relation between mode of pacing and long-term survival in the very elderly. J Am Coll Cardiol 1999; 33:1208. 36. Link MS, Hellkamp AS, Estes NA 3rd, et al. High incidence of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based pacing in the Mode Selection Trial (MOST). J Am Coll Cardiol 2004; 43:2066. 37. Sulke N, Chambers J, Dritsas A, Sowton E. A randomized double-blind crossover comparison of four rate-responsive pacing modes. J Am Coll Cardiol 1991; 17:696. 38. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. Topic 950 Version 30.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 18/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate GRAPHICS Guidelines for choice of pacemaker generator in selected indications for pacing Neurally-mediated Type of Sinus node syncope or carotid AV block pacemaker dysfunction sinus hypersensitivity Single-chamber No suspected Not appropriate Not appropriate (unless atrial abnormality of AV AV block systematically conduction and not at increased risk for excluded) future AV block Maintenance of AV synchrony during pacing desired Rate response available if desired Single-chamber ventricular Maintenance of AV synchrony during pacing not necessary Chronic atrial fibrillation or other atrial tachyarrhythmia or maintenance of AV synchrony during pacing not necessary Chronic atrial fibrillation or other atrial tachyarrhythmia Rate response available if desired Rate response available if desired Rate response available if desired Dual-chamber AV synchrony during pacing desired AV synchrony during pacing desired Sinus mechanism present Rate response available if Suspected abnormality of AV conduction or Atrial pacing desired desired increased risk for future AV block Rate response available if desired Rate response available if desired Single-lead, Not appropriate Normal sinus node function Not appropriate atrial-sensing ventricular and no need for atrial pacing https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 19/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Desire to limit number of pacemaker leads AV: atrioventricular. Data from Gregoratos G, Cheitlin MD, Conill A, et al. Circulation 1998; 97:1325. Graphic 51504 Version 3.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 20/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Revised NBG code for pacing nomenclature I II III IV V Position Chamber(s) paced Chamber(s) sensed Response to sensing Rate modulation Multisite pacing Category O = None O = None O = None O = None O = None A = Atrium A = Atrium T = R = Rate A = Atrium Triggered modulation V = Ventricle V = Ventricle V = I = Inhibited Ventricle D = Dual (A+V) D = Dual (A+V) D = Dual (T+I) D = Dual (A+V) S = Single (A S = Single (A Manufacturer's or V) or V) designation only: Note: Positions I through III are used exclusively for antibradyarrythmia function. Adapted from Bernstein AD, Daubert JC, Fletcher RD, et al. Pacing Clin Electrophysiol 2002; 25:260. Graphic 68327 Version 3.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 21/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Types of cardiac pacemakers and NBG codes Code Meaning VOO Asynchronous ventricular pacemaker; no adaptive rate control or antitachyarrhythmia functions VVI Ventricular "demand" pacemaker with electrogram-waveform telemetry; no adaptive rate control or antitachyarrhythmia functions DVI Multiprogrammable atrioventricular-sequential pacemaker; no adaptive rate control DDD Multiprogrammable "physiologic" dual-chamber pacemaker; no adaptive rate control or antitachyarrhythmia functions DDI Multiprogrammable DDI pacemaker (with dual-chamber pacing and sensing but without atrial-synchronous ventricular pacing); no adaptive rate control or antitachycardia functions VVIR Adaptive-rate VVI pacemaker with escape interval controlled adaptively by one or more unspecified variables DDDR Programmable DDD pacemaker with escape interval controlled adaptively by one or more unspecified variables Graphic 79459 Version 1.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 22/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Rhythms seen with a normal DDD pacemaker The rhythms that occur in a patient with a DDD pacemaker depend upon the underlying heart rate and atrioventricular (AV) nodal conduction. The pacemaker spike is represented in blue. First panel: The pacemaker may be completely inhibited when the sinus rate is greater than the lower rate limit of the pacemaker. Second panel: P- wave synchronous pacing occurs when there is intrinsic AV nodal delay which is greater than the AV delay in the pacemaker. Third panel: Atrial pacing occurs when the sinus rate falls below the lower limit of the pacemaker and AV nodal conduction is intact. Fourth panel: If there is sinus bradycardia and AV nodal conduction delay, the pacemaker paces both atrium and ventricle, known as AV sequential pacing. Graphic 52858 Version 3.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 23/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Pacing modes indications and contraindications Generally agreed Controversial Mode Contraindications upon indications indications VVI/VVIR Fixed atrial arrhythmias (atrial Symptomatic bradycardia in the Patients with known pacemaker syndrome or fibrillation or flutter) patient with associated hemodynamic with symptomatic bradycardia in the CC patient (VVI) or CI terminal illness or other medical conditions from which deterioration with ventricular pacing at the time of implant patient (VVIR) recovery is not CI patient who will benefit from rate anticipated and pacing is life-sustaining only response Patients with hemodynamic need for dual-chamber pacing AAI/AAIR Symptomatic bradycardia as a result Sinus node dysfunction with associated AV block of sinus node dysfunction; used when AV conduction can be proven normal in the otherwise CC patient (AAI) or CI either demonstrated spontaneously or during pre-implant testing When adequate atrial sensing cannot be patient (AAIR) attained DVI* VDD /VDDR Congenital AV block Sinus node dysfunction AV block when sinus node function can be AV block when accompanied by sinus proven normal in the CC patient (VDD) or CI node dysfunction When adequate atrial patient (VDDR) sensing cannot be attained AV block when accompanied by PSVT DDI/DDIR Need for dual-chamber Sinus node dysfunction CI patient with a pacing in the presence of significant PSVT in in the absence of AV block in the presence demonstrated need or improvement with rate the CC patient (DDI) or CI patient (DDIR) of significant PSVT in the CC patient (DDI) or responsiveness CI patient (DDIR) https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 24/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate DDD/DDDR AV block and sinus For any rhythm Presence of chronic node dysfunction in the CC patient (DDD) or disturbance when atrial sensing and atrial fibrillation, atrial flutter, giant inexcitable CI patient (DDDR) capture is possible for atrium or other the potential purpose of minimizing future frequent PSVTs Need for AV synchrony to maximize cardiac output in CC active When adequate atrial sensing cannot be atrial fibrillation and improved morbidity patients (DDD) attained and survival Previous pacemaker syndrome CC: chronotropically competent (ie, the ability to achieve an appropriate heart rate for a given physiologic activity); CI: chronotropically incompetent (ie, the inability to achieve an appropriate heart rate for a given physiologic activity); AV: atrioventricular; PSVT: paroxysmal supraventricular tachycardia. DVI as a stand-alone pacing mode (ie, a pacemaker capable of DVI as the only dual-chamber mode of operation) is obsolete. All primary uses of this mode should be considered individually. VDD as a stand-alone pacing mode (ie, a pacemaker capable of VDD as the only dual-chamber mode of operation) is currently used primarily as a single-lead VDD system. If a dual-lead system is implanted, then the capability of DDD pacing is desirable. In current single-lead VDDR pacemakers, P-wave tracking occurs as long as the sinus rate is appropriate. However, in the presence of sinus bradycardia or chronotropic incompetence, the pacemaker operates in the VVIR mode. DDIR has been supplanted by DDD or DDDR pacemakers with the capability of mode-switching (ie, the pacemaker automatically reprograms to a mode incapable of tracking the atrial rhythm in the presence of an atrial rhythm that the pacemaker classifies as a pathological rhythm). When the pacemaker recognizes the atrial rhythm as being physiological, the pacemaker reprograms to the previously programmed mode. Graphic 120148 Version 1.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 25/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Pacemaker algorithm Algorithm for the use of the different types of pacemakers depending upon the need for atrioventricular (AV) sequential pacing, the presence of sinoatrial (SA) node chronotropic competence, the AV conduction rate, and the need for rate-responsiveness. Refer to UpToDate content on modes of cardiac pacing: nomenclature and selection. Courtesy of MD McGoon, MD. Graphic 64626 Version 3.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 26/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Simplified pacemaker algorithm for use with rate adaptive pacemakers Simplified algorithm for the choice of pacemaker mode assuming that a rate-responsive pacemaker (DDDR or VVIR) will be used. Courtesy of MD McGoon, MD. Graphic 76446 Version 2.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 27/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Selection of pacemaker systems for patients with sinus node dysfunction Decisions are illustrated by diamonds. Shaded boxes indicate type of pacemaker. AV: atrioventricular. Reproduced with permission from: Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008; 51(21):e1-e62. Illustration used with permission of Elsevier Inc. All rights reserved. Copyright 2008 Elsevier Inc. Graphic 77929 Version 5.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 28/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Selection of pacemaker systems for patients with atrioventricular block Decisions are illustrated by diamonds. Shaded boxes indicate type of pacemaker. AV: atrioventricular. Reproduced with permission from: Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008; 51(21):e1-e62. Illustration used with permission of Elsevier Inc. All rights reserved. Copyright 2008 Elsevier Inc. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 29/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Graphic 71370 Version 4.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 30/31 7/6/23, 3:09 PM Modes of cardiac pacing: Nomenclature and selection - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 31/31

7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management : Peter J Zimetbaum, MD, John V Wylie, MD, FACC : Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 26, 2022. INTRODUCTION Nonsustained ventricular tachycardia (NSVT) is a common but poorly understood arrhythmia. It is usually asymptomatic and most often diagnosed during cardiac monitoring (eg, continuous ambulatory electrocardiography or inpatient telemetry) or on an exercise test performed for other reasons. The presence of NSVT has long been recognized as a potential marker for the development of sustained ventricular arrhythmias and sudden death. However, while NSVT predicts overall mortality, it doesn t specifically predict sudden cardiac death (SCD). Unfortunately, our understanding of which patients with NSVT are at greatest risk for lethal arrhythmias or how the NSVT relates to the lethal arrhythmias is still quite rudimentary. One clearly established premise is that NSVT in the presence of structural heart disease carries a more serious prognosis than NSVT in the absence of a cardiac abnormality. Since NSVT doesn t specifically predict SCD, the nature of the underlying structural heart disease is the primary determinant of mortality. (See "Nonsustained VT in the absence of apparent structural heart disease".) There are two general goals in the management of NSVT: Identification of patients at risk for malignant, sustained arrhythmias and SCD Treatment to suppress symptoms caused by NSVT, when present and clinically significant https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 1/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate This topic will review the diagnosis and management of NSVT. Detailed discussions of risk stratification for arrhythmic death after a myocardial infarction, and the roles of implantable cardioverter-defibrillators and antiarrhythmic drugs in such patients, are presented separately. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction" and "Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment".) DEFINITION OF NSVT A variety of definitions of NSVT have been published, but the most commonly used definition is [1]: Three or more consecutive ventricular beats Rate of >100 beats per minute Duration of less than 30 seconds The variable published definitions of NSVT have included: Rates ranging from as low as 100 beats per minute to as high as 140 beats per minute Between three and five consecutive ventricular complexes Durations as short as 15 seconds to as high as one minute Beat limits as low as 15 beats or as high as 99 beats, beyond which the arrhythmia is considered sustained The approach to distinguishing VT from other causes of wide QRS complex tachycardias (ie, supraventricular tachycardia [SVT] with aberrant conduction, SVT with preexcitation, pacemaker- associated tachycardia, or artifact) is discussed separately. (See 'Differential diagnosis' below and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Differential diagnosis'.) CLINICAL MANIFESTATIONS The history, physical examination, and 12-lead electrocardiogram (ECG) can all provide information helping to confirm the diagnosis of NSVT. History and associated symptoms Patients with NSVT are usually asymptomatic, although some patients may notice symptoms associated with episodes of NSVT. Most patients with NSVT will have a history of underlying structural heart disease (eg, coronary heart disease, heart failure, hypertrophic cardiomyopathy, congenital heart disease, etc), although NSVT can also be https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 2/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate seen in patients without known structural heart disease. (See "Nonsustained VT in the absence of apparent structural heart disease".) The type and intensity of symptoms, if present, will vary depending upon the rate and duration of the NSVT along with the presence or absence of significant comorbid conditions. Patients with NSVT who notice symptoms typically present with one or more of the following symptoms: Palpitations Chest pain Shortness of breath Syncope or presyncope Most commonly, symptomatic patients will report palpitations that may or may not be associated with chest pain and/or shortness of breath. If the duration of the episode approaches 20 to 30 seconds with an associated rate of NSVT that is rapid enough to result in hemodynamic compromise, patients may experience presyncope or even syncope. Physical examination Few physical examination findings in patients with NSVT are unique and specific. By definition, patients will have a pulse exceeding 100 beats per minute during the episode. In addition, if the physical examination coincides with an episode of NSVT, this can reveal evidence of atrioventricular (AV) dissociation, which is present in up to 75 percent of patients with VT, although it is not always easy to detect [2-4]. During AV dissociation, the normal coordination of atrial and ventricular contraction is lost, which may produce characteristic physical examination findings including (see "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'AV dissociation'): Marked fluctuations in the blood pressure because of the variability in the degree of left atrial contribution to left ventricular filling, stroke volume, and cardiac output. Variability in the occurrence and intensity of heart sounds (especially S1) ("cacophony of heart sounds"), which is heard more frequently when the rate of the tachycardia is slower. Cannon "A" waves Cannon A waves are intermittent and irregular jugular venous pulsations of greater amplitude than normal waves. They reflect simultaneous atrial and ventricular activation, resulting in contraction of the right atrium against a closed tricuspid valve. Prominent A waves can also be seen during some SVTs. Such prominent waves result from simultaneous atrial and ventricular contraction occurring with every beat. (See "Examination of the jugular venous pulse".) Electrocardiogram All patients with suspected NSVT should have a 12-lead electrocardiogram, although NSVT is frequently identified on continuous telemetric monitoring, https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 3/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate in which case only one or two leads may be available for review. As with the interpretation of any ECG, the standard initial approach to diagnosis of NSVT includes an assessment of rate, regularity, axis, QRS duration, and QRS morphology. NSVT typically generates a wide QRS complex, usually with a QRS width >0.12 seconds. A full discussion of the ECG features of VT is presented separately. (See "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Electrocardiogram' and "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'Evaluation of the electrocardiogram'.) Diagnostic evaluation Once NSVT has been identified, reversible causes of arrhythmia should be sought, including electrolyte imbalances, myocardial ischemia, hypoxia, adverse drug effects, anemia, hypotension, and heart failure. For patients who have only a single asymptomatic episode of NSVT, often no further investigation is required. However, for patients with multiple episodes or for those with symptoms felt to be related to NSVT, a thorough diagnostic evaluation to exclude structural heart disease is warranted, including cardiac imaging and ambulatory ECG monitoring for most patients and invasive electrophysiology studies (EPS) only on rare occasions. For patients with recurrent episodes or those who are highly symptomatic, even young, otherwise healthy patients need a thorough cardiac imaging evaluation to exclude entities such as undiagnosed dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy. Typically, the evaluation for structural heart disease includes an imaging study of the heart, most commonly echocardiography, although cardiac magnetic resonance (CMR) imaging is also reasonable (if locally available) as it provides the most detailed structural information. Continuous ambulatory ECG monitoring is indicated in many patients with NSVT with vague symptoms to establish a correlation between symptoms and arrhythmia and to quantify the frequency of the arrhythmia. Ambulatory monitoring is also useful to exclude the presence of sustained VT. Exercise treadmill testing is indicated in patients with exercise-related symptoms or NSVT and in patients with suspected coronary ischemia. In patients with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), a signal-averaged ECG can be useful. Invasive EPS are rarely required in the initial evaluation of NSVT. In patients with syncope, near-syncope, or sustained palpitations, EPS should be considered to evaluate for the presence of sustained VT. In addition, in patients with ischemic cardiomyopathy, ejection https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 4/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate fraction 35 to 40 percent, and NSVT, invasive EPS may be used to risk stratify patients for implantable cardioverter-defibrillator implantation [5,6]. An in-depth discussion of the diagnostic evaluation of patients with VT is presented separately. (See "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Additional diagnostic evaluation'.) DIFFERENTIAL DIAGNOSIS The differential diagnosis for a wide QRS complex tachycardia (WCT) includes NSVT, supraventricular tachycardia with aberrant conduction (either preexistent or rate-related), supraventricular tachycardia with preexcitation, supraventricular tachycardia in a pacemaker- dependent patient, and electrocardiogram (ECG) artifact. Differentiating VT from other causes of WCT may be difficult, particularly if a high-quality 12-lead ECG is not available during the time of the arrhythmia. In general, however, a WCT, particularly when poorly tolerated, should be considered to be VT until proven otherwise. The approach to the differential diagnosis of VT from other causes of WCT is discussed separately. (See "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Differential diagnosis'.) TREATMENT Symptomatic patients Patients with symptomatic NSVT should usually be treated with beta blockers as the initial therapy. Many patients with NSVT will have coexisting cardiac conditions in which beta blockers are also indicated (eg, coronary heart disease, heart failure), in which case the patient may derive multiple benefits from the use of beta blockers. For patients with NSVT who remain symptomatic in spite of beta blockers, or who are unable to tolerate beta blockers due to side effects, nondihydropyridine calcium channel blockers (ie, verapamil and diltiazem) can be added to the medical regimen, although these agents should only be used in patients with structurally normal hearts and should not be used in patients with uncontrolled heart failure. Antiarrhythmic medications are generally reserved for patients with severely symptomatic NSVT despite therapy with beta blockers and nondihydropyridine calcium channel blockers who are not candidates for catheter ablation of the VT. NSVT is most often asymptomatic, but some patients experience palpitations, chest pain, shortness of breath, presyncope, or syncope. Because many of the symptoms that may be https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 5/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate attributed to NSVT are vague and nonspecific, it is important to try to correlate symptoms to episodes of NSVT before initiating therapy specifically to treat NSVT. Beta blockers For the initial treatment of patients with symptomatic NSVT, we suggest beta blockers. This preference is based on significant indirect evidence of the efficacy of beta blockers for reducing ventricular ectopy and tachyarrhythmias in other cardiac conditions, as well as coadministration of beta blockers for other cardiac conditions and the fact that beta blockers are generally safe and well tolerated [5]. Metoprolol (usual effective dose 50 to 200 mg daily) and carvedilol (usual effective dose 12.5 to 50 mg daily) are the most commonly prescribed beta blockers for the suppression of NSVT. Nondihydropyridine calcium channel blockers For patients with NSVT who remain symptomatic in spite of beta blockers, or who are unable to tolerate beta blockers due to side effects, we suggest adding a nondihydropyridine calcium channel blockers (ie, verapamil [usual effective dose 360 to 480 mg daily] or diltiazem [usual effective dose 240 to 360 mg daily]) rather than an antiarrhythmic medication. For most patients, nondihydropyridine calcium channel blockers are better tolerated and associated with less toxicity than antiarrhythmic drugs. However, nondihydropyridine calcium channel blockers should not be used in patients with structural heart disease or uncontrolled heart failure. (See "Calcium channel blockers in the treatment of cardiac arrhythmias", section on 'Ventricular arrhythmia'.) Antiarrhythmic drugs For some patients who have frequent, highly symptomatic NSVT not adequately suppressed by beta blockers or calcium channel blockers, the addition of antiarrhythmic medications ( table 1) may be helpful. We suggest amiodarone as the initial choice, rather than other antiarrhythmic drugs, based on its efficacy. However, due to potential toxicities of antiarrhythmic drugs, we use them sparingly and only in the most symptomatic patients who have failed other medical therapy and who are not candidates, decline, or fail ablation therapy. Amiodarone may be given at a dose of 200 mg three times daily for two weeks, then 200 mg two times daily for two weeks, and then 200 mg daily. The dose can be further reduced to 100 mg daily if there is concern over toxicity, and follow-up monitoring should be performed. Mexiletine is usually given as 150 to 200 mg every eight hours. These two drugs require careful monitoring, particularly in patients with structural heart disease. In selected cases, other agents such as sotalol or procainamide can be used for suppression of NSVT, but these medications are rarely used and must be used with caution. Amiodarone Amiodarone is the most effective antiarrhythmic agent for suppressing VT, an effect that has clearly been demonstrated in multiple trials of amiodarone in post-myocardial https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 6/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate infarction (MI) and congestive heart failure patients in whom baseline and follow-up 24-hour ambulatory ECGs were performed [7-9]. In the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) pilot study, which compared amiodarone with placebo in patients with frequent or repetitive asymptomatic ventricular premature beats (VPBs), patients receiving amiodarone had significantly fewer VPBs and episodes of NSVT [7]. In the CHF-STAT trial, which compared amiodarone with placebo in patients with heart failure, left ventricular ejection fraction (LVEF) of 40 percent or less, and frequent ventricular premature beats (more than 10 per hour), significantly fewer patients on amiodarone had ventricular tachycardia on Holter monitor (33 versus 76 percent) after two weeks of therapy [10]. Similar results have been seen in patients treated with both amiodarone and a beta blocker [11,12]. In an analysis of eight trials that included over 5000 patients with a prior MI and frequent VPBs (median frequency 18 per hour), amiodarone therapy was associated with a significant 35 percent reduction in arrhythmic/sudden death, and a nonsignificant 8 percent reduction in total mortality [12]. While amiodarone has never been shown to reduce overall mortality, its use is not associated with an increase in mortality due to proarrhythmia (as is the case with class IC antiarrhythmic drugs). However, its well-described, potentially toxic side effects need to be considered before prescribing, and routine monitoring of liver, thyroid, and lung function should be performed in patients on amiodarone. (See "Amiodarone: Clinical uses" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Class I agents In selected cases, Class IA drugs (eg, procainamide) and class IB drugs (eg, mexiletine) can be used for suppression of NSVT, but these medications must be used with caution. Class IC drugs are generally not used in patients with structural heart disease because of safety concerns. (See "Nonsustained VT in the absence of apparent structural heart disease".) The Cardiac Arrhythmia Suppression Trial (CAST) evaluated the efficacy of flecainide, encainide, and moricizine in suppressing ventricular ectopy in almost 1500 post-MI patients, many of whom had depressed LV function [13,14]. Additionally, only 20 percent of patients had NSVT and only 10 percent had more than one run in 24 hours. The findings were dramatic, showing an increase in arrhythmic sudden death and total cardiovascular mortality in the treated patients even though the original ventricular ectopy was suppressed ( figure 1). Thus, class IC agents are not used in the treatment of NSVT in coronary heart disease. https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 7/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate Radiofrequency catheter ablation In patients who have very frequent, symptomatic monomorphic NSVT not controlled by medications or who are unable or unwilling to take medications, catheter ablation can be effective for reducing or eliminating NSVT and associated symptoms [1]. It would be appropriate to consider catheter ablation as a primary alternative to antiarrhythmic drugs. This strategy is most commonly used in patients with idiopathic, triggered arrhythmias, which often originate in the outflow tracts, septum, or papillary muscles. In such patients, catheter ablation can be a highly successful procedure to eliminate the symptoms of arrhythmia [15]. (See "Ventricular tachycardia in the absence of apparent structural heart disease".) Implantable cardioverter-defibrillators Implantable cardioverter-defibrillators (ICDs) are not indicated for the treatment of NSVT as NSVT is self-limited and self-terminating. However, some patients with NSVT who are found to have a cardiomyopathy may be a candidate for ICD placement for primary prevention of sudden cardiac death related to sustained ventricular tachyarrhythmias. The use of an ICD for primary prevention is discussed in detail separately. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Asymptomatic patients Patients with NSVT and no identified symptoms do not require any specific therapy directed toward the NSVT. However, patients with NSVT and associated underlying cardiac comorbidities (eg, coronary heart disease, heart failure) should be treated with optimal medical therapy as indicated for the relevant associated condition. (See "Chronic coronary syndrome: Overview of care".) The Multicenter Unsustained Tachycardia Trial (MUSTT trial), which was not primarily designed as a randomized ICD clinical trial but rather to study the management of high-risk patients using the results of electrophysiology study (EPS), enrolled 704 patients with a prior MI (less than one month to more than three years previously), asymptomatic NSVT, an LVEF 40 percent, and inducible sustained ventricular tachycardia [6,16]. Patients were randomly assigned to no therapy or EP-guided antiarrhythmic therapy, which included either an antiarrhythmic agent (class IA with or without mexiletine, propafenone, sotalol, or amiodarone) or an ICD if at least one antiarrhythmic agent was ineffective; the primary end point was arrhythmic death or resuscitated cardiac arrest, with a secondary endpoint of total mortality. The reduction in the primary and secondary end points in the electrophysiologically guided group was largely attributable to ICD therapy; at five years the primary end point occurred in 9 percent of those receiving an ICD, compared with 37 percent of those receiving an antiarrhythmic drug, and the secondary end point occurred in 24 and 55 percent, respectively. There was no difference in outcome between patients receiving no therapy and those treated with an antiarrhythmic drug ( figure 2) [17]. https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 8/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate Patients with asymptomatic NSVT may also be considered for an ICD in the presence of structural heart disease with LVEF <40 percent. Many patients will meet other criteria for primary prevention with an ICD. For post-MI patients with moderate LV dysfunction (ie, LVEF 35 to 40 percent), who do not otherwise meet current criteria for ICD implantation, NSVT remains an indication for EPS and possible ICD implantation. A full discussion of the role of ICDs in primary and secondary prevention of sudden cardiac death is presented separately. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ventricular arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Ventricular tachycardia (The Basics)") SUMMARY AND RECOMMENDATIONS Definition The most common definition is three or more consecutive ventricular beats, a heart rate of >100 beats per minute, and a duration of arrhythmia of less than 30 seconds. https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 9/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate (See 'Definition of NSVT' above.) Symptoms Patients with nonsustained ventricular tachycardia (NSVT) are usually asymptomatic, although some patients may notice symptoms associated with episodes of NSVT. Symptoms may include palpitations, chest pain, shortness of breath, syncope, or presyncope. Symptoms may vary depending upon the rate and duration of the NSVT along with the presence or absence of significant comorbid conditions. (See 'History and associated symptoms' above.) Physical examination By definition, the pulse rate is >100 beats per minute. Few physical examination findings are unique and specific for NSVT. If the physical examination coincides with an episode of NSVT, this can reveal evidence of atrioventricular (AV) dissociation, including marked fluctuations in blood pressure, variability in the occurrence and intensity of heart sounds (especially S1), and cannon A waves. (See 'Physical examination' above.) Evaluation All patients with suspected NSVT should have a 12-lead electrocardiogram (ECG), although NSVT is frequently identified on continuous telemetry monitoring, in which case only one or two leads may be available for review. (See 'Electrocardiogram' above.) Reversible causes Once identified, reversible causes of NSVT should be sought, including electrolyte imbalances, myocardial ischemia, hypoxia, adverse drug effects, anemia, hypotension, and heart failure. Single asymptomatic episode Often, for these patients, no further investigation is required. Multiple or symptomatic episodes For patients with multiple episodes or with symptoms felt to be related to NSVT, a thorough diagnostic evaluation to exclude structural heart disease is warranted, including cardiac imaging and ambulatory ECG monitoring for most patients and invasive electrophysiology studies (EPS) only on rare occasions. (See 'Diagnostic evaluation' above.) Treatment Asymptomatic patients In general, asymptomatic patients do not require any specific therapy directed toward the NSVT. However, some asymptomatic patients with NSVT who are found to have infarct-related cardiomyopathy with significantly reduced left ventricular systolic function may be https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 10/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate evaluated for implantable cardioverter-defibrillator placement for primary prevention of sudden cardiac death related to sustained ventricular tachyarrhythmias. (See 'Asymptomatic patients' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Symptomatic patients Initial therapy For the initial treatment of patients with symptomatic NSVT, we suggest beta blockers rather than calcium channel blockers or antiarrhythmic medications (Grade 2C). (See 'Beta blockers' above.) For patients with NSVT who remain symptomatic in spite of beta blockers, or who are unable to tolerate beta blockers due to side effects, we suggest adding a nondihydropyridine calcium channel blocker (ie, verapamil or diltiazem) rather than an antiarrhythmic medication (Grade 2C). (See 'Nondihydropyridine calcium channel blockers' above.) Alternative therapy For some patients who have frequent, highly symptomatic NSVT not adequately suppressed by beta blockers or calcium channel blockers, the addition of antiarrhythmic medications ( table 1) may be helpful. We suggest amiodarone as the initial choice, rather than other antiarrhythmic drugs, based on its efficacy (Grade 2C). (See 'Antiarrhythmic drugs' above.) In patients with very frequent symptomatic monomorphic NSVT not controlled by medications or who are unable or unwilling to take medications, catheter ablation can be effective for reducing or eliminating NSVT and associated symptoms. (See 'Radiofrequency catheter ablation' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges the late Mark E. Josephson, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 11/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 2. Gupta AK, Thakur RK. Wide QRS complex tachycardias. Med Clin North Am 2001; 85:245. 3. Tchou P, Young P, Mahmud R, et al. Useful clinical criteria for the diagnosis of ventricular tachycardia. Am J Med 1988; 84:53. 4. Wellens HJ, B r FW, Lie KI. The value of the electrocardiogram in the differential diagnosis of a tachycardia with a widened QRS complex. Am J Med 1978; 64:27. 5. Pedersen CT, Kay GN, Kalman J, et al. EHRA/HRS/APHRS expert consensus on ventricular arrhythmias. Europace 2014; 16:1257. 6. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999; 341:1882. 7. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 1997; 349:675. 8. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta- blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006; 295:165. 9. Julian DG, Camm AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 1997; 349:667. 10. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995; 333:77. 11. Boutitie F, Boissel JP, Connolly SJ, et al. Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT Investigators. Circulation 1999; 99:2268. 12. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators. Lancet 1997; 350:1417. 13. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 12/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate 1991; 324:781. 14. Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992; 327:227. 15. Coggins DL, Lee RJ, Sweeney J, et al. Radiofrequency catheter ablation as a cure for idiopathic tachycardia of both left and right ventricular origin. J Am Coll Cardiol 1994; 23:1333. 16. Buxton AE, Fisher JD, Josephson ME, et al. Prevention of sudden death in patients with coronary artery disease: the Multicenter Unsustained Tachycardia Trial (MUSTT). Prog Cardiovasc Dis 1993; 36:215. 17. Wyse DG, Talajic M, Hafley GE, et al. Antiarrhythmic drug therapy in the Multicenter UnSustained Tachycardia Trial (MUSTT): drug testing and as-treated analysis. J Am Coll Cardiol 2001; 38:344. Topic 917 Version 33.0 https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 13/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 14/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 15/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 16/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate ICD reduces sudden death in MUSTT The MUSTT trial enrolled 704 patients with coronary artery disease, nonsustained ventricular tachycardia (VT), and a left ventricular ejection fraction 40 percent who had sustained VT induced during electrophysiologic (EP) study. Kaplan-Meier estimates show that the incidence of cardiac arrest or death from arrhythmia is significantly lower in those receiving an implantable cardioverter-defibrillator (ICD) compared with those receiving no therapy or those with EP-guided (EPG) antiarrhythmic drug (AAD) therapy. Data from: Buxton AE, Lee KL, Fisher JD, et al. N Engl J Med 1999; 341:1882. Graphic 68247 Version 4.0 https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 17/18 7/6/23, 3:09 PM Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management - UpToDate Contributor Disclosures Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. John V Wylie, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/nonsustained-ventricular-tachycardia-clinical-manifestations-evaluation-and-management/print 18/18

7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Permanent cardiac pacing: Overview of devices and indications : Mark S Link, MD : N A Mark Estes, III, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 27, 2023. INTRODUCTION Cardiac pacemakers are effective treatments for a variety of bradyarrhythmias. By providing an appropriate heart rate and heart rate response, cardiac pacing can reestablish effective circulation and normalize hemodynamics that are compromised by a slow heart rate. This topic will present a broad review of the role of cardiac pacing in a variety of settings. The management of the specific disorders is discussed separately as is a description of the different types of pacemakers and pacing modes. (See "Sinus node dysfunction: Treatment" and "Third- degree (complete) atrioventricular block" and "Second-degree atrioventricular block: Mobitz type II" and "Modes of cardiac pacing: Nomenclature and selection".) GENERAL CONSIDERATIONS Despite the myriad of clinical situations in which permanent pacing is considered, most management decisions regarding permanent pacemaker implantation are driven by the following clinical factors: The association of symptoms with a bradyarrhythmia The location of the conduction abnormality The absence of a reversible cause https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 1/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Symptoms Patients are often evaluated for permanent cardiac pacemaker placement because of symptoms that may be due to bradyarrhythmias (eg, dizziness, lightheadedness, syncope, fatigue, and poor exercise tolerance). These patients will often have evidence of persistent or intermittent sinus node dysfunction or atrioventricular (AV) conduction abnormalities. Establishing a direct correlation between symptoms and bradyarrhythmias, typically by taking a careful history and documenting the cardiac rhythm with either an electrocardiogram or ambulatory monitoring (external or insertable cardiac monitor [also sometimes referred to as an implantable cardiac monitor or an implantable loop recorder]), is essential for choosing the optimal candidates for pacemaker insertion [1,2]. A direct correlation between symptoms and bradyarrhythmias will increase the likelihood of pacemaker therapy resulting in clinical improvement. Conversely, failure to document such a correlation, or the presence of an alternative explanation for symptoms, decreases the likelihood of benefit from pacemaker insertion. Location of conduction abnormality The location of an AV conduction abnormality (ie, within the AV node or below the AV node in the His-Purkinje system) is an important determinant of both the probability and the likely pace of progression of conduction system disease ( figure 1). (See "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)" and "Second-degree atrioventricular block: Mobitz type II".) Disease within the AV node is suggested by the following: First-degree AV block with significant PR prolongation (see "First-degree atrioventricular block") Second-degree AV block, Mobitz type I (Wenckebach) (see "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)") Normal QRS complex Disease below the AV node, in the His-Purkinje system, is suggested by: Normal or minimally prolonged PR interval Second-degree AV block, Mobitz type II (see "Second-degree atrioventricular block: Mobitz type II") Third-degree (complete) AV block (see "Third-degree (complete) atrioventricular block") A wide QRS complex (bundle branch block and/or fascicular block) Disease in the His-Purkinje system is generally considered to be more concerning because it can progress quickly and lead to complete heart block. As a result, permanent pacemaker placement https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 2/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate is likely to be recommended, as it is more likely to provide significant clinical benefit in such patients. Reversible causes In addition to intrinsic conduction system disease, there are a number of extrinsic causes of bradyarrhythmias which are reversible. While patients who have a reversible bradyarrhythmia may require temporary pacemaker support, in most circumstances permanent cardiac pacing is not indicated or required. Some of the more common reversible causes of bradyarrhythmia include: Medications (eg, beta blockers, nondihydropyridine calcium channel blockers, antiarrhythmic medications [eg, sotalol, amiodarone]). (See "Etiology of atrioventricular block", section on 'Medications'.) Toxic, metabolic, and electrolyte disturbances (eg, hyperkalemia, digoxin toxicity). Acute myocardial ischemia or infarction. (See 'Post-myocardial infarction' below and "Conduction abnormalities after myocardial infarction", section on 'Management of patients with AV block'.) Cardiac trauma (eg, postoperative, blunt chest trauma, indwelling pulmonary artery catheters). Lyme disease. Cardiac surgery, especially valve disorder surgery. Transcatheter aortic valve implantation. Reversible causes of bradyarrhythmias and the management of reversible causes with temporary cardiac pacing are discussed in detail separately. (See "Temporary cardiac pacing", section on 'Reversible conditions'.) Concurrent ICD Some patients with an indication for a permanent pacemaker require an upgrade to an implantable cardioverter-defibrillator (ICD) or may require cardiac resynchronization therapy. ICDs (with the exception of the subcutaneous ICD) have antitachycardia and antibradycardia pacing therapeutic capabilities. In patients who have a permanent pacemaker and require an ICD or cardiac resynchronization therapy, the pacemaker should be upgraded to the appropriate device so that all functions can be served by one pulse generator. (See "Subcutaneous implantable cardioverter defibrillators".) TYPES OF PERMANENT PACEMAKER SYSTEMS https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 3/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Cardiac pacemakers generally consist of two components: a pulse generator ( picture 1), which provides the electrical impulse for myocardial stimulation; and one or more electrodes (commonly referred to as leads), which deliver the electrical impulse from the pulse generator to the myocardium. A "leadless" pacemaker is now also available ( picture 2). Transvenous leads have potential long-term complications (eg, venous thrombosis, infection, lead malfunction, etc). Leadless cardiac pacing systems offer the promise of long-term pacing capability without lead- associated complications. Pulse generators Pulse generators are the "battery" component of the pacemaker ( picture 1), generating the electrical impulse which is transmitted to the myocardium, resulting in the heart beat. Pulse generators are currently implanted most commonly in the infraclavicular region of the anterior chest wall. The majority are placed in a pre-pectoral position, but in some cases a sub-pectoral position is advantageous. The pulse generator transmits the electrical impulse to the myocardium via transvenous leads. Epicardial systems are still available and may be necessary as a result of anatomical limitations to placing a transvenous lead(s). But these epicardial leads typically do not last as long. For the leadless systems, the pulse generator and the electrode are one self-contained unit, which is positioned via the femoral vein into the right ventricle (RV). (See 'Leadless systems' below.) Transvenous systems The vast majority of contemporary cardiac pacing systems utilize transvenous electrodes (leads) for transmission of the pacing impulses from the pulse generator to the myocardium. Transvenous leads, however, are associated with a nontrivial rate of long- term complications, including: Infection Venous thrombosis and resultant subclavian vein occlusion Lead malfunction Tricuspid valve injury (resulting in tricuspid regurgitation) The approach to the management of long-term transvenous lead complications is discussed separately. (See "Cardiac implantable electronic devices: Periprocedural complications" and "Cardiac implantable electronic devices: Long-term complications" and "Cardiac implantable electronic device lead removal".) His bundle pacing His bundle pacing has been developed to prevent the harmful effects of RV pacing. In this modality, the RV lead is actively fixed in the area of the His bundle with subsequent ventricular activation via the His-Purkinje system. Theoretically, this will reduce the https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 4/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate odds that dyssynchrony will occur. His bundle pacing may be beneficial in those with an anticipated high percent of RV pacing and possibly even those who have an indication for cardiac resynchronization therapy (CRT) such as a left bundle branch block. Clinical trials are ongoing [3,4]. While clinical trials are ongoing, registry data on His bundle pacing indicate a high rate of intervention for lead dislodgement. High capture thresholds result in more rapid battery depletion of the pacemaker pulse generator. This form of conduction system pacing is less commonly used than pacing in the region of the left bundle, as described below. (See 'Left bundle pacing' below.) Left bundle pacing Left bundle pacing has emerged as a competitor to His bundle pacing. While His bundle pacing typically occurs with the lead placed at the junction of the AV node and His bundle, left bundle pacing occurs with placement of the lead in the septum of the RV. Observational data show lower capture thresholds and dislodgement rates with left bundle area pacing compared with His bundle pacing. However, there are no large-scale randomized controlled trials. Epicardial systems Epicardial cardiac pacemaker systems utilize a pulse generator with leads that are surgically attached directly to the epicardial surface of the heart. These systems have largely been replaced by transvenous systems for patients requiring long-term cardiac pacing, although there is still a role for the occasional patient with vascular access problems (eg, venous thrombosis, congenital anatomical variations, prosthetic tricuspid valve). The major role for epicardial pacing systems in current practice is for temporary pacing following cardiac surgery; such systems, however, are designed as temporary systems that must be removed within the first days to weeks following cardiac surgery. Leadless systems In response to the limitations of both transvenous and epicardial pacing systems, efforts have been made to develop leadless cardiac pacing systems [5-12]. Leadless ventricular pacing Contemporary leadless systems include the pulse generator and the electrode within a single unit that is placed into the RV via a transvenous approach [13]. Multiple prospective, nonrandomized, multicenter trials with single-chamber RV leadless pacemakers followed for up to 12 months have demonstrated safety and efficacy [6,9,11,14-17]. In the SELECT-LV study, a prospective, nonrandomized study of safety and efficacy of leadless pacing for CRT among patients who "failed" conventional CRT, the leadless device was successfully implanted in 34 of 35 patients [12]. The primary efficacy endpoint (biventricular pacing on ECG at one month) was achieved in 33 of 34 patients; however, significant procedure https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 5/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate and device-related complication occurred in three patients (9 percent) at the time of implant and in eight patients (23 percent) within the first month postimplant. Leadless cardiac pacing systems have been approved for use in Europe since 2013, and, in April 2016, the first leadless cardiac pacing system was approved for use in the United States [18]. As of December 2016, two leadless pacemaker systems are approved by the US Food and Drug Administration (FDA) and commercially available, with slightly different sizes and implantation requirements [19]: Micra measures 2.6 x 0.7 cm, requires a 23-French introducer sheath, and was approved by the US FDA in 2016. Nanostim measures 4.2 x 0.6 cm and requires an 18-French sheath. However, the Nanostim was pulled from the market in 2017 because of early battery depletion issues. In 2022, the Aveir (a modification of the Nanostim device) was approved by the US FDA. In general, leadless pacemakers have been placed via the transfemoral approach, but in select patients the leadless pacemaker has been successfully implanted via a transjugular approach [20]. Following device approval and introduction into general clinical practice, patients have been prospectively enrolled in a registry to allow for postmarketing "real world" evaluation of safety and efficacy [6,7,9,21-29]. Among a cohort of 1817 patients from the postapproval registry, 1801 (99.1 percent) had successful implantation of the Micra leadless pacemaker at 179 centers [21]. A total of 41 major complications were reported at 30-day follow-up (2.3 percent), comparable to the major complication rate in the pre-approval investigational trial. Among 16 patients from three leadless pacemaker trials [6,7,9] who subsequently required device removal, the device was successfully extracted in 15 of 16 patients (94 percent), including all five patients in whom the device was in place for <6 weeks [22]. In a subsequent report on the extraction experience among 1423 worldwide recipients of the Nanostim device, among whom 73 patients underwent attempted device retrieval (implant duration ranging from one day to four years), 66 devices (90 percent) were successfully retrieved [23]. Of the 73 attempted retrievals, 53 were done in response to the clinical alert about potential battery malfunction, with the other 20 patients (1.4 percent) having another clinical indication for device retrieval. This rate of necessary revision is similar to the reported experience with the Micra device, in which an actuarial revision rate of 1.4 percent has also been reported [24]. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 6/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate A report has been published describing the successful removal of the Nanostim device up to nearly three years postimplant [25]. Leadless pacemakers have been successfully implanted, with good short-term results, in patients at high risk of device infection, including hemodialysis patients (197 of 201 patients successfully implanted with no infections over mean 6.2 month follow-up) [26] and patients with a prior cardiac implantable electronic device (CIED) infection (105 patients implanted 30 days from prior infected CIED explant with no infections over mean 8.5 month follow-up) [27]. Among a small cohort of 43 patients who had the device implanted while on anticoagulant therapy, only one patient experienced a bleeding complication [28]. While implantation appears safe in patients treated with warfarin or another oral anticoagulant, additional data are required to guide the optimal approach to implantation in this setting. Leadless cardiac pacing holds promise as a long-term permanent cardiac pacing option for patients requiring single ventricle (RV only) pacing and appears both safe and efficacious in the short term. Leadless AV sequential pacing While initial leadless pacemakers could only sense and pace the RV, contemporary devices have the capacity to maintain AV synchrony: The US FDA-approved Micra AV uses an accelerometer-based algorithm to sense atrial activity and pace the ventricle and thus provide VDD pacing [30]. The device is used to treat patients with normal sinus function and complete AV block. The investigational leadless pacing system (Aveir DR) is composed of one device implanted in the right atrium and one device implanted in the RV. A prospective multicenter study of this system enrolled 190 patients with sinus node dysfunction and 100 with AV block [31]. The implantation procedure was successful in 98.3 percent of patients. The primary safety endpoint of freedom from complications at 90 days was met in 90.3 percent of patients. The first primary performance endpoint of adequate atrial capture threshold and sensing amplitude was met in 90.2 percent of patients. The second primary performance endpoint of at least 70 percent AV synchrony at three months while sitting was met in 97.3 percent of patients. COMMON INDICATIONS https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 7/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Permanent pacemaker implantation is most commonly indicated for sinus node dysfunction or high-grade/symptomatic AV block. Guidelines for implantation of cardiac pacemakers have been published jointly by the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society (ACC/AHA/HRS) [1]. Although there are occasional cases that cannot be categorized according to these guidelines, they are, for the most part, comprehensive and have been widely endorsed. Similar guidelines have been established by the European Society of Cardiology [2]. Some indications for permanent pacing are relatively certain or unambiguous, while others require considerable expertise and judgment. It is helpful to divide the indications for pacemaker implantation into three specific categories, or classes, as defined by the ACC/AHA/HRS guidelines [1]: Class I Conditions in which permanent pacing is definitely beneficial, useful, and effective. In such conditions, implantation of a cardiac pacemaker is considered acceptable and necessary, provided that the condition is not due to a transient cause. Class II Conditions in which permanent pacing may be indicated but there is conflicting evidence and/or divergence of opinion; class IIA refers to conditions in which the weight of evidence/opinion is in favor of usefulness/efficacy, while class IIb refers to conditions in which the usefulness/efficacy is less well established by evidence/opinion. Class III Conditions in which permanent pacing is not useful/effective and in some cases may be harmful. Sinus node dysfunction The need for permanent pacing in patients with sinus node dysfunction is based largely upon the correlation of bradycardia with symptoms ( table 1) [1,2]. While patients with a heart rate of less than 40 beats per minute or pauses of greater than four seconds are more likely to develop symptoms, there is no definitive threshold for heart rate (or pause length) that determines the absolute need for a permanent pacemaker. This is especially true if the bradycardia occurs during sleep. Class I The following conditions are considered class I indications for pacemaker placement [1,2]: Sinus bradycardia in which symptoms are clearly related to the bradycardia (usually in patients with a heart rate below 40 beats per minute or frequent sinus pauses). Symptomatic chronotropic incompetence (an impaired heart rate response to exercise, generally defined as failure to achieve 85 percent of the age-predicted maximum heart rate during a formal or informal stress test or the inability to mount an age-appropriate heart https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 8/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate rate during activities of daily living, [ie, as documented by ambulatory monitoring]). (See "Prognostic features of stress testing in patients with known or suspected coronary disease", section on 'Heart rate response to exercise'.) Symptomatic sinus bradycardia due to the effects of clinically necessary evidence-based therapy (eg, antianginal or antiarrhythmic medications) with no effective alternative. Class II The following are considered to be class II indications for pacemaker placement in patients with sinus node dysfunction: Sinus bradycardia (heart rate <40 beats per minute) in a patient with symptoms suggestive of bradycardia, but without a clearly demonstrated association between bradycardia and symptoms. Sinus node dysfunction in a patient with unexplained syncope. Chronic heart rates <40 beats per minute while awake in a minimally symptomatic patient. Patients with sinus bradycardia of lesser severity (heart rate >40 beats per minute) who complain of dizziness or other symptoms that correlate with the slower rates are also potential candidates for pacemaker therapy. Acquired AV block Acquired AV block is the second most common indication for permanent pacemaker placement. Many disorders can cause acquired AV block, and these are discussed in detail separately. (See "Etiology of atrioventricular block" and "Third-degree (complete) atrioventricular block" and "Second-degree atrioventricular block: Mobitz type II" and "Second- degree atrioventricular block: Mobitz type I (Wenckebach block)".) Class I The following conditions represent severe conduction disease and are generally considered to be class I indications for pacing when not attributable to reversible causes: Complete (third-degree) AV block with or without symptoms Advanced second-degree AV block (block of two or more consecutive P waves) Second-degree AV block, Mobitz type II (with or without symptoms) Symptomatic second-degree AV block, Mobitz type I (Wenckebach) Exercise-induced second- or third-degree AV block (in the absence of myocardial ischemia) Some controversy exists concerning asymptomatic patients with congenital complete heart block (eg, complete heart block and a structurally normal heart). The ACC/AHA/HRS guidelines recommend permanent pacemaker implantation in patients with congenital complete heart block and any high-risk feature (symptoms attributed to bradycardia, wide QRS rhythm, mean https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 9/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate daytime heart rate <50 beats per minute, complex ventricular ectopy, or ventricular dysfunction), while noting that permanent pacing is reasonable in individuals with congenital complete heart block without these risk factors [1]. Similar recommendations are included in the European guidelines [2]. (See "Congenital third-degree (complete) atrioventricular block", section on 'Treatment'.) Class II Patients with varying degrees of acquired AV block may still benefit from pacemaker placement. In such patients, determinations are often based upon correlation of bradycardia with symptoms, exclusion of other causes of symptoms, and in rare instances based on results of electrophysiology (EP) testing. Conditions in which pacemaker placement can be considered include the following: First-degree AV block when there is hemodynamic compromise because of effective AV dissociation secondary to a very long PR interval. (See "First-degree atrioventricular block", section on 'Management'.) Bifascicular or trifascicular block associated with syncope that can be attributed to transient complete heart block, based upon the exclusion of other plausible causes of syncope ( table 2). Alternating bundle-branch block would also fulfill this criterion. (See "Chronic bifascicular blocks".) AV block in some patients may be due to the effects of medications (eg, antianginal or antiarrhythmic medications), a potentially reversible cause. However, if the pertinent medications cannot be discontinued (ie, alternative therapies are unavailable), permanent pacemaker insertion may be performed to allow for ongoing therapy with the drugs causing AV block [1,32]. Post-myocardial infarction The indications for permanent pacing, including those related to patients after an MI, are presented in detail separately. In general, our approach is in agreement with published professional society guidelines for implantation of a permanent cardiac pacemaker [1,33]. (See "Conduction abnormalities after myocardial infarction".) Neurally-mediated syncope Evaluation of the patient with syncope can be clinically challenging. Once a diagnosis of neurocardiogenic syncope is established or suspected, effective treatment can be similarly challenging. The use of pacemakers in this disorder is limited to very selected patients whose syncopal events are clearly associated with a marked cardioinhibitory or bradycardic event. Pacemaker treatment is effective only in patients with a marked isolated cardioinhibitory or bradycardic cause of syncope. However, since many patients have both bradycardic and vasodepressor https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 10/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate components, some patients with an indication for pacemaker placement may not have a significant improvement in symptoms with pacing. In fact, pacing is rarely necessary in neutrally- mediated syncope. (See "Reflex syncope in adults and adolescents: Treatment".) OTHER INDICATIONS Congenital complete heart block Congenital complete heart block has a variety of causes but most commonly is due to maternal neonatal lupus. Congenital complete heart block can present in utero, as a neonate, or later in childhood, with management directed by the time of presentation (ie, prenatal or postnatal) as well as the severity of symptoms. This topic is discussed separately. (See "Congenital third-degree (complete) atrioventricular block".) Neuromuscular diseases A number of neuromuscular diseases are associated with AV block, including myotonic muscular dystrophy, Kearns-Sayre syndrome, Erb dystrophy (limb-girdle), and peroneal muscular atrophy. Patients with these disorders have a class I indication for pacemaker placement once any evidence of second- or third-degree block develops. This is true even if the patient is asymptomatic, because there may be unpredictably rapid progression of AV conduction disease. (See "Inherited syndromes associated with cardiac disease".) Due to this potential for rapid progression, patients with these disorders are considered to have a class IIb indication for pacemaker placement even with first-degree AV block, regardless of symptoms [1,34]. Some of these patients may also require an implantable cardioverter- defibrillator or cardiac resynchronization therapy (CRT) [35]. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Long QT syndrome High-risk patients with congenital long QT syndrome have been treated with pacemakers to prevent ventricular arrhythmias, generally with a dual chamber pacemaker. However, most of these patients are now treated with an implantable cardioverter-defibrillator, which has pacing capability as well. (See "Congenital long QT syndrome: Treatment".) Bradycardia-induced ventricular arrhythmias Bradycardia and/or prolonged pauses can precipitate ventricular arrhythmias. Although this phenomenon is most commonly associated with QT prolongation, it can occur in patients with a normal QT interval. Patients with pause- dependent ventricular arrhythmias, with or without QT prolongation, have an indication for pacemaker implantation. As noted above, however, many of these patients will be treated with an implantable cardioverter-defibrillator, which also has pacing capability. (See 'Long QT syndrome' above.) https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 11/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Hypertrophic cardiomyopathy Pacing for medically refractory, symptomatic hypertrophic cardiomyopathy with significant resting or provoked left ventricular outflow obstruction is not generally recommended, particularly in patients who are candidates for septal reduction therapy [36]. The role of pacing in patients with HCM, along with the utilization of implantable cardioverter-defibrillators, is discussed in detail separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction", section on 'Therapies of limited benefit'.) Heart failure Neither single-chamber RV pacing nor dual-chamber right heart pacing (RA and RV) are indicated for the treatment of heart failure symptoms in patients with heart failure. However, CRT, also referred to as biventricular pacing, is used to improve symptoms and survival in patients with medically refractory advanced heart failure, nonischemic or ischemic cardiomyopathy, and left bundle branch block. The use of CRT is discussed in detail separately, including the potential use of CRT in patients who have reduced left ventricular systolic function and an indication for permanent pacing in whom pacing will be frequent (ie, >40 percent cumulative pacing). (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) CLASS III: PACING NOT INDICATED These are conditions that do not reliably improve with cardiac pacing, or are considered to lack adequate evidence of benefit from permanent pacing. Most of these conditions are bradyarrhythmias that are asymptomatic or due to reversible causes. Syncope of undetermined etiology. This may require extensive investigation, including ambulatory monitoring, neurologic evaluation, electrophysiologic testing, and perhaps tilt- table testing. Cardiac pacing may be considered if no other etiology of syncope is uncovered, and the history strongly suggests a cardiogenic origin. In such cases, the patient must understand that permanent pacing may not alleviate the symptoms, since no correlation between symptoms and rhythm has been documented. In addition, if a pacemaker is implanted because of a strong clinical suspicion that the patient's symptoms are due to a bradyarrhythmia, in the absence of any objective evidence of conduction system disease, reimbursement may be disallowed. Sinus bradycardia without significant symptoms. Sinoatrial block or sinus arrest without significant symptoms. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 12/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Asymptomatic prolonged RR intervals with atrial fibrillation or other causes of transient ventricular pause. Asymptomatic bradycardia during sleep. Asymptomatic second-degree Mobitz I (Wenckebach) AV block. A hyperactive cardioinhibitory response to carotid sinus stimulation in the absence of symptoms or in the presence of vague symptoms such as dizziness, lightheadedness, or both. Right bundle branch block with left axis deviation without syncope or other symptoms compatible with intermittent AV block. Reversible AV block, such as those associated with electrolyte abnormalities, Lyme disease, sleep apnea, enhanced vagal tone, and some cases that occur postoperatively. AV block associated with drugs such as beta blockers, diltiazem, or verapamil is not always reversible and can be associated with underlying conduction system disease [32]. (See "Etiology of atrioventricular block", section on 'Medications'.) Long QT syndrome or torsades de pointes due to reversible causes. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 13/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Pacemakers (The Basics)" and "Patient education: Bradycardia (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS General considerations Two general factors guide the vast majority of decisions regarding permanent pacemaker insertion: the association of symptoms with an arrhythmia and the potential for progression of the rhythm disturbance, which is largely dependent on the anatomical location of the conduction abnormality. (See 'General considerations' above.) Association of symptoms with arrhythmia Patients frequently present for consideration of pacemaker placement because of symptoms that may be due to bradyarrhythmias (eg, dizziness, lightheadedness, syncope, fatigue, and poor exercise tolerance). It is critical to attempt to establish a direct correlation between symptoms and bradyarrhythmias, which will increase the likelihood of recommending pacemaker placement. (See 'Symptoms' above.) Risk of progression The location of an atrioventricular (AV) conduction abnormality (ie, within the AV node or below the AV node in the His-Purkinje system) is an important determinant of both the probability and the likely pace of progression of conduction system disease. Disease below the AV node, in the His-Purkinje system, is generally considered to be less stable; as a result, permanent pacemaker placement is more likely to be recommended. (See 'Location of conduction abnormality' above.) Types of pacemaker systems Pacemakers ( picture 1) are most commonly placed in a thoracic pre-pectoral position and connected to one or two transvenous leads, which are positioned endocardially. Epicardial lead placement is still a viable option for patients with limited transvenous access. Leadless pacing systems are now available and hold significant promise for the future. (See 'Types of permanent pacemaker systems' above.) Indications for pacemaker implantation The most common indications for pacemaker implantation are sinus node dysfunction followed by AV block. All other indications are https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 14/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate much less common and include neurocardiogenic syncope and iatrogenic causes (eg, post- AV node ablation). While patients with a heart rate of less than 40 beats per minute, or pauses of greater than four seconds, are more likely to develop symptoms, there is no definitive threshold for heart rate (or pause length) which determines the absolute need for a permanent pacemaker. (See 'Common indications' above.) When to consider CRT or ICD With the advent of cardiac resynchronization therapy (CRT), it is important to also take into consideration the patient's left ventricular function at the time a pacemaker is considered. If the patient has left ventricular dysfunction and requires frequent pacing, it would be appropriate to consider CRT and/or an implantable cardioverter-defibrillator. Whether His bundle or left bundle pacing will provide benefits similar to CRT is yet to be determined. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Pacing not indicated Conditions with a lack of adequate evidence of benefit from permanent pacing, in which permanent pacing is generally non indicated, include, among others, syncope of undetermined etiology, asymptomatic sinus bradycardia, asymptomatic first-degree and second-degree Mobitz I (Wenckebach) AV block, reversible AV block, and long QT syndrome or torsades de pointes due to a reversible cause. (See 'Class III: Pacing not indicated' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. 2. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021; 42:3427. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 15/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate 3. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of the His-SYNC Pilot Trial. Heart Rhythm 2019; 16:1797. 4. Upadhyay GA, Vijayaraman P, Nayak HM, et al. His Corrective Pacing or Biventricular Pacing for Cardiac Resynchronization in Heart Failure. J Am Coll Cardiol 2019; 74:157. 5. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace 2014; 16:681. 6. Reddy VY, Knops RE, Sperzel J, et al. Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation 2014; 129:1466. 7. Knops RE, Tjong FV, Neuzil P, et al. Chronic performance of a leadless cardiac pacemaker: 1-

A hyperactive cardioinhibitory response to carotid sinus stimulation in the absence of symptoms or in the presence of vague symptoms such as dizziness, lightheadedness, or both. Right bundle branch block with left axis deviation without syncope or other symptoms compatible with intermittent AV block. Reversible AV block, such as those associated with electrolyte abnormalities, Lyme disease, sleep apnea, enhanced vagal tone, and some cases that occur postoperatively. AV block associated with drugs such as beta blockers, diltiazem, or verapamil is not always reversible and can be associated with underlying conduction system disease [32]. (See "Etiology of atrioventricular block", section on 'Medications'.) Long QT syndrome or torsades de pointes due to reversible causes. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 13/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Pacemakers (The Basics)" and "Patient education: Bradycardia (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS General considerations Two general factors guide the vast majority of decisions regarding permanent pacemaker insertion: the association of symptoms with an arrhythmia and the potential for progression of the rhythm disturbance, which is largely dependent on the anatomical location of the conduction abnormality. (See 'General considerations' above.) Association of symptoms with arrhythmia Patients frequently present for consideration of pacemaker placement because of symptoms that may be due to bradyarrhythmias (eg, dizziness, lightheadedness, syncope, fatigue, and poor exercise tolerance). It is critical to attempt to establish a direct correlation between symptoms and bradyarrhythmias, which will increase the likelihood of recommending pacemaker placement. (See 'Symptoms' above.) Risk of progression The location of an atrioventricular (AV) conduction abnormality (ie, within the AV node or below the AV node in the His-Purkinje system) is an important determinant of both the probability and the likely pace of progression of conduction system disease. Disease below the AV node, in the His-Purkinje system, is generally considered to be less stable; as a result, permanent pacemaker placement is more likely to be recommended. (See 'Location of conduction abnormality' above.) Types of pacemaker systems Pacemakers ( picture 1) are most commonly placed in a thoracic pre-pectoral position and connected to one or two transvenous leads, which are positioned endocardially. Epicardial lead placement is still a viable option for patients with limited transvenous access. Leadless pacing systems are now available and hold significant promise for the future. (See 'Types of permanent pacemaker systems' above.) Indications for pacemaker implantation The most common indications for pacemaker implantation are sinus node dysfunction followed by AV block. All other indications are https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 14/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate much less common and include neurocardiogenic syncope and iatrogenic causes (eg, post- AV node ablation). While patients with a heart rate of less than 40 beats per minute, or pauses of greater than four seconds, are more likely to develop symptoms, there is no definitive threshold for heart rate (or pause length) which determines the absolute need for a permanent pacemaker. (See 'Common indications' above.) When to consider CRT or ICD With the advent of cardiac resynchronization therapy (CRT), it is important to also take into consideration the patient's left ventricular function at the time a pacemaker is considered. If the patient has left ventricular dysfunction and requires frequent pacing, it would be appropriate to consider CRT and/or an implantable cardioverter-defibrillator. Whether His bundle or left bundle pacing will provide benefits similar to CRT is yet to be determined. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Pacing not indicated Conditions with a lack of adequate evidence of benefit from permanent pacing, in which permanent pacing is generally non indicated, include, among others, syncope of undetermined etiology, asymptomatic sinus bradycardia, asymptomatic first-degree and second-degree Mobitz I (Wenckebach) AV block, reversible AV block, and long QT syndrome or torsades de pointes due to a reversible cause. (See 'Class III: Pacing not indicated' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. 2. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021; 42:3427. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 15/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate 3. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of the His-SYNC Pilot Trial. Heart Rhythm 2019; 16:1797. 4. Upadhyay GA, Vijayaraman P, Nayak HM, et al. His Corrective Pacing or Biventricular Pacing for Cardiac Resynchronization in Heart Failure. J Am Coll Cardiol 2019; 74:157. 5. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace 2014; 16:681. 6. Reddy VY, Knops RE, Sperzel J, et al. Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation 2014; 129:1466. 7. Knops RE, Tjong FV, Neuzil P, et al. Chronic performance of a leadless cardiac pacemaker: 1- year follow-up of the LEADLESS trial. J Am Coll Cardiol 2015; 65:1497. 8. Ritter P, Duray GZ, Steinwender C, et al. Early performance of a miniaturized leadless cardiac pacemaker: the Micra Transcatheter Pacing Study. Eur Heart J 2015; 36:2510. 9. Reddy VY, Exner DV, Cantillon DJ, et al. Percutaneous Implantation of an Entirely Intracardiac Leadless Pacemaker. N Engl J Med 2015; 373:1125. 10. Miller MA, Neuzil P, Dukkipati SR, Reddy VY. Leadless Cardiac Pacemakers: Back to the Future. J Am Coll Cardiol 2015; 66:1179. 11. Reynolds D, Duray GZ, Omar R, et al. A Leadless Intracardiac Transcatheter Pacing System. N Engl J Med 2016; 374:533. 12. Reddy VY, Miller MA, Neuzil P, et al. Cardiac Resynchronization Therapy With Wireless Left Ventricular Endocardial Pacing: The SELECT-LV Study. J Am Coll Cardiol 2017; 69:2119. 13. Sperzel J, Burri H, Gras D, et al. State of the art of leadless pacing. Europace 2015; 17:1508. 14. Tjong FVY, Knops RE, Neuzil P, et al. Midterm Safety and Performance of a Leadless Cardiac Pacemaker: 3-Year Follow-up to the LEADLESS Trial (Nanostim Safety and Performance Trial for a Leadless Cardiac Pacemaker System). Circulation 2018; 137:633. 15. Sperzel J, Defaye P, Delnoy PP, et al. Primary safety results from the LEADLESS Observational Study. Europace 2018; 20:1491. 16. Piccini JP, Stromberg K, Jackson KP, et al. Long-term outcomes in leadless Micra transcatheter pacemakers with elevated thresholds at implantation: Results from the Micra Transcatheter Pacing System Global Clinical Trial. Heart Rhythm 2017; 14:685. 17. Duray GZ, Ritter P, El-Chami M, et al. Long-term performance of a transcatheter pacing system: 12-Month results from the Micra Transcatheter Pacing Study. Heart Rhythm 2017; https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 16/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate 14:702. 18. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandCl earances/Recently-ApprovedDevices/ucm494390.htm (Accessed on April 08, 2016). 19. El-Chami MF, Merchant FM, Leon AR. Leadless Pacemakers. Am J Cardiol 2017; 119:145. 20. Saleem-Talib S, van Driel VJ, Chaldoupi SM, et al. Leadless pacing: Going for the jugular. Pacing Clin Electrophysiol 2019; 42:395. 21. El-Chami MF, Al-Samadi F, Clementy N, et al. Updated performance of the Micra transcatheter pacemaker in the real-world setting: A comparison to the investigational study and a transvenous historical control. Heart Rhythm 2018; 15:1800. 22. Reddy VY, Miller MA, Knops RE, et al. Retrieval of the Leadless Cardiac Pacemaker: A Multicenter Experience. Circ Arrhythm Electrophysiol 2016; 9. 23. Lakkireddy D, Knops R, Atwater B, et al. A worldwide experience of the management of battery failures and chronic device retrieval of the Nanostim leadless pacemaker. Heart Rhythm 2017; 14:1756. 24. Grubman E, Ritter P, Ellis CR, et al. To retrieve, or not to retrieve: System revisions with the Micra transcatheter pacemaker. Heart Rhythm 2017; 14:1801. 25. Gonz lez Villegas E, Al Razzo O, Silvestre Garc a J, Mesa Garc a J. Leadless pacemaker extraction from a single-center perspective. Pacing Clin Electrophysiol 2018; 41:101. 26. El-Chami MF, Clementy N, Garweg C, et al. Leadless Pacemaker Implantation in Hemodialysis Patients: Experience With the Micra Transcatheter Pacemaker. JACC Clin Electrophysiol 2019; 5:162. 27. El-Chami MF, Johansen JB, Zaidi A, et al. Leadless pacemaker implant in patients with pre- existing infections: Results from the Micra postapproval registry. J Cardiovasc Electrophysiol 2019; 30:569. 28. San Antonio R, Chipa-Ccasani F, Apolo J, et al. Management of anticoagulation in patients undergoing leadless pacemaker implantation. Heart Rhythm 2019; 16:1849. 29. Tachibana M, Banba K, Matsumoto K, Ohara M. The feasibility of leadless pacemaker implantation for superelderly patients. Pacing Clin Electrophysiol 2020; 43:374. 30. Steinwender C, Khelae SK, Garweg C, et al. Atrioventricular Synchronous Pacing Using a Leadless Ventricular Pacemaker: Results From the MARVEL 2 Study. JACC Clin Electrophysiol 2020; 6:94. 31. Knops RE, Reddy VY, Ip JE, et al. A Dual-Chamber Leadless Pacemaker. N Engl J Med 2023; 388:2360. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 17/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate 32. Zeltser D, Justo D, Halkin A, et al. Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug. J Am Coll Cardiol 2004; 44:105. 33. American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, O'Gara PT, et al. 2013 ACCF/AHA guideline for the management of ST- elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:e78. 34. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 35. Groh WJ. Arrhythmias in the muscular dystrophies. Heart Rhythm 2012; 9:1890. 36. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2020; 142:e558. Topic 941 Version 43.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 18/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate GRAPHICS Normal conduction system Schematic representation of the normal intraventricular conduction system (His- Purkinje system). The Bundle of His divides into the left bundle branch and right bundle branch. The left bundle branch divides into anterior, posterior, and, in some cases, median fascicles. AV: atrioventricular; RA: right atrium; LA: left atrium; RV: right ventricle; LV: left ventricle. Graphic 63340 Version 6.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 19/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Examples of cardiac pacemaker pulse generators Examples of cardiac pacemaker pulse generators commonly used in practice in 2015. Graphic 104720 Version 1.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 20/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate A leadless pacing system: The Medtronic Micra This pacing system includes the pulse generator and the electrode within a single unit that is placed into the right ventricle via a transvenous approach. Reproduced with permission of Medtronic, Inc. Copyright 2021. Graphic 130297 Version 1.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 21/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Indications for pacing for sinus node dysfunction Pacemaker not Pacemaker necessary Pacemaker probably necessary necessary Symptomatic bradycardia Symptomatic patients with sinus node dysfunction with documented rates of <40 bpm without a clear-cut association between significant symptoms and the Asymptomatic sinus node dysfunction bradycardia Symptomatic sinus bradycardia due to long-term drug therapy of a type and dose for which there is no accepted alternative Graphic 70519 Version 2.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 22/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Indications for pacing in multifascicular block Pacemaker probably Pacemaker not Pacemaker necessary necessary necessary Symptomatic patients with fascicular Patients with syncope and Asymptomatic block and significantly prolonged H-V interval by electrophysiologic study bifascicular or trifascicular block with other etiologies of syncope excluded fascicular block without AV block Symptomatic patients with block distal to His at atrial paced rates of less than 100-120 bpm Pacing-induced block distal to His at atrial paced rates of less than 130 bpm Asymptomatic fascicular block and first degree AV block Symptomatic patients with bifascicular block and intermittent type II second Asymptomatic patients with fascicular block and intermittent degree AV block or third degree AV block type II second degree or third degree AV block Graphic 80379 Version 1.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 23/24 7/6/23, 3:09 PM Permanent cardiac pacing: Overview of devices and indications - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 24/24

7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Pharmacologic therapy in survivors of sudden cardiac arrest : Philip J Podrid, MD, FACC : Scott Manaker, MD, PhD, Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 24, 2021. INTRODUCTION Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden cessation of cardiac activity with hemodynamic collapse, typically due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). The event is referred to as SCA (or aborted SCD) if an intervention (eg, defibrillation, cardioversion, or drug therapy) or spontaneous reversion restores circulation, while the SCD terminology is employed if the patient dies. However, the use of SCD to describe both fatal and nonfatal cardiac arrest often persists by convention. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Definitions'.) The treatment of SCA consists of acute resuscitation using standardized advanced cardiac life- support protocols, followed by therapy to prevent recurrent arrhythmias and SCD. Patients who survive SCA caused by VT/VF not due to a reversible cause generally receive an implantable cardioverter-defibrillator (ICD). Antiarrhythmic drugs are used in select patients as adjunctive therapy, or as primary therapy when an ICD is not indicated or refused by the patient. This approach, endorsed by numerous professional societies, is based on the significant survival benefit of patients receiving an ICD compared with antiarrhythmic drugs alone or no therapy. This topic will review the role of pharmacologic therapy in survivors of SCA, with an emphasis on the role of antiarrhythmic drugs. Issues related to the acute management of SCA, the evaluation of survivors, and the utility of an ICD, arrhythmic surgery, or radiofrequency ablation are discussed separately. (See "Advanced cardiac life support (ACLS) in adults" and "Cardiac https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 1/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate evaluation of the survivor of sudden cardiac arrest" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) INDICATIONS FOR PHARMACOLOGIC THERAPY Nearly all survivors of SCA without a reversible cause should be evaluated for placement of an ICD. Because an ICD treats, but does not prevent, arrhythmias, patients who have arrhythmias with symptoms or device discharges may require adjunctive antiarrhythmic therapy. In addition to ICD therapy for survivors of SCA, there are three main indications for concomitant antiarrhythmic drug therapy [1-3]: To reduce the frequency of ventricular arrhythmias in patients with frequent ICD shocks. In one analysis, the occurrence of frequent ICD shocks was the primary reason for adding an antiarrhythmic drug (64 percent) [3]. To suppress supraventricular arrhythmias that may cause symptoms or interfere with ICD function, potentially resulting in "inappropriate" shocks. "Inappropriate" shocks result from non-life-threatening arrhythmias which meet the programmed parameters for ICD therapy, primarily based upon rate (eg, atrial fibrillation with a rapid ventricular response exceeding the programmed threshold for delivering a shock). "Inappropriate" shocks have been reported in up to 29 percent of ICD patients and can have a substantial impact on the patient s quality of life [4]. These shocks are caused by a variety of arrhythmias including sinus tachycardia, atrial tachycardia, atrial flutter, atrial fibrillation, and nonsustained VT (NSVT) [4,5]. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Inappropriate shocks'.) More sophisticated programming features of current-generation ICDs may allow the device to ignore clinically unimportant and non-life-threatening arrhythmias rather than delivering an unnecessary shock. (See "Implantable cardioverter-defibrillators: Optimal programming".) To reduce the ventricular rate of VT so that it is better tolerated hemodynamically and/or more amenable to termination by anti-tachycardia pacing or low energy cardioversion. CHOICE OF PHARMACOLOGIC THERAPY For patients with an ICD who require adjunctive antiarrhythmic therapy due to ongoing ventricular arrhythmias, we recommend treatment with the combination of amiodarone plus a https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 2/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate beta blocker rather than treatment with amiodarone alone or other antiarrhythmic agents. On occasion, therapy with mexiletine or sotalol may be useful. In general, the class I antiarrhythmic drugs are not used as the majority of patients with SCA have structural heart disease, and these drugs are not recommended in patients with structural heart disease. Pharmacologic therapy, in the form of beta blockers and antiarrhythmic medications, can be helpful in controlling ventricular arrhythmias in survivors of SCA. Virtually all patients who have survived SCA should be considered for beta blocker therapy. However, due to the efficacy of the ICD in treating sustained ventricular tachyarrhythmias and improving mortality, antiarrhythmic drugs are generally reserved for use in select patients as adjunctive therapy, or as primary therapy when an ICD is not indicated or refused by the patient. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Empiric versus guided pharmacologic therapy Empiric pharmacologic therapy for SCA survivors, primarily with beta blockers and/or an antiarrhythmic drug, is an effective approach for survivors of SCA who have refused ICD placement or are not candidates for an ICD. Beta blockers have some efficacy with relatively few side effects, while for most patients amiodarone is the most efficacious antiarrhythmic drug for preventing recurrent ventricular arrhythmias. In the past, the choice of antiarrhythmic drug was guided by objective criteria based upon either noninvasive (ambulatory electrocardiogram [ECG] monitoring) or invasive testing (electrophysiologic studies). An effective drug, identified by either technique, was noted to prevent recurrent arrhythmia and potentially improve survival compared with no therapy or an ineffective drug [6-13]. In current practice, however, when pharmacologic therapy is administered to a patient with or without (because of refusal or noncandidacy for) an ICD, empiric treatment with beta blockers and/or amiodarone is the preferred approach. Other antiarrhythmic drugs (for example mexiletine or sotalol) are considered if there is recurrent arrhythmia despite therapy with amiodarone and/or a beta blocker. Beta blockers Nearly all patients who have survived SCA should receive a beta blocker as part of their therapy. Beta blockers are not generally considered to be adequate monotherapy and should be used in conjunction with an antiarrhythmic drug for most patients resuscitated from SCA due to VT or ventricular fibrillation (VF). However, the associated anti-adrenergic effects of beta blockers may be effective at reducing both arrhythmias and SCA when no specific antiarrhythmic treatment is given. In an analysis from the AVID trial, patients who were discharged from the hospital on a beta blocker had a mortality reduction compared with those patients not receiving a beta blocker [14]. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 3/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Most SCA survivors will have multiple indications for a beta blocker (eg, post-myocardial infarction, heart failure, etc) from which they derive clinical benefit. Beta blockers reduce the incidence of sudden death and total mortality in patients with a recent myocardial infarction and in those with symptomatic heart failure or congenital long QT syndrome. However, even in the absence of any additional indications, beta blockers should be used as part of the medical regimen following SCA due to VT/VF. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Congenital long QT syndrome: Treatment".) Beta blockers can potentiate the effects of class I antiarrhythmic drugs by preventing the effect of sympathetic stimulation on reversing the depressant effect on slowing conduction. They can also potentiate the action of class III antiarrhythmic drugs by preventing the sympathetic effect on shortening repolarization. Antiarrhythmic drugs Among antiarrhythmic medications, amiodarone is the most effective for preventing recurrent ventricular tachyarrhythmias, although mexiletine or sotalol are also efficacious for reducing recurrent ventricular arrhythmias. We prefer empiric therapy with amiodarone for treatment immediately following SCA in patients with recurrent ventricular tachyarrhythmias as well as for those who have refused (or are not candidates for) ICD placement [15]. Following stabilization of the patient, if there are concerns about potential toxicity related to amiodarone, particularly for anticipated long-term use, mexiletine or sotalol may be considered. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Efficacy Several clinical trials and systematic reviews have evaluated the efficacy of antiarrhythmic drugs as adjuvant therapy in ICD patients [5,16-21]. There were significant differences in trial methodologies, which limit direct comparisons. Amiodarone has generally been the most effective antiarrhythmic drug for preventing ventricular arrhythmias (and associated ICD shocks). In one systematic review which included eight randomized trials involving 1889 patients, there was significant heterogeneity among the trials, including variation on the active therapy, control therapy, and outcomes assessed, and the results were divided into those trials that compared class III antiarrhythmic drugs (usually sotalol and amiodarone) with beta blockers, and those trials that compared class III drugs (sotalol, dofetilide, and azimilide) with placebo or no antiarrhythmic therapy [20]. Key findings included: Amiodarone in combination with a beta blocker significantly reduced the incidence of shocks compared with beta blocker alone (hazard ratio [HR] 0.27, 95% CI 0.14-0.52). These results were largely driven by the OPTIC trial. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 4/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Sotalol reduced the incidence of ICD shocks when compared with placebo (HR 0.55, 95% CI 0.4-0.78). There was also a trend toward fewer shocks in patients treated with sotalol versus another beta blocker. Treatment with either azimilide or dofetilide resulted in nonsignificant trends towards reduction in total ICD shocks (generally due to a decrease in supraventricular arrhythmias) compared with placebo. However, the incidence of appropriate ICD therapies (shocks plus antitachycardia pacing) was significantly reduced by azimilide (HR 0.31, 95% CI 0.29-0.34). In a second systematic review of 17 randomized trials involving 5875 patients, patients taking an antiarrhythmic drug had significantly fewer ICD shocks compared with those not on an antiarrhythmic (odds ratio [OR] 0.59, 95% CI 0.36-0.96) [22]. However, the reduction in shocks seen in patients receiving an antiarrhythmic drug was not associated with improved survival (OR 1.07, 95% CI 0.72-1.59). In the OPTIC trial, a multicenter trial that randomized 412 patients with an ICD to treatment with a beta blocker alone, a beta blocker plus amiodarone, or sotalol alone, the rate of any ICD shock at one year was significantly lower with amiodarone plus a beta blocker than with sotalol or a beta blocker alone (10.3 versus 24.3 and 38.5 percent, respectively) [16]. There was a trend toward fewer total ICD shocks in the sotalol group compared with beta blockers alone; however, sotalol had no significant effect compared with a beta blocker alone in reducing the incidence of appropriate shocks or antitachycardia pacing. Another major advantage of amiodarone is a very low frequency of proarrhythmia. Although amiodarone can markedly prolong the QT/QTc interval, torsades de pointes is rare. However, caution is necessary when amiodarone is given with other drugs that can prolong the QT interval or therapy is complicated by hypokalemia or hypomagnesemia. Caution is necessary when combining amiodarone with a beta blocker, as amiodarone also has beta blocking effects and significant bradycardia or AV block may occur. This is not a concern in patients who have an ICD, as there is backup pacing. However, for patients without an ICD or pacemaker this should be considered and patients should be monitored carefully. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Administration When patients are started on an antiarrhythmic drug, they should have a baseline ECG prior to drug initiation and then serial ECGs for the first two to three days, particularly to monitor heart rate and assess for any significant QT/QTc interval prolongation. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 5/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Amiodarone The initial dosing of amiodarone will vary depending on the route (intravenous [IV] or oral) as well as the clinical situation ( table 1): For patients with electrical storm or incessant VT, we recommend IV amiodarone (150 mg IV push, followed by 1 mg/minute IV infusion for six hours, followed by 0.5 mg/minute IV infusion for 18 additional hours) as the initial antiarrhythmic agent. (See "Electrical storm and incessant ventricular tachycardia", section on 'Initial antiarrhythmic medical therapy'.) For patients who have been on IV therapy for more than two weeks, we start maintenance oral amiodarone at a dose of 200 to 400 mg/day. (See "Amiodarone: Clinical uses", section on 'Amiodarone for ventricular arrhythmias'.) For patients who have been on IV therapy for one to two weeks, we start an intermediate maintenance oral amiodarone dose of 400 to 800 mg/day until an adequate loading dose has been achieved, then the dose should be reduced to the usual maintenance dose of 200 mg/day. The recommended IV loading dose is 10 grams or the oral equivalent. As oral amiodarone is approximately 50 percent bioavailable, a total of 20 to 30 grams of oral amiodarone is equivalent to the IV loading dose. For patients who have been on IV therapy for one week or less, we usually start with a full oral amiodarone loading dose of 400 to 1200 mg/day (typically in two or three divided doses). This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 mg/day. Sotalol In contrast to amiodarone, sotalol is not universally available in IV form. Bradycardic and proarrhythmic events (especially due to QT/QTc prolongation) can occur after the initiation of sotalol therapy and with each upward dosing adjustment. As a result, sotalol should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. We start sotalol at a dose of 80 mg twice daily, with dose adjustments at three-day intervals once steady-state plasma concentrations have been achieved and the QT interval has been reviewed on a surface ECG. Patients with renal insufficiency require a modification of the dosing interval. (See "Clinical uses of sotalol", section on 'Dosing'.) Mexiletine Mexiletine, which is a lidocaine-like antiarrhythmic drug, is only available for oral use. It is often used with or without amiodarone for treating patients with an ICD who have ventricular arrhythmias that are of concern. The usual dose is 200 to 400 mg three times daily. Treatment of breakthrough arrhythmias Patients who have recurrent, or breakthrough, arrhythmias resulting in repeat ICD shocks or sudden cardiac arrest in spite of therapy with a https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 6/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate beta blocker and/or antiarrhythmic drug represent a significant clinical challenge. As with the occurrence of any ventricular arrhythmia, any identifiable reversible causes (eg, myocardial ischemia, electrolyte disturbances) should be corrected. In the absence of any reversible causes, we approach treatment in the following way: For patients who are taking only a beta blocker, we add an antiarrhythmic drug, ideally amiodarone. For patients who are taking only an antiarrhythmic drug, we add a beta blocker. For patients who are taking both a beta blocker and an antiarrhythmic drug, treatment options include upward titration of either or both existing drugs or the discontinuation of the current antiarrhythmic drug in favor of an alternative antiarrhythmic drug. We prefer to first increase the dose of the beta blocker and the current antiarrhythmic drug to the maximum recommended dose (or maximum tolerated dose if side effects arise). If this approach is ineffective and the patient continues to have recurrent ventricular arrhythmias and shocks, we would consider stopping the current antiarrhythmic drug and initiating treatment with another agent. Another important option for patients with recurrent arrhythmia despite amiodarone and beta blocker is the addition of a class I antiarrhythmic agent ( table 2) that does not alter the QT/QTc interval (ie, mexiletine or propafenone). For patients with recurrent ventricular tachyarrhythmia despite the use of multiple antiarrhythmic drugs, cardiac ablation is often the next step in management. Further details on the treatment of refractory VT can be found elsewhere. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.) IMPACT ON ICD THERAPIES The primary goal of using blockers and/or antiarrhythmic drugs in patients with an ICD is to minimize the frequency of recurrent ventricular arrhythmias, thereby decreasing the likelihood of the patient receiving additional ICD shocks. Beyond reducing the likelihood of ICD shocks, however, antiarrhythmic drug therapy may impact the efficacy of ICD therapies by potentially increasing defibrillation thresholds beyond the device s capability to defibrillate or by slowing the ventricular rates of any recurrent sustained tachyarrhythmias below the device s threshold for arrhythmia detection. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 7/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Alterations in DFTs Any antiarrhythmic drug can potentially alter the defibrillation threshold (DFT), although the effect has been most pronounced with amiodarone and its major metabolite desethylamiodarone, which increase the DFT in a dose-dependent fashion [23-25]. DFT testing has historically been performed at the time of ICD implantation, although the routine necessity for this evaluation with the current generation of ICDs has been questioned. However, repeat DFT testing may be warranted after the initiation of amiodarone if there is concern about rising DFT thresholds (as may occur in certain clinical situations, including atrial fibrillation, hypertension, and left ventricular hypertrophy). In the report on the efficacy of routine ICD testing discussed above, 71 patients had an ICD test due to the initiation or dose-adjustment of an antiarrhythmic drug (primarily amiodarone or sotalol), and the ICD failed to defibrillate only two patients [26]. The role of ICD testing after the initiation of antiarrhythmic therapy was more directly assessed in a substudy of the OPTIC trial, in which 94 patients underwent serial ICD testing to determine the impact of each of three drug regimens (beta blockers, amiodarone plus a beta blocker, and sotalol) on DFTs [27]. At a mean follow-up of 60 days after drug initiation, the mean DFT decreased from baseline in the patients assigned to beta blockers or sotalol (8.8 to 7.1 and 8.1 to 7.2 joules, respectively), while among patients taking amiodarone there was a nonsignificant increase in the mean DFT from 8.5 to 9.8 joules. Given the relatively small number of patients in each arm of this study, the small mean increase in DFT does not preclude the possibility that there may be a larger increase in some patients. Thus, the necessity for ICD testing after the initiation of antiarrhythmic drugs, primarily amiodarone, remains uncertain. Programming changes for VT detection In patients receiving chronic antiarrhythmic drug therapy, the rate of recurrent VT is often slower than the rate seen during the index arrhythmia. Thus, it is common practice to lower the VT detection rate when initiating antiarrhythmic drug therapy; the specific detection threshold rate is determined by the characteristics of the patient s prior events. However, reducing the VT detection rate can have both positive and negative consequences for the patient: If the VT detection rate is reduced and the ICD therapy program includes antitachycardia pacing (ATP), episodes of slow VT may be terminated with ATP before the patient is aware of the event. If the detection rate is set too low, the ICD will not treat the arrhythmia unless it accelerates above the detection rate or progresses to ventricular fibrillation (VF). Thus, some patients who have their detection threshold rate decreased may not receive ICD treatments during episodes of slow VT and may have symptomatic VT (eg, syncope, palpitations, chest pain, dyspnea, or even SCA). https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 8/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Close follow-up with remote device interrogation can help determine whether new VT detection settings are appropriate. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Basic and advanced cardiac life support in adults".) SUMMARY AND RECOMMENDATIONS Because of the survival benefit associated with an implantable cardioverter-defibrillator (ICD) compared with antiarrhythmic therapy alone, most survivors of sudden cardiac arrest (SCA) due to ventricular tachycardia (VT) or ventricular fibrillation (VF) not associated with a reversible cause should receive an ICD. Antiarrhythmic drugs can be considered as the primary therapy when an ICD is not indicated or refused by the patient. (See 'Indications for pharmacologic therapy' above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Nearly all patients who have survived SCA should receive a beta blocker as part of their therapy, which may also provide additional antiarrhythmic benefits. (See 'Empiric versus guided pharmacologic therapy' above.) Because an ICD does not prevent arrhythmias, patients who have arrhythmias (ventricular or supraventricular) with symptoms or device discharges may require adjunctive antiarrhythmic therapy or consideration of catheter ablation. The three main indications for concomitant antiarrhythmic drug therapy are (see 'Indications for pharmacologic therapy' above): To reduce the frequency of ventricular arrhythmias in patients with frequent ICD shocks. To suppress other arrhythmias that cause symptoms or interfere with ICD function (eg, causing "inappropriate" shocks). To reduce the ventricular rate of VT so that it is better tolerated hemodynamically and more amenable to termination by anti-tachycardia pacing or low-energy cardioversion. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 9/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate For patients with an ICD who require adjunctive antiarrhythmic therapy due to ongoing arrhythmias, we recommend treatment with the combination of amiodarone plus a beta blocker rather than treatment with amiodarone alone or other antiarrhythmic agents (Grade 1B). This approach is especially preferred in patients with significant left ventricular dysfunction who require adjunctive antiarrhythmic therapy, since amiodarone does not exacerbate heart failure and is less proarrhythmic than other agents. (See 'Choice of pharmacologic therapy' above.) Antiarrhythmic drug therapy may impact the efficacy of ICD therapies by potentially increasing defibrillation thresholds beyond the device s capability to defibrillate or by slowing the ventricular rates of any recurrent sustained tachyarrhythmias below the device s threshold for arrhythmia detection.(See 'Impact on ICD therapies' above.) ACKNOWLEDGMENT The UpToDate editorial staff thanks Jie Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Knilans TK, Prystowsky EN. Antiarrhythmic drug therapy in the management of cardiac arrest survivors. Circulation 1992; 85:I118. 2. Manz M, Jung W, L deritz B. Interactions between drugs and devices: experimental and clinical studies. Am Heart J 1994; 127:978. 3. Steinberg JS, Martins J, Sadanandan S, et al. Antiarrhythmic drug use in the implantable defibrillator arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study. Am Heart J 2001; 142:520. 4. Nanthakumar K, Paquette M, Newman D, et al. Inappropriate therapy from atrial fibrillation and sinus tachycardia in automated implantable cardioverter defibrillators. Am Heart J 2000; 139:797. 5. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Engl J Med 1999; 340:1855. 6. Kim SG. The management of patients with life-threatening ventricular tachyarrhythmias: https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 10/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate programmed stimulation or Holter monitoring (either or both)? Circulation 1987; 76:1. 7. Wilber DJ, Garan H, Finkelstein D, et al. Out-of-hospital cardiac arrest. Use of electrophysiologic testing in the prediction of long-term outcome. N Engl J Med 1988; 318:19. 8. Graboys TB, Lown B, Podrid PJ, DeSilva R. Long-term survival of patients with malignant ventricular arrhythmia treated with antiarrhythmic drugs. Am J Cardiol 1982; 50:437. 9. Lampert S, Lown B, Graboys TB, et al. Determinants of survival in patients with malignant ventricular arrhythmia associated with coronary artery disease. Am J Cardiol 1988; 61:791. 10. Vlay SC, Kallman CH, Reid PR. Prognostic assessment of survivors of ventricular tachycardia and ventricular fibrillation with ambulatory monitoring. Am J Cardiol 1984; 54:87. 11. Mason JW. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993; 329:445. 12. Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993; 329:452. 13. Swerdlow CD, Winkle RA, Mason JW. Determinants of survival in patients with ventricular tachyarrhythmias. N Engl J Med 1983; 308:1436. 14. Exner DV, Reiffel JA, Epstein AE, et al. Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 1999; 34:325. 15. Weinberg BA, Miles WM, Klein LS, et al. Five-year follow-up of 589 patients treated with amiodarone. Am Heart J 1993; 125:109. 16. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta- blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006; 295:165. 17. Dorian P, Borggrefe M, Al-Khalidi HR, et al. Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Circulation 2004; 110:3646. 18. Singer I, Al-Khalidi H, Niazi I, et al. Azimilide decreases recurrent ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators. J Am Coll Cardiol 2004; 43:39. 19. K hlkamp V, Mewis C, Mermi J, et al. Suppression of sustained ventricular tachyarrhythmias: a comparison of d,l-sotalol with no antiarrhythmic drug treatment. J Am Coll Cardiol 1999; https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 11/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate 33:46. 20. Ferreira-Gonz lez I, Dos-Subir L, Guyatt GH. Adjunctive antiarrhythmic drug therapy in patients with implantable cardioverter defibrillators: a systematic review. Eur Heart J 2007; 28:469. 21. Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE Study). The CASCADE Investigators. Am J Cardiol 1993; 72:280. 22. Ha AH, Ham I, Nair GM, et al. Implantable cardioverter-defibrillator shock prevention does not reduce mortality: a systemic review. Heart Rhythm 2012; 9:2068. 23. Zhou L, Chen BP, Kluger J, et al. Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold. J Am Coll Cardiol 1998; 31:1672. 24. Pelosi F Jr, Oral H, Kim MH, et al. Effect of chronic amiodarone therapy on defibrillation energy requirements in humans. J Cardiovasc Electrophysiol 2000; 11:736. 25. Nielsen TD, Hamdan MH, Kowal RC, et al. Effect of acute amiodarone loading on energy requirements for biphasic ventricular defibrillation. Am J Cardiol 2001; 88:446. 26. Brunn J, B cker D, Weber M, et al. Is there a need for routine testing of ICD defibrillation capacity? Results from more than 1000 studies. Eur Heart J 2000; 21:162. 27. Hohnloser SH, Dorian P, Roberts R, et al. Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial. Circulation 2006; 114:104. Topic 972 Version 27.0 https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 12/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate GRAPHICS Amiodarone dosing in adults by indication Indications Loading dose Maintenance dose Atrial arrhythmias Prevention of recurrent PAF Total loading dose: 6 to 10 grams Lowest effective dose, usually 100 to 200 mg orally once per day Pharmacologic cardioversion of PAF Outpatient: Given as 400 to 600 mg orally per day in divided doses with meals Maximum 200 mg orally per day Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals Pretreatment before elective cardioversion or Total loading dose: 6 to 10 grams orally over 2 to 6 Lowest effective dose, usually 100 to 200 mg orally catheter ablation of AF weeks once per day Given as 400 to 1200 mg Maximum 400 mg orally per orally per day in divided doses day in most circumstances Restoration and maintenance of NSR in critically ill patients with AF Total IV loading dose: 1050 mg Given as 150 mg IV bolus over 10 to 30 minutes, followed by continuous IV infusion at 1 mg per minute for 6 hours, then 0.5 mg per Ventricular rate control in critically ill patients with AF and rapid ventricular response minute for 18 hours* IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy If amiodarone will be used chronically: Following IV infusion, give 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams; consider overlapping IV and oral amiodarone for 24 to 48 hours https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 13/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Ventricular arrhythmias Primary and secondary prevention of SCD in patients with LV dysfunction who are not candidates for or refuse ICD implantation Total oral loading dose: 6 to 10 grams Maximum 400 mg orally per day in most circumstances Outpatient: 400 to 600 mg orally per day in divided doses with meal Lowest effective dose, ideally 200 mg or less orally once per day or in divided doses Inpatient: 400 to 1200 mg orally per day in divided doses with meals for 1 to 2 weeks Prevention of ventricular arrhythmias in patients Total loading dose: 6 to 10 grams Maximum 400 mg orally per day in most circumstances with ICDs to decrease risk of shocks Outpatient: Given as 400 to 600 mg orally per day in Lowest effective dose, ideally 200 mg or less orally per day divided doses with meals Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals until desired dose is achieved Cardiac arrest associated with VF or pulseless VT 300 mg IV or IO rapid bolus with a repeat dose of 150 mg as indicated Upon return of spontaneous circulation follow with an infusion of 1 mg per minute for 6 hours and then 0.5 mg per minute for 18 hours* Electrical (VT) storm and incessant VT in hemodynamically stable Total IV loading dose: 1050 mg If amiodarone is used chronically: Lowest effective dose, ideally 200 mg or less 150 mg IV bolus over 10 minutes, followed by continuous IV infusion at 1 mg per minute for 6 hours, patients orally per day; maximum 400 mg orally per day in most circumstances then 0.5 mg per minute for 18 hours IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 14/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Additional 150 mg boluses may be given if VT storm recurs If amiodarone will be used chronically: Following IV infusion 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams. Consider overlapping IV and oral amiodarone for 24-48 hours PAF: paroxysmal atrial fibrillation; AF: atrial fibrillation; NSR: normal sinus rhythm; IV: intravenous; SCD: sudden cardiac death; LV: left ventricular; ICD: implantable cardioverter-defibrillator; VF: ventricular fibrillation; VT: ventricular tachycardia; IO: intraosseous. When administered to critically ill patients with atrial fibrillation and rapid ventricular response, repeated 150 mg boluses can be given over 10 to 30 minutes if needed, but no more than six to eight additional boluses should be administered in any 24-hour period. Typically, patients are given 1 or 2 doses of oral amiodarone prior to discontinuation of the IV infusion. Graphic 117524 Version 5.0 https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 15/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 16/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 17/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in medical negligence matters [General pulmonary and critical care medicine]; National Board for Respiratory Care [Director]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

12/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate GRAPHICS Amiodarone dosing in adults by indication Indications Loading dose Maintenance dose Atrial arrhythmias Prevention of recurrent PAF Total loading dose: 6 to 10 grams Lowest effective dose, usually 100 to 200 mg orally once per day Pharmacologic cardioversion of PAF Outpatient: Given as 400 to 600 mg orally per day in divided doses with meals Maximum 200 mg orally per day Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals Pretreatment before elective cardioversion or Total loading dose: 6 to 10 grams orally over 2 to 6 Lowest effective dose, usually 100 to 200 mg orally catheter ablation of AF weeks once per day Given as 400 to 1200 mg Maximum 400 mg orally per orally per day in divided doses day in most circumstances Restoration and maintenance of NSR in critically ill patients with AF Total IV loading dose: 1050 mg Given as 150 mg IV bolus over 10 to 30 minutes, followed by continuous IV infusion at 1 mg per minute for 6 hours, then 0.5 mg per Ventricular rate control in critically ill patients with AF and rapid ventricular response minute for 18 hours* IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy If amiodarone will be used chronically: Following IV infusion, give 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams; consider overlapping IV and oral amiodarone for 24 to 48 hours https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 13/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Ventricular arrhythmias Primary and secondary prevention of SCD in patients with LV dysfunction who are not candidates for or refuse ICD implantation Total oral loading dose: 6 to 10 grams Maximum 400 mg orally per day in most circumstances Outpatient: 400 to 600 mg orally per day in divided doses with meal Lowest effective dose, ideally 200 mg or less orally once per day or in divided doses Inpatient: 400 to 1200 mg orally per day in divided doses with meals for 1 to 2 weeks Prevention of ventricular arrhythmias in patients Total loading dose: 6 to 10 grams Maximum 400 mg orally per day in most circumstances with ICDs to decrease risk of shocks Outpatient: Given as 400 to 600 mg orally per day in Lowest effective dose, ideally 200 mg or less orally per day divided doses with meals Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals until desired dose is achieved Cardiac arrest associated with VF or pulseless VT 300 mg IV or IO rapid bolus with a repeat dose of 150 mg as indicated Upon return of spontaneous circulation follow with an infusion of 1 mg per minute for 6 hours and then 0.5 mg per minute for 18 hours* Electrical (VT) storm and incessant VT in hemodynamically stable Total IV loading dose: 1050 mg If amiodarone is used chronically: Lowest effective dose, ideally 200 mg or less 150 mg IV bolus over 10 minutes, followed by continuous IV infusion at 1 mg per minute for 6 hours, patients orally per day; maximum 400 mg orally per day in most circumstances then 0.5 mg per minute for 18 hours IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 14/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Additional 150 mg boluses may be given if VT storm recurs If amiodarone will be used chronically: Following IV infusion 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams. Consider overlapping IV and oral amiodarone for 24-48 hours PAF: paroxysmal atrial fibrillation; AF: atrial fibrillation; NSR: normal sinus rhythm; IV: intravenous; SCD: sudden cardiac death; LV: left ventricular; ICD: implantable cardioverter-defibrillator; VF: ventricular fibrillation; VT: ventricular tachycardia; IO: intraosseous. When administered to critically ill patients with atrial fibrillation and rapid ventricular response, repeated 150 mg boluses can be given over 10 to 30 minutes if needed, but no more than six to eight additional boluses should be administered in any 24-hour period. Typically, patients are given 1 or 2 doses of oral amiodarone prior to discontinuation of the IV infusion. Graphic 117524 Version 5.0 https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 15/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 16/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 17/18 7/6/23, 3:09 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in medical negligence matters [General pulmonary and critical care medicine]; National Board for Respiratory Care [Director]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 18/18

7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation : Robert Phang, MD, FACC, FHRS, Warren J Manning, MD : Bradley P Knight, MD, FACC, Brian Olshansky, MD, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 02, 2022. INTRODUCTION Spontaneous or intended conversion of atrial fibrillation (AF) to sinus rhythm (SR) is associated with a short-term increase from the baseline risk of clinical thromboembolism. This topic will discuss management strategies that attempt to decrease this thromboembolic risk, based on the duration of the AF episode, prior anticoagulant therapy, and the patient s individualized risk of stroke (CHA DS -VASc score ( 2 table 1)). 2 The modalities used to perform cardioversion, long-term anticoagulation in patients with AF, and an overview of the management of AF are presented separately. (See "Atrial fibrillation: Cardioversion" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) EXTREMELY HIGH-RISK PATIENTS Patients with AF and certain types of valvular heart disease (rheumatic mitral stenosis or a mechanical valve), are at extremely high risk of thromboembolic complications at all times, not only at the time of cardioversion. The approach to antithrombotic therapy in such patients is discussed in other UpToDate topics. (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism' and "Antithrombotic therapy for mechanical heart valves".) https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 1/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate RATIONALE FOR ANTICOAGULATION All patients with AF, whether paroxysmal, persistent, or permanent, have an increased risk of embolization compared with those without AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) At the time of reversion to SR, whether pharmaceutical, electrical, or spontaneous, there is a transient incremental increase from the baseline risk. Most embolic events occur within 10 days of reversion to SR [1-5]. Patients undergoing cardioversion of AF of more than 48 hours duration represent a particularly high-risk group (compared with AF of less than 48 hours duration), with an embolic risk from as low as 1 to as high as 5 percent in the first month after reversion to SR in the absence of anticoagulation [2-4,6-8]. This rate is substantially higher than the rate that would be calculated for the general population of patients with AF, in whom the yearly rate is between 1.3 and 5.1 (or higher) percent, depending on age and additional comorbidities. The most common source of stroke associated with cardioversion in these patients is embolism of a thrombus from the left atrial appendage during or in the first two weeks after the procedure. Possible causes include embolism of a left atrial thrombus that was already present at the time of conversion to SR, embolism of a thrombus that formed after conversion due to depressed left atrial appendage ejection velocity postconversion, or delay in recovery of left atrial mechanical function after conversion, and thrombus formation during subsequent episodes of AF: Precardioversion left atrial thrombus. Embolization after return of synchronous atrial contraction is due to the dislodgement of left atrial thrombi present at the time of cardioversion. This is felt to be the dominant cause of postcardioversion thromboembolism and the rationale for performing transesophageal echocardiogram (TEE) prior to cardioversion. The prevalence of left atrial thrombus in nonanticoagulated patients with AF of less than 72 hours undergoing TEE is 12 and 14 percent [9,10]. This value is similar to that found among AF patients with a duration of unknown or more than two days duration [11,12]. The prevalence of left atrial appendage thrombus is increased in high-risk patients with severe left ventricular systolic dysfunction, left atrial enlargement, depressed left atrial appendage ejection velocity, or left atrial appendage spontaneous echo contrast (a marker of blood stasis). https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 2/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Postcardioversion atrial mechanical dysfunction creates a milieu that promotes new (postcardioversion) thrombus formation. The transient atrial contractile dysfunction after cardioversion is referred to as atrial "stunning" and can occur whether SR is restored spontaneously, by external or internal direct current cardioversion, or by antiarrhythmic medications. The duration of the left atrial contractile dysfunction appears to be related in part to the duration of AF prior to cardioversion. Recovery of atrial mechanical function may be delayed for several weeks [13] for those who have been in AF for a few months prior to cardioversion. In comparison, for those with AF for only a few days, left atrial mechanical recovery occurs within a day (but may still be associated with more pronounced but transient dysfunction immediately after cardioversion). (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial stunning'.) In support of the atrial stunning after cardioversion hypothesis, there have been case reports and small series of patients developing TEE evidence for de novo left atrial appendage thrombi (primarily in the setting of no anticoagulation) immediately following cardioversion, when the precardioversion TEE showed no left atrial appendage thrombus [9,14-16]. (See "Role of echocardiography in atrial fibrillation", section on 'Spontaneous echo contrast' and "Mechanisms of thrombogenesis in atrial fibrillation".) Recurrent AF is common during the first month after conversion [17]. Up to 90 percent of these episodes are asymptomatic [18], and asymptomatic episodes lasting more than 48 hours are not uncommon, occurring in 17 percent of patients in a report using continuous monitoring [17]. Anticoagulation during the four weeks postcardioversion thereby provides prophylaxis against new thrombus formation and facilitates early cardioversion without a screening TEE should recurrent AF occur. The rationale and indications for chronic anticoagulation after the period of postconversion anticoagulation are similar to those for the broad population of patients with AF and are discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) PATIENTS WITH SPONTANEOUS CONVERSION Some patients with AF have spontaneous conversion prior to planned cardioversion. The risk of thromboembolism after spontaneous conversion or electrical cardioversion is relatively low, but the risk during this time is likely higher than the ambient rate of thromboembolic events associated with AF. There is no evidence that risk of embolization in the first few weeks after https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 3/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate spontaneous conversion differs from that for patients with AF undergoing electrical or chemical cardioversion. In a study of 1041 patients who were anticoagulated prior to and after cardioversion, 16 percent experienced spontaneous conversion (prior to planned electrical cardioversion) [19]. The rate of thromboembolism was similar in patients with spontaneous conversion compared with patients who underwent electrical cardioversion (<1 percent in both groups) although this comparison is limited by the small number of events). Though of unproven efficacy, some of our contributors recommend anticoagulation for four weeks after reversion to SR (either spontaneous or via cardioversion) for patients with AF of less than 48 hours duration, even for those with a low CHA DS -VASc score ( table 1). The rationale 2 2 for this approach is concern regarding the high likelihood of AF recurrence in the first month after reversion to SR, as well as transient postcardioversion atrial stunning in the immediate pericardioversion period. This approach may be modified in patients at very high bleeding risk. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Management of long-term anticoagulation (after the initial four weeks) including the role of CHA DS -VASc score is discussed separately. (See "Atrial fibrillation in adults: Selection of 2 2 candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) URGENT CARDIOVERSION Patients with new onset AF in whom the ventricular rate is rapid may require urgent (or emergent) cardioversion to prevent adverse clinical consequences such as hemodynamic decompensation. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Symptom and hemodynamic management'.) The indications for urgent cardioversion of AF are uncommon, but in the setting of hemodynamic instability due to rapid AF that is refractory to pharmacologic support, such as in patients with Wolff-Parkinson-White syndrome, the need for restoration of SR may take precedence over the need for protection from thromboembolism. When possible, the patient should receive precardioversion anticoagulation (eg, bolus of unfractionated heparin or dose of direct oral anticoagulant [DOAC; also referred to as non-vitamin K oral anticoagulant [NOAC]) as soon as possible due to the risk of postcardioversion left atrial appendage stunning. Anticoagulation should be considered for four weeks postcardioversion, unless it is contraindicated [20] (see 'AF duration less than 48 hours' below). Management of long-term anticoagulation (after the initial four weeks) is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 4/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) AF DURATION LESS THAN 48 HOURS Anticoagulation prior to cardioversion If conversion to SR (either spontaneous or via cardioversion) occurs within 48 hours of the onset of AF, the thromboembolic risk appears to be very low [21-23]. However, many, and perhaps most, patients cannot accurately define the onset of AF. As a result, we categorize a patient as having AF of less than 48 hours duration only if we have a high level of confidence in the patient s history. Otherwise, we approach the patient as if AF has been present for more than 48 hours. (See 'AF duration uncertain or 48 or more hours' below.) For most patients in whom cardioversion will take place less than 48 hours after the onset of AF, we start a DOAC prior to cardioversion rather than no anticoagulant. Intravenous heparin is a reasonable alternative for hospitalized patients. When a DOAC is used, the specific choice of DOAC should be individualized for each patient. We generally choose the agent that will be given at the time of discharge. Of note, the approach presented here is in contrast to the historical approach of some cardiologists proceeding to early cardioversion without anticoagulation if the duration was less than 24 hours. I(See "Atrial fibrillation in adults: Use of oral anticoagulants".) We generally wait at least three hours after the first dose of a DOAC to cardiovert. For patients at very high bleeding risk, some of our experts suggest cardioversion without anticoagulation if normal SR can be restored within 48 hours of documented onset. Other experts recommend anticoagulation prior to cardioversion even in these high-bleeding-risk patients. If cardioversion needs to take place within three hours, whether for patient instability or convenience (see 'Urgent cardioversion' above), we start intravenous unfractionated heparin (bolus and continuous drip goal partial thromboplastin time 1.5 to 2.0 times control) or a low molecular weight heparin (1 mg/kg subcutaneously every 12 hours); we do not give DOAC and heparin together. However, if warfarin is the agent selected for longer term anticoagulation, warfarin is started while heparin therapy is continued until the international normalized ratio exceeds 2.0. For extremely high-risk patients (eg, those with rheumatic mitral stenosis, mechanical valves, prior thromboembolism, severe left ventricular dysfunction, heart failure, or diabetes), we anticoagulate for at least three weeks or initiate therapeutic anticoagulation (with heparin or DOAC) in combination with TEE prior to an attempt at cardioversion as described above for AF of more than 48 hours duration. (See 'AF duration uncertain or 48 or more hours' below.) https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 5/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The 48 hour cut point is based on limited evidence and is somewhat arbitrary. For example, the prevalence of left atrial thrombus on TEE is substantially lower when the duration of AF is less than 48 hours (1.4 percent) [24]. Among patients with a history of AF of less than 48 hours in duration, there is likely a range of risk based on CHA DS -VASc score ( table 1). A retrospective 2 2 study of 3143 patients with AF of less than 48 hours duration demonstrated that patients with heart failure and diabetes were at high risk for clinical thromboembolism (up to 10 percent if both risk factors were present). The absence of both risk factors and age <60 years conveyed a very low risk of 0.2 percent [23]. (See 'AF duration uncertain or 48 or more hours' below and 'Rationale for anticoagulation' above.) No randomized trial has evaluated anticoagulation compared with no anticoagulation in AF patients undergoing cardioversion with a definite duration of AF <48 hours. Observational data suggest that the risk of stroke/thromboembolism is very low (0 to 0.2 percent) in patients with a definite AF duration of <12 hours and a very low stroke risk (CHA DS -VASc 0 in men, 1 in 2 2 women), in whom the benefit of four-week anticoagulation after cardioversion is undefined. The 2020 European Society of Cardiology guidelines for the diagnosis and management of AF suggest that prescription of anticoagulants can be optional, based on an individualized approach [25]. With regard to the question as to whether to anticoagulate these patients or not, there are no studies comparing heparin with no heparin in patients with AF of less than 48 hours duration. However, data regarding the rate of clinical thromboembolization after cardioversion in patients with AF of less than 48 hours duration have raised a concern about the safety of cardioversion without anticoagulation in this population. In an observational study of 2481 such individuals (5116 successful cardioversions) who were not treated with peri- or postprocedural anticoagulant, definite thromboembolic events occurred in 38 (0.7 percent) within 30 days (median of two days); of these, 31 were strokes [23]. Four additional patients suffered a transient ischemic attack. Age greater than 60 years, female sex, heart failure, and diabetes were the strongest predictors of embolization, with nearly 10 percent of those with both heart failure and diabetes experiencing a stroke. The risk of stroke in those without heart failure and age less than 60 years was 0.2 percent. An observational study of 16,274 patients undergoing direct current cardioversion with and without oral anticoagulant therapy also demonstrated that the absence of postcardioversion anticoagulation was associated with a high risk of thromboembolism, regardless of CHA DS -VASc scores [26]. There was a greater-than-twofold 2 2 increased risk of thromboembolism in those not treated with postcardioversion anticoagulation (hazard ratio 2.21; 95% CI 0.79-6.77 and 2.40; 95% CI 1.46-3.95 with CHA DS -VASc score 0 to 1 2 2 and CHA DS -VASc score 2 or more, respectively). The rationale for lack of postcardioversion 2 2 anticoagulation could not be exactly discerned in this trial but was deemed to be multifactorial, https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 6/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate including presumed short-duration AF, perceived low thromboembolic risk, and lack of guideline adherence. With regard to the question of which anticoagulant to use, there are no studies comparing differing forms of heparin in patients with AF of short duration nor are there studies comparing a DOAC with heparin. Indirect evidence comparing the two heparins comes from a trial of 496 patients with AF of more than 48 hours duration who were randomly assigned to either low molecular weight heparin or unfractionated heparin followed by oral anticoagulation [27]. Patients were cardioverted after either 21 days of anticoagulation or after a TEE that was negative for thrombus; anticoagulation continued for 28 days after cardioversion. Low molecular weight heparin was noninferior to unfractionated heparin followed by oral anticoagulation in terms of the combined primary end point of ischemic neurologic events, major hemorrhage, or death by the end of study treatment (2.8 versus 4.8 percent). Low molecular weight heparin also has a safety and efficacy profile similar to unfractionated heparin when used as a bridge to oral anticoagulation in patients undergoing TEE-based therapy [28]. Anticoagulation after reversion to sinus rhythm Though of unproven in efficacy, some of our contributors recommend anticoagulation for four weeks after reversion to SR (either spontaneous or intended) for patients with AF of less than 48 hours duration, even for those with a low CHA DS -VASc score. The rationale for this approach is a concern regarding the high 2 2 likelihood of AF recurrence in the first month after reversion to SR, as well as transient postcardioversion atrial stunning in the immediate pericardioversion period. This decision may be modified in patients at very high bleeding risk. Some of our contributors do not anticoagulate patients with a low CHA DS -VASc score (0 in men 2 2 or 1 in women) after restoration of SR if AF was less than 48 hours duration [23,29]. Management of long-term anticoagulation (after the initial four weeks) is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) AF DURATION UNCERTAIN OR 48 OR MORE HOURS Patients with AF of more than 48 hours or of unknown duration should receive at least three weeks of therapeutic anticoagulation prior to cardioversion and four weeks of anticoagulation after cardioversion. In this setting, this treatment regimen can reduce the risk of thromboembolism during the four weeks after cardioversion from 6 percent to less than 1 percent [2-4,6,7,30-32]. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 7/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate For patients in whom there is a reason to not wait three weeks, an option for management is precardioversion therapeutic anticoagulation in conjunction with a screening TEE to guide early cardioversion. This strategy can be used for patients in whom cardioversion needs to be performed before at least three weeks of therapeutic anticoagulation have been completed [12]. While the TEE approach shortens the precardioversion duration of anticoagulation, it does not change our recommendation for four weeks of anticoagulation after cardioversion or the need to be therapeutically anticoagulated at the time of the cardioversion due to the risk associated with postcardioversion atrial appendage stunning. (See 'Transesophageal echocardiography- based approach' below.) Prospective studies have shown that the risk of clinical stroke or systemic embolism ranges from 0 to 0.9 percent if preceded by at least three weeks of therapeutic anticoagulation with warfarin (target international normalized ratio [INR] 2.0 to 3.0) or one of the DOACs [2-4,12], or shorter- term anticoagulation with TEE-guided approach discussed directly above. Retrospective data demonstrated that the thromboembolism risk is 4 to 7 percent in nonanticoagulated patients [7,8,33]. Anticoagulant approach Since many patients will require long-term anticoagulation, we prefer the DOACs to warfarin before and after cardioversion (see "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'). While there has been longer experience with use of warfarin than DOACs prior to cardioversion, we believe there is sufficient evidence that DOACs are as effective and as safe as warfarin in this setting. Advantages of DOAC therapy include convenience (no INR testing required) and the possibility of a shorter duration of precardioversion anticoagulation in reliably adherent patients, since it often takes five or more weeks for a patient to have at least three continuous weeks of therapeutic anticoagulation with warfarin (INR 2.0 to 3.0). In patients in whom adherence to DOAC therapy is questionable, with possible missed doses leading up to the cardioversion, we often obtain precardioversion TEE to exclude an atrial (appendage) thrombus. Routine precardioversion TEE is not recommended for patients who have been therapeutically anticoagulated (INR 2.0 or greater) with warfarin for three weeks or who have been compliant with their daily DOAC. (See 'Transesophageal echocardiography-based approach' below.) Compliance with warfarin can be ascertained with INR monitoring. For patients started on warfarin, the target INR should be 2.5 (range 2.0 to 3.0), and cardioversion should not take place until an INR of 2.0 or greater has been documented for at least three consecutive weeks ( figure 1 and figure 2) [34,35]. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 8/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The following data are available for the DOACs: Dabigatran In a post-hoc analysis of the RE-LY trial, which compared dabigatran with warfarin, in which there were 1983 cardioversions in 1270 participants, there was no significant difference in the rate of thromboembolism and stroke within 30 days between those who received at least three weeks of dabigatran 110 or 150 mg twice daily or warfarin (0.8, 0.3, and 0.6 percent, respectively) [2]. Apixaban In a post-hoc analysis of the ARISTOTLE trial, which compared apixaban with warfarin, 743 cardioversions were performed in 540 patients. No strokes or systemic embolism occurred during the 30-day follow-up period of both warfarin and apixaban groups [3]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Rivaroxaban In the X-VeRT study, 1504 patients with AF of unknown or longer than 48 hours duration were randomly assigned in a 2:1 manner to cardioversion after at least three weeks of rivaroxaban or a vitamin K antagonist. There was no significant difference in the rate of the primary efficacy outcome (a composite of stroke, transient ischemic attack, peripheral embolism, myocardial infarction, and cardiovascular death) or the safety outcome of major bleeding (0.51 versus 1.02 percent and 0.6 percent versus 0.8 percent, respectively) [4]. Similarly, in a post-hoc analysis of the ROCKET-AF trial, which compared rivaroxaban with warfarin, 143 patients underwent 181 electric cardioversions, 142 patients underwent 194 pharmacologic cardioversions, and 79 patients underwent 85 catheter ablations. There was no significant difference in the long-term rate of stroke or systemic embolism (hazard ratio 1.38; 95% CI 0.61-3.11) [36]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Edoxaban In the ENSURE-AF trial, 2199 patients were randomly assigned to receive edoxaban or enoxaparin and warfarin with discontinuation of enoxaparin when the INR was >2.0 [5]. There was no significant difference in the primary efficacy end point (0.5 percent in the edoxaban group versus 1 percent in the enoxaparin warfarin group; odds ratio [OR] 0.46, 95% CI 0.12-1.43). The primary safety end point occurred in 1.6 percent of the edoxaban group versus 1.1 percent in the enoxaparin warfarin group (OR 1.48, 95% CI 0.64-3.55). The results were independent of the TEE-guided strategy and anticoagulation status. Therapeutic anticoagulation prior to cardioversion appears to be effective largely due to thrombus resolution, rather than organization and adherence of left atrial thrombi [37,38]. (See https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 9/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 'Rationale for anticoagulation' above.) Transesophageal echocardiography-based approach We suggest a TEE-based approach ( table 2A-B) for symptomatic patients and for patients for whom there is a concern about a three-week (or more) delay to cardioversion. Such a concern might arise from a preference to not have ongoing symptoms of AF or a possible lower likelihood of successful cardioversion with a longer period of AF. Other individuals for whom this strategy may be reasonable include those at high bleeding risk, as the TEE-guided approach shortens the total precardioversion anticoagulation time for those without thrombus; and those at highest risk for a cardioversion- related thromboembolic event, including prior thromboembolism and elderly women with diabetes and heart failure. Patients who require hospitalization are also candidates for this approach [39,40]. This recommendation for a focused use of the TEE-based approach is based on our concerns about cost, the small potential for complications, and the possibility of worse outcomes. We also recommend precardioversion TEE for all patients with a percutaneous left atrial appendage occlusion device in place (eg, Watchman, Lariat, Amulet,) or who have undergone surgical LAA exclusion (eg, by stapling, suture or approved device closure). Following LAA occlusion, adjacent thrombus may occur (with or without incomplete closure) with associated risk of thromboembolism. Limited data are available to guide the anticoagulation strategy in this setting [41]. (See "Atrial fibrillation: Left atrial appendage occlusion".) In a TEE-based approach, the imaging study is performed after therapeutic anticoagulation (of short duration) and prior to anticipated cardioversion. Patients without evidence of left and right atrial (specifically the left atrial appendage, which is the site for the vast majority of thrombi) thrombus proceed to cardioversion. If thrombus is found (or cannot be confidently excluded) on TEE, cardioversion should not be performed, and therapeutic anticoagulation should be continued for at least four weeks after which time we recommend that a TEE be repeated (to screen for residual thrombus, which would be a contraindication to cardioversion) if cardioversion is desired. The TEE approach should include the following sequential steps before cardioversion: For inpatients, the options include using heparin plus warfarin or using an DOAC. With the former, we administer either low molecular weight or unfractionated heparin (bolus and continuous drip with a goal partial thromboplastin time 1.5 to 2 times control) and simultaneously initiate oral warfarin (target INR 2.0 to 3.0). With the latter, we give at least two doses of a DOAC. As the pharmacokinetics of the DOACs are different than warfarin, https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 10/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate the combination of a heparin plus DOAC may lead to supratherapeutic anticoagulation. We do not recommend overlap of or combined use of heparin and a DOAC. For most outpatients, we prefer DOAC to warfarin. There are multiple factors that determine whether a DOAC or warfarin would be used, including cost and patient preference, but DOACs have the advantage of faster onset of action and ease of dosing. A strategy of at least two days of DOAC prior to TEE-guided cardioversion can be used. As an alternative, oral warfarin can be started five days before TEE with the target INR 2.0 to 3.0 [12]. A minimal precardioversion INR of 2.0 is acceptable, though 2.5 may be preferred. Obtain a TEE to assess for the presence of atrial thrombi. The use of an endocardial border definition echo contrast agent may help in cases where there is uncertainty about the presence or absence of thrombus [42]. If no thrombus is seen, proceed with cardioversion. Continue therapeutic anticoagulation from the time of TEE through cardioversion and extend for another four weeks. If a thrombus is seen on TEE, the patient should receive a minimum of four weeks of therapeutic anticoagulation and a repeat TEE to document thrombus resolution if cardioversion is desired [37]. If no cardioversion is desired, a follow-up TEE is not needed, as the patient should receive lifelong antithrombotic therapy. If thrombus is absent on repeat TEE, cardioversion may be performed. If thrombus is still evident, the rhythm control strategy may be changed to a rate control strategy, especially when AF-related symptoms are controlled, since there is a high risk of thromboembolism if cardioversion is performed. However, the evidence supporting this latter recommendation of avoidance of cardioversion with a residual thrombus is minimal. It is best to be conservative with at least three weeks of precardioversion oral anticoagulant if an atrial thrombus cannot be confidently excluded on TEE. Continuous oral anticoagulation (warfarin INR 2.0 to 3.0 or full-dose DOAC) for at least four weeks after cardioversion in all eligible patients, regardless of the cardioversion method, CHA DS -VASc score, or apparent maintenance of SR. In patients who have not achieved 2 2 therapeutic anticoagulation with warfarin at the time of cardioversion, unfractionated or low molecular weight heparin should be continued until the INR is therapeutic. Observational studies have suggested that patients with AF of more than 48 hours duration can be acutely anticoagulated with heparin/oral anticoagulant and proceed directly to cardioversion without prolonged anticoagulation if no atrial thrombus is seen on precardioversion TEE ( table 2A-B) [11,43-45]. The ACUTE trial compared a TEE-guided strategy with a conventional https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 11/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate strategy (including therapeutic warfarin [INR 2.0 to 3.0] anticoagulation for at least three weeks prior to electrical cardioversion) in 1222 patients with AF of more than two days duration (median duration 13 days) who were undergoing electrical cardioversion [12,46]. Patients assigned to the TEE-guided strategy were anticoagulated with heparin before TEE if they were inpatients or with oral warfarin for five days (target INR 2.0 to 3.0) before TEE if they were outpatients. TEE was then followed by cardioversion if no atrial thrombi were identified. With both approaches, warfarin therapy was continued for four weeks after cardioversion. If the initial TEE demonstrated thrombus (which was present in 12 percent), cardioversion was postponed and patients received therapeutic (INR 2.0 to 3.0) anticoagulation for three weeks, at which time a repeat TEE was performed. Patients assigned to conventional strategy received three weeks of therapeutic anticoagulation before cardioversion. The following findings were noted: Within the eight weeks after study enrollment, there was no significant difference between the TEE and conventional groups in the incidence of ischemic stroke (0.6 versus 0.3 percent, respectively; relative risk [RR] 1.95, 95% CI 0.36-10.60) or all embolic events, including stroke, transient ischemic attack, and peripheral embolism (0.8 versus 0.5 percent, respectively; RR 1.62, 95% CI 0.39-6.76). One important difference is that the majority of thromboembolic events in the TEE arm occurred in patients who had reverted back to AF and/or had a subtherapeutic INR at the time of the event, while the thromboembolic events in the warfarin arm occurred in patients with SR with a therapeutic INR. There were significantly fewer hemorrhagic events with the TEE strategy (2.9 versus 5.5 percent), but no significant difference in the incidence of major bleeding (0.8 versus 1.5 percent) [12,47]; in addition, there was no significant difference in all-cause mortality (2.4 versus 1 percent) or cardiac deaths (1.3 versus 0.7). The TEE strategy led to a shorter mean time to cardioversion (3 versus 31 days) and a greater incidence of successful restoration of SR (71 versus 65 percent). Thromboembolism has been reported after a negative precardioversion TEE in some patients who were not therapeutically anticoagulated at the time of TEE and continuing for one month after cardioversion [9,14,15]. These adverse events may be related to the limited sensitivity of TEE for small thrombi, or to new thrombus formation that has been reported during the period between TEE and cardioversion or after cardioversion [9,14,15]. Thus, we recommend therapeutic anticoagulation for all patients undergoing a TEE-based approach to cardioversion. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 12/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The development of impaired left atrial mechanical function and of new thrombi after cardioversion provides the rationale for four weeks of therapeutic anticoagulation after cardioversion (INR 2.0 to 3.0 or daily DOAC), even when the precardioversion TEE shows no thrombus [15,16]. There is suggestive evidence that such an approach reduces the incidence of embolic events [16]. (See 'Rationale for anticoagulation' above.) Although the results of the ACUTE study discussed above raise concerns about possible worse outcomes in patients treated with this strategy [39], some experts have suggested that the TEE strategy is a reasonable alternative to a conventional approach in some patients, such as those with a strong preference for early cardioversion, those with AF of less than three to four weeks duration who would benefit most from left atrial mechanical recovery, and those at increased risk of hemorrhagic complications (as the duration of precardioversion anticoagulation may be shortened). Another potential reason to consider this strategy is that a shorter period of AF may increase the likelihood of successful cardioversion and long-term maintenance of SR. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) RECOMMENDATIONS OF OTHERS Our recommendations are in broad agreement with those from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the European Heart Rhythm Association [20,25,48,49]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 13/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Conversion of atrial fibrillation (AF) to sinus rhythm (SR), either spontaneously or intended, is associated with a clinically important transient increase in the risk of thromboembolism, particularly stroke. This risk increases significantly after 48 hours of AF and can be lowered by therapeutic anticoagulation before cardioversion. (See 'Rationale for anticoagulation' above.)

cardioversion with a residual thrombus is minimal. It is best to be conservative with at least three weeks of precardioversion oral anticoagulant if an atrial thrombus cannot be confidently excluded on TEE. Continuous oral anticoagulation (warfarin INR 2.0 to 3.0 or full-dose DOAC) for at least four weeks after cardioversion in all eligible patients, regardless of the cardioversion method, CHA DS -VASc score, or apparent maintenance of SR. In patients who have not achieved 2 2 therapeutic anticoagulation with warfarin at the time of cardioversion, unfractionated or low molecular weight heparin should be continued until the INR is therapeutic. Observational studies have suggested that patients with AF of more than 48 hours duration can be acutely anticoagulated with heparin/oral anticoagulant and proceed directly to cardioversion without prolonged anticoagulation if no atrial thrombus is seen on precardioversion TEE ( table 2A-B) [11,43-45]. The ACUTE trial compared a TEE-guided strategy with a conventional https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 11/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate strategy (including therapeutic warfarin [INR 2.0 to 3.0] anticoagulation for at least three weeks prior to electrical cardioversion) in 1222 patients with AF of more than two days duration (median duration 13 days) who were undergoing electrical cardioversion [12,46]. Patients assigned to the TEE-guided strategy were anticoagulated with heparin before TEE if they were inpatients or with oral warfarin for five days (target INR 2.0 to 3.0) before TEE if they were outpatients. TEE was then followed by cardioversion if no atrial thrombi were identified. With both approaches, warfarin therapy was continued for four weeks after cardioversion. If the initial TEE demonstrated thrombus (which was present in 12 percent), cardioversion was postponed and patients received therapeutic (INR 2.0 to 3.0) anticoagulation for three weeks, at which time a repeat TEE was performed. Patients assigned to conventional strategy received three weeks of therapeutic anticoagulation before cardioversion. The following findings were noted: Within the eight weeks after study enrollment, there was no significant difference between the TEE and conventional groups in the incidence of ischemic stroke (0.6 versus 0.3 percent, respectively; relative risk [RR] 1.95, 95% CI 0.36-10.60) or all embolic events, including stroke, transient ischemic attack, and peripheral embolism (0.8 versus 0.5 percent, respectively; RR 1.62, 95% CI 0.39-6.76). One important difference is that the majority of thromboembolic events in the TEE arm occurred in patients who had reverted back to AF and/or had a subtherapeutic INR at the time of the event, while the thromboembolic events in the warfarin arm occurred in patients with SR with a therapeutic INR. There were significantly fewer hemorrhagic events with the TEE strategy (2.9 versus 5.5 percent), but no significant difference in the incidence of major bleeding (0.8 versus 1.5 percent) [12,47]; in addition, there was no significant difference in all-cause mortality (2.4 versus 1 percent) or cardiac deaths (1.3 versus 0.7). The TEE strategy led to a shorter mean time to cardioversion (3 versus 31 days) and a greater incidence of successful restoration of SR (71 versus 65 percent). Thromboembolism has been reported after a negative precardioversion TEE in some patients who were not therapeutically anticoagulated at the time of TEE and continuing for one month after cardioversion [9,14,15]. These adverse events may be related to the limited sensitivity of TEE for small thrombi, or to new thrombus formation that has been reported during the period between TEE and cardioversion or after cardioversion [9,14,15]. Thus, we recommend therapeutic anticoagulation for all patients undergoing a TEE-based approach to cardioversion. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 12/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The development of impaired left atrial mechanical function and of new thrombi after cardioversion provides the rationale for four weeks of therapeutic anticoagulation after cardioversion (INR 2.0 to 3.0 or daily DOAC), even when the precardioversion TEE shows no thrombus [15,16]. There is suggestive evidence that such an approach reduces the incidence of embolic events [16]. (See 'Rationale for anticoagulation' above.) Although the results of the ACUTE study discussed above raise concerns about possible worse outcomes in patients treated with this strategy [39], some experts have suggested that the TEE strategy is a reasonable alternative to a conventional approach in some patients, such as those with a strong preference for early cardioversion, those with AF of less than three to four weeks duration who would benefit most from left atrial mechanical recovery, and those at increased risk of hemorrhagic complications (as the duration of precardioversion anticoagulation may be shortened). Another potential reason to consider this strategy is that a shorter period of AF may increase the likelihood of successful cardioversion and long-term maintenance of SR. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) RECOMMENDATIONS OF OTHERS Our recommendations are in broad agreement with those from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the European Heart Rhythm Association [20,25,48,49]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 13/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Conversion of atrial fibrillation (AF) to sinus rhythm (SR), either spontaneously or intended, is associated with a clinically important transient increase in the risk of thromboembolism, particularly stroke. This risk increases significantly after 48 hours of AF and can be lowered by therapeutic anticoagulation before cardioversion. (See 'Rationale for anticoagulation' above.) The following recommendations apply to patients with AF of clearly less than 48 hours duration (See 'AF duration less than 48 hours' above.): For patients one or more high risk factors for thromboembolism (eg, prior thromboembolism, heart failure, or diabetes mellitus), we suggest deferral of cardioversion to allow for three weeks of effective therapeutic precardioversion anticoagulation rather than early cardioversion (Grade 2C). Anticoagulation with heparin or a direct-acting oral anticoagulant (DOAC) before, during, and after cardioversion along with precardioversion transesophageal echocardiography (TEE) is an alternative approach for these high-risk patients. For patients not at high risk of thromboembolism (listed in the above bulleted recommendation), we anticoagulate most patients with a CHA DS -VASc score 1 2 2 (Grade 2C). We start either DOAC or a combination of heparin and warfarin prior to cardioversion. For patients with low risk of thromboembolism (CHA DS -VASc score 0 in men, 1 in 2 2 women), our experts have differing approaches regarding postcardioversion anticoagulation, with some using four weeks of postcardioversion warfarin or DOAC anticoagulation and others not. The following recommendations apply to patients with AF of more than 48 hours duration or when the duration is unknown (see 'AF duration uncertain or 48 or more https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 14/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate hours' above): We recommend a minimum of three consecutive weeks of therapeutic anticoagulation (warfarin with an international normalized ratio [INR] greater than 2.0 or DOAC) prior to cardioversion, rather than proceeding directly to cardioversion (Grade 1B). We recommend a DOAC prior to elective cardioversion rather than warfarin irrespective of whether the anticoagulant will be given long term (Grade 1B). (See 'Anticoagulant approach' above.) For symptomatic patients in whom there is a strong preference to not delay cardioversion, or in whom there is a concern about bleeding with prolonged oral anticoagulation, or who are not likely to tolerate AF despite adequate rate slowing, a TEE strategy is a reasonable approach using therapeutic anticoagulation with heparin/warfarin or DOAC throughout the pericardioversion period. (See 'Transesophageal echocardiography-based approach' above.) We recommend therapeutic oral anticoagulation (with a DOAC or warfarin with target INR of 2.0 to 3.0) for four weeks after cardioversion in all patients, rather than discontinuing anticoagulation after cardioversion (Grade 1B). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Berger M, Schweitzer P. Timing of thromboembolic events after electrical cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol 1998; 82:1545. 2. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011; 123:131. 3. Flaker G, Lopes RD, Al-Khatib SM, et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 2014; 63:1082. 4. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014; 35:3346. 5. Goette A, Merino JL, Ezekowitz MD, et al. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 15/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 3b trial. Lancet 2016; 388:1995. 6. Kinch JW, Davidoff R. Prevention of embolic events after cardioversion of atrial fibrillation. Current and evolving strategies. Arch Intern Med 1995; 155:1353. 7. Gentile F, Elhendy A, Khandheria BK, et al. Safety of electrical cardioversion in patients with atrial fibrillation. Mayo Clin Proc 2002; 77:897. 8. Arnold AZ, Mick MJ, Mazurek RP, et al. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992; 19:851. 9. Stoddard MF, Dawkins PR, Prince CR, Longaker RA. Transesophageal echocardiographic guidance of cardioversion in patients with atrial fibrillation. Am Heart J 1995; 129:1204. 10. Stoddard MF, Dawkins PR, Prince CR, Ammash NM. Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study. J Am Coll Cardiol 1995; 25:452. 11. Weigner MJ, Thomas LR, Patel U, et al. Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year. Am J Med 2001; 110:694. 12. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344:1411. 13. Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol 1989; 13:617. 14. Black IW, Hopkins AP, Lee LC, Walsh WF. Evaluation of transesophageal echocardiography before cardioversion of atrial fibrillation and flutter in nonanticoagulated patients. Am Heart J 1993; 126:375. 15. Black IW, Fatkin D, Sagar KB, et al. Exclusion of atrial thrombus by transesophageal echocardiography does not preclude embolism after cardioversion of atrial fibrillation. A multicenter study. Circulation 1994; 89:2509. 16. Moreyra E, Finkelhor RS, Cebul RD. Limitations of transesophageal echocardiography in the risk assessment of patients before nonanticoagulated cardioversion from atrial fibrillation and flutter: an analysis of pooled trials. Am Heart J 1995; 129:71. 17. Israel CW, Gr nefeld G, Ehrlich JR, et al. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient care. J Am Coll Cardiol 2004; 43:47. 18. Page RL, Wilkinson WE, Clair WK, et al. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 16/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Circulation 1994; 89:224. 19. Tejan-Sie SA, Murray RD, Black IW, et al. Spontaneous conversion of patients with atrial fibrillation scheduled for electrical cardioversion: an ACUTE trial ancillary study. J Am Coll Cardiol 2003; 42:1638. 20. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 21. Gallagher MM, Hennessy BJ, Edvardsson N, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol 2002; 40:926. 22. Weigner MJ, Caulfield TA, Danias PG, et al. Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours. Ann Intern Med 1997; 126:615. 23. Airaksinen KE, Gr nberg T, Nuotio I, et al. Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study. J Am Coll Cardiol 2013; 62:1187. 24. Kleemann T, Becker T, Strauss M, et al. Prevalence of left atrial thrombus and dense spontaneous echo contrast in patients with short-term atrial fibrillation < 48 hours undergoing cardioversion: value of transesophageal echocardiography to guide cardioversion. J Am Soc Echocardiogr 2009; 22:1403. 25. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 26. Hansen ML, Jepsen RM, Olesen JB, et al. Thromboembolic risk in 16 274 atrial fibrillation patients undergoing direct current cardioversion with and without oral anticoagulant therapy. Europace 2015; 17:18. 27. Stellbrink C, Nixdorff U, Hofmann T, et al. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004; 109:997. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 17/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 28. Klein AL, Jasper SE, Katz WE, et al. The use of enoxaparin compared with unfractionated heparin for short-term antithrombotic therapy in atrial fibrillation patients undergoing transoesophageal echocardiography-guided cardioversion: assessment of Cardioversion Using Transoesophageal Echocardiography (ACUTE) II randomized multicentre study. Eur Heart J 2006; 27:2858. 29. Garg A, Khunger M, Seicean S, et al. Incidence of Thromboembolic Complications Within 30 Days of Electrical Cardioversion Performed Within 48 Hours of Atrial Fibrillation Onset. JACC Clin Electrophysiol 2016; 2:487. 30. Pritchett EL. Management of atrial fibrillation. N Engl J Med 1992; 326:1264. 31. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139. 32. Botkin SB, Dhanekula LS, Olshansky B. Outpatient cardioversion of atrial arrhythmias: efficacy, safety, and costs. Am Heart J 2003; 145:233. 33. Weinberg DM, Mancini J. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:745. 34. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333:5. 35. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019. 36. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013; 61:1998. 37. Collins LJ, Silverman DI, Douglas PS, Manning WJ. Cardioversion of nonrheumatic atrial fibrillation. Reduced thromboembolic complications with 4 weeks of precardioversion anticoagulation are related to atrial thrombus resolution. Circulation 1995; 92:160. 38. Jaber WA, Prior DL, Thamilarasan M, et al. Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: A transesophageal echocardiographic study. Am Heart J 2000; 140:150. 39. Silverman DI, Manning WJ. Strategies for cardioversion of atrial fibrillation time for a change? N Engl J Med 2001; 344:1468. 40. Seto TB, Taira DA, Tsevat J, Manning WJ. Cost-effectiveness of transesophageal echocardiographic-guided cardioversion: a decision analytic model for patients admitted to the hospital with atrial fibrillation. J Am Coll Cardiol 1997; 29:122. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 18/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 41. Sharma SP, Turagam MK, Gopinathannair R, et al. Direct Current Cardioversion of Atrial Fibrillation in Patients With Left Atrial Appendage Occlusion Devices. J Am Coll Cardiol 2019; 74:2267. 42. Jung PH, Mueller M, Schuhmann C, et al. Contrast enhanced transesophageal echocardiography in patients with atrial fibrillation referred to electrical cardioversion improves atrial thrombus detection and may reduce associated thromboembolic events. Cardiovasc Ultrasound 2013; 11:1. 43. Klein AL, Murray RD, Grimm RA. Role of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation. J Am Coll Cardiol 2001; 37:691. 44. Manning WJ, Silverman DI, Gordon SP, et al. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328:750. 45. Manning WJ, Silverman DI, Keighley CS, et al. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol 1995; 25:1354. 46. Klein AL, Grimm RA, Jasper SE, et al. Efficacy of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation at 6 months: a randomized controlled trial. Am Heart J 2006; 151:380. 47. Klein AL, Murray RD, Grimm RA, et al. Bleeding complications in patients with atrial fibrillation undergoing cardioversion randomized to transesophageal echocardiographically guided and conventional anticoagulation therapies. Am J Cardiol 2003; 92:161. 48. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 49. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non- valvular atrial fibrillation: Executive summary. Eur Heart J 2016. Topic 906 Version 62.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 19/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate GRAPHICS Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) 2 2 CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients (n = 73,538) Stroke and thromboembolism event 2 2 rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 20/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 5 8942 15.26 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 21/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Optimal INR to minimize both bleeding and thromboembo lism in patients with atrial fibrillation (A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. (B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 22/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE: thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval. Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient characteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright 2009 Lippincott Williams & Wilkins. Graphic 65373 Version 13.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 23/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation. Reproduced with permission from: Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial brillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2011; 123:e269. Copyright 2011 Lippincott Williams & Wilkins. Graphic 87025 Version 4.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 24/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Advantages and disadvantages of the conventional approach to cardioversion (one month of pretreatment with warfarin) in patients with atrial fibrillation Advantages Disadvantages Use of warfarin for one month before Delaying cardioversion to normal sinus rhythm for one cardioversion may lower the stroke rate month potentially decreases functional capacity. from 5.6 percent to a very low stroke rate of <2 percent. Relatively easy to administer with regular Prolonging treatment for seven to eight weeks one monitoring of INRs. month prior to and one month after cardioversion increases the risk of bleeding complications. Suitable for community hospitals. Not followed by routine clinical practice, especially in the elderly. The conventional approach has withstood the "test of time" since the 1960s. Patients who are at the highest risk for developing systemic embolization who should receive more prolonged or intensive anticoagulation are not routinely identified. Reprinted with permission from the American College of Cardiology. J Am Coll Cardiol 2001; 37:691. https://www.journals.elsevier.com/journal-of-the-american-college-of-cardiology. Graphic 72971 Version 6.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 25/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Advantages and disadvantages of the transesophageal echocardiography- guided approach to cardioversion of patients with atrial fibrillation undergoing cardioversion Advantages Disadvantages Transesophageal echocardiography (TEE) should be able to detect left atrial appendage thrombi, TEE is performed without any definitive guidelines about who should receive the which increase the risk of embolic stroke after procedure (high versus low risk) electrical cardioversion, thus sparing patients with thrombi from undergoing cardioversion In the majority of patients without left atrial Residual thrombus on repeat TEE may diminish appendage thrombi, earlier cardioversion may shorten the period of anticoagulation and lower the cost-effectiveness of the TEE-guided approach the corresponding risk of bleeding complications A TEE-guided approach may prove more cost- effective owing to the reduction in laboratory Transesophageal echocardiography requires a level III-trained physician and availability of monitoring costs and the reduction in bleeding complications expensive echocardiographic machines Earlier cardioversion is believed to increase the Transesophageal echocardiography may miss likelihood of a successful return to and thrombi that may embolize after cardioversion. In maintenance of sinus rhythm contrast, TEE may render false positive results by erroneously identifying spontaneous echocardiographic contrast, sludge, multilobed appendages or pectinate muscles as thrombus. Reprinted with permission from: The American College of Cardiology. J Am Coll of Cardiol 2001; 37:691-704. https://www.journals.elsevier.com/journal-of-the-american-college-of-cardiology. Graphic 54077 Version 6.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 26/27 7/6/23, 3:09 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Contributor Disclosures Robert Phang, MD, FACC, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 27/27

7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF : Joseph E Marine, MD, FACC, FHRS, Andrea M Russo, MD, FACC, FHRS : Samuel L vy, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 12, 2021. INTRODUCTION Life-threatening ventricular arrhythmias, including sustained ventricular tachycardia (VT) and ventricular fibrillation (VF), are common in patients with systolic heart failure (HF) and dilated cardiomyopathy and may lead to sudden cardiac death (SCD). Primary prevention of SCD refers to medical or interventional therapy undertaken to prevent SCD in patients who have not experienced symptomatic life-threatening sustained VT/VF or sudden cardiac arrest (SCA) but who are felt to be at an increased risk for such an event. The primary prevention of SCD in patients with HF and cardiomyopathy with reduced ejection fraction, either due to coronary heart disease or a dilated nonischemic etiology, will be reviewed here with emphasis on the role of implantable cardioverter-defibrillators (ICDs). The different types of ventricular arrhythmias, the effects of HF therapy on ventricular arrhythmias, the role of electrophysiologic testing, and the secondary prevention of SCD are discussed separately. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) The approaches to the treatment of ventricular arrhythmias related to specific heart muscle diseases or primary electrical system diseases such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, isolated left ventricular noncompaction, Chagas disease, Brugada syndrome, long QT syndrome, and other channelopathies are discussed elsewhere. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 1/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Recommendations for ICD therapy'.) (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis".) (See "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis".) (See "Chronic Chagas cardiomyopathy: Management and prognosis".) (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) (See "Congenital long QT syndrome: Treatment".) CAUSES OF DEATH IN HEART FAILURE Causes of death in patients with heart failure include: Progressive pump failure. Unexpected SCD (usually from a ventricular tachyarrhythmia, but asystole and pulseless electrical activity [PEA] are also seen less frequently). SCD in the setting of worsening heart failure. The mode of death in patients with HF is more likely to be "sudden" in patients with class II or III HF, while the mode of death is more likely to be related to "pump" failure in patients with class IV HF ( figure 1) [1]. Therefore, primary prevention implantable cardioverter-defibrillator (ICD) trials (in the absence of cardiac resynchronization therapy [CRT]) have excluded patients with NYHA class IV HF. In fact, the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) Guidelines state that "ICD therapy is not indicated for NYHA Class IV patients with medication-refractory HF who are not also candidates for cardiac transplantation, an LVAD (left ventricular assist device), or CRT-D," listing this as a class III indication [2]. (See 'Class IV heart failure' below and "Heart transplantation in adults: Indications and contraindications" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) RISK STRATIFICATION STRATEGIES While implantable cardioverter-defibrillators (ICDs) are highly efficacious in the treatment of ventricular tachyarrhythmias and prevention of SCD, they are costly, require ongoing follow-up, and have numerous risks at the time of implantation (eg, bleeding, pneumothorax, perforation, etc) as well as over the lifetime of the device (eg, infection, device and lead malfunction, etc). In https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 2/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate addition, only a subset of patients with cardiomyopathy develop sustained ventricular tachyarrhythmias or SCD. As such, the risk stratification of patients prior to ICD therapy is important for providing therapy to patients at highest risk of SCD and minimizing the number of ICD implantations in patients who are unlikely to benefit. Numerous patient-related clinical markers as well as data derived from testing have been associated with increased risk of sudden death, and a variety of attempts have been made to develop risk stratification schema to more specifically identify an individual patient's risk of SCD. To date, however, the optimal approach to SCD risk stratification for placement of a primary prevention ICD continues to rely primarily upon the following: Etiology of left ventricular dysfunction Left ventricular ejection fraction Heart failure symptom classification Life expectancy greater than one year Inducible sustained ventricular tachycardia Nonsustained ventricular tachycardia on electrocardiogram (ECG) monitoring LVEF and risk Patients with significant reductions in left ventricular ejection fraction (LVEF) appear to be at greatest risk, and derive the greatest benefit, from primary prevention ICD implantation. (See 'Trials of primary prevention ICDs in ischemic cardiomyopathy' below and 'Trials of primary prevention ICDs in nonischemic dilated cardiomyopathy' below.) Though most studies of prophylactic ICD implantation have included patients with an LVEF 35 percent, the large majority of patients included in most trials have had ejection fractions under 30 percent, resulting in some uncertainty regarding the potential benefit of prophylactic ICD insertion for patients with LVEF between 30 and 35 percent. This issue was addressed in a retrospective cohort study using registry data from the NCDR ICD registry of patients who underwent ICD implantation in 2006 or 2007 (median follow-up 4.4 years) and Get With The Guidelines-Heart Failure (GWTG-HF) patients without an ICD (enrolled between 2005 and 2009 with median follow-up of 2.9 years), in which the benefits of ICD implantation were separately evaluated among patients with LVEF <30 percent and those with LVEF 30 to 35 percent [3]. All- cause mortality was significantly lower in patients with an ICD and any level of LVEF, compared with those without an ICD: LVEF 30 to 35 percent hazard ratio (HR) 0.83, 95% CI 0.69-0.99 LVEF <30 percent HR 0.72, 95% CI 0.65-0.81 While this study is nonrandomized, the data suggest that patients with LVEF between 30 and 35 percent do appear to benefit from prophylactic ICD insertion. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 3/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate SCD risk prediction post-MI A number of clinical features have been evaluated as a means for identifying patients at the greatest risk of SCD following an acute myocardial infarction (MI). These include: Left ventricular (LV) dysfunction or reduced LVEF HF symptoms and the degree of heart failure LV aneurysm Q-waves on the surface ECG Intraventricular conduction delay Spontaneous ventricular premature beats (VPBs) and nonsustained ventricular tachycardia (NSVT) Late potentials on a signal-averaged ECG (SAECG) VT induced by electrophysiologic study (EPS) Reduced heart rate variability (HRV) Microvolt T-wave (repolarization) alternans (TWA) A detailed discussion of the utility of these clinical predictors is presented separately. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) Clinical risk markers A variety of novel risk stratification schemes derived from retrospective studies have shown the ability to predict SCD risk, but none have been prospectively validated in independent populations or have become part of the routine practice for primary prevention ICD placement [4-13]. Therefore, traditional risk stratification based on etiology of cardiomyopathy, LVEF, HF class, and select other risk markers (eg, inducible sustained ventricular arrhythmias) continues to form the basis for recommendations regarding ICD use. Initial studies evaluating the role of ICD therapy in reducing mortality focused on patients with reduced LV systolic function and class II-III heart failure. As the mode of death in patients with class II-III heart failure was more likely sudden (in 59 to 64 percent of cases [1]), and enrollment criteria for ICD trials often included patients with class II-III HF symptoms. In contrast, patients with class IV heart failure were more likely to die from heart failure (56 percent) than from sudden death (33 percent). Studies examining the relationship between one-year mortality and LV function after MI in the pre- and post-thrombolytic era demonstrated a much higher cardiac mortality rate in patients with LVEF <40 percent [14,15]. The presence of NSVT or frequent ventricular ectopy was also associated with increased mortality post-MI, so NSVT was also used as a risk factor for inclusion in some of the randomized ICD trials. Earlier studies also demonstrated that inducible sustained monomorphic VT was associated with an increased risk of sudden death or sustained ventricular arrhythmias [16]. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 4/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Myocardial fibrosis on CMR The presence of myocardial fibrosis, identified by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging appears to be a robust predictor of ventricular arrhythmias or SCD across a wide spectrum of patients with non- ischemic cardiomyopathy, including those with a mean LVEF >35 percent. A 2017 systematic review and meta-analysis, which included 2948 patients from 29 observational studies, assessed the relationship between LGE and ventricular arrhythmias in patients with non-ischemic dilated cardiomyopathy [17]. Over a mean follow-up of three years, the primary endpoint (sustained ventricular arrhythmia, appropriate ICD intervention, or SCD) occurred in 350 patients, including 21 percent of patients with LGE (compared with 4.7 percent of patients without LGE; pooled odds ratio [OR] 4.3, 95% CI 3.3- 5.8). LGE was able to risk stratify patients at all levels of LVEF (both above and below 35 percent) and was most powerful among patients with ICDs previously placed for primary prevention (OR 7.8, 95% CI 1.7-35.8). In a 2019 Australian prospective, nonrandomized study of 452 patients with non-ischemic cardiomyopathy (LVEF 35 percent) who had all undergone CMR imaging and who met ESC/AHA criteria for primary prevention ICD placement, half received a primary prevention ICD according to the judgment of the treating physician and prevailing local practice [18]. Patients with myocardial fibrosis (manifest by LGE on CMR imaging) who received an ICD had lower mortality than those who did not get an ICD (HR 0.45, 95% CI 0.26-0.77). However, there was no difference in survival with or without an ICD for the 175 patients without myocardial fibrosis. The MARVEN (Clinical, Electrocardiographic, and Cardiac Magnetic Resonance Imaging Risk Factors Associated with Ventricular Tachyarrhythmias in Nonischemic Cardiomyopathy) Study is an NHLBI-sponsored prospective, observational study aimed at developing optimal risk stratification strategies to predict ventricular tachyarrhythmias in patients with nonischemic cardiomyopathy undergoing CRT-D implantation to determine whether LGE-CMR will further improve risk stratification in patients with nonischemic cardiomyopathy, LVEF 35 percent, and QRS 120 milliseconds [19]. While not currently utilized in SCD risk stratification guidelines, if these data are confirmed in additional prospective studies, then LGE on CMR may become a criterion used in future risk stratification schemes. USE OF AN ICD Malignant ventricular arrhythmias potentially leading to SCD are more frequently seen in patients with certain cardiomyopathies (compared with the general population), particularly in https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 5/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate association with heart failure (HF) symptoms. As in secondary prevention, randomized clinical trials have established a clear role for primary prevention implantable cardioverter-defibrillators (ICDs) in selected patients ( table 1). In contrast, antiarrhythmic drugs other than beta blockers do not appear to improve outcomes. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) The role of an ICD in the primary prevention of SCD among patients with HF and cardiomyopathy depends upon several factors: The severity of left ventricular (LV) systolic dysfunction. The severity of clinical HF ( table 2). The etiology of LV dysfunction (ie, ischemic or nonischemic cardiomyopathy). Competing co-morbidities that affect longevity and risk of ICD complications (eg, chronic kidney disease, chronic obstructive pulmonary disease, etc). The risk of SCD increases with the severity of both LV systolic dysfunction and clinical HF [20]. However, the risk of death due to other causes (eg, progressive HF) also increases with worsening HF and LV systolic dysfunction, reinforcing the importance of appropriate patient selection prior to primary prevention ICD placement. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Epidemiology'.) Cardiac resynchronization therapy (CRT) may be appropriate treatment for selected HF patients with ischemic or non-ischemic cardiomyopathy and reduced left ventricular ejection fraction (LVEF) ( 35 percent) with a wide QRS complex (especially if left bundle branch block QRS morphology), if left ventricular function does not improve with guideline-directed medical therapy. Ventricular dyssynchrony refers to the loss of coordinated contraction across the left ventricle. Dyssynchrony can further impair the pump function of a failing ventricle and exacerbate HF symptoms. CRT can improve pump performance, reverse the deleterious process of ventricular remodeling, and improve survival in appropriately selected patients. CRT can be achieved with a device designed for pacing only (CRT-P) or can be incorporated into a combination device with an ICD (CRT-D) ( figure 2) [21]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Ischemic cardiomyopathy Our approach for patients with ischemic cardiomyopathy We recommend ICD therapy for primary prevention of SCD in the following groups of patients with ischemic cardiomyopathy: https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 6/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate For patients with cardiomyopathy due to ischemic heart disease, left ventricular ejection fraction (LVEF) 35 percent, and associated HF with New York Heart Association (NYHA) functional class II or III status [2]. For patients with cardiomyopathy due to ischemic heart disease, LVEF 30 percent, and NYHA functional class I status [2]. In both instances, patients should be at least 40 days post-myocardial infarction (MI) and more than three months following revascularization and taking guideline-directed medical therapy. These restrictions recognize that revascularization and medical therapy may result in significant improvement in LVEF and/or HF class. For patients with nonsustained ventricular tachycardia (NSVT) associated with prior MI, LVEF 40 percent, and inducible sustained VT or ventricular fibrillation at electrophysiology study [2,22,23]. Patients should be past the acute phase of MI, on guideline-directed medical therapy, and have reasonable expectation for survival for at least one year. Patients who have had an MI resulting in reduced LVEF are at increased risk of SCD, most often due to a ventricular tachyarrhythmia. Prophylactic ICD implantation for the primary prevention of SCD reduces mortality in selected patients with ischemic cardiomyopathy. Coronary revascularization itself may also reduce the future risk of malignant arrhythmias and SCD, as shown in the early versus late ICD implantation strategies and differing results in various randomized trials. The best approach to selecting patients with ischemic cardiomyopathy for ICD therapy for primary prevention has been explored in several major randomized trials, with the indications for ICD implantation derived largely from the inclusion criteria of these trials. One caveat, however, is that these trials took place prior to the contemporary guideline-based approaches to optimal medical therapy for patients with heart failure and cardiomyopathy. Trials of primary prevention ICDs in ischemic cardiomyopathy MADIT-I trial The Multicenter Automatic Defibrillator Implantation Trial (MADIT, now called MADIT-I) was the first trial to demonstrate that the ICD has a role in primary prevention of SCD in certain high-risk, asymptomatic patients [22]. Patients had a prior MI with reduced LVEF ( 35 percent), NSVT on ECG monitoring, and inducible sustained monomorphic VT during electrophysiology study (EPS) that was also inducible after administration of intravenous procainamide. Among 196 patients who were randomly assigned to pharmacologic therapy (including an antiarrhythmic drug at the discretion of the clinician, with amiodarone administered to most patients) or an ICD and followed for an average of 27 months, patients assigned to ICD therapy had significant reductions in overall mortality, cardiac mortality, and arrhythmic deaths compared with patients assigned to medical therapy ( figure 3). While the https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 7/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate MADIT-I trial remains an important landmark study in the utilization of ICDs for primary prevention, it has largely been supplanted by subsequent studies with larger numbers of patients, better methodologies, and simpler risk stratification schemes for study entry. MUSTT trial The Multicenter Unsustained Tachycardia Trial (MUSTT trial), which was not primarily designed as a randomized ICD clinical trial but rather to study the management of high-risk patients using the results of electrophysiology study (EPS), enrolled patients with prior MI, reduced LVEF ( 40 percent), asymptomatic NSVT on ECG monitoring, inducible sustained VT during EPS, and no history of VT or syncope [23]. A total of 704 patients were randomly assigned to either standard medical therapy (353 patients) or EPS-guided antiarrhythmic therapy, which included either an antiarrhythmic agent (154 patients received a class IA drug with or without mexiletine, propafenone, sotalol, or amiodarone) or an ICD (161 patients) if at least one antiarrhythmic agent was ineffective. After a median follow-up of 39 months, the five-year (25 versus 32 percent, relative risk [RR] 0.73, 95% CI 0.53-0.99) rates for the primary endpoint (arrhythmic death or resuscitated SCD) were significantly lower for EPS-guided therapy compared with standard medical therapy. The reduction in the primary endpoint in the EPS- guided group was largely attributable to ICD therapy; at five years, the primary endpoint occurred in 9 percent of those receiving an ICD, compared with 37 percent of those receiving an antiarrhythmic drug (RR 0.24, 95% CI 0.13-0.45) ( figure 4). Whether inducible arrhythmia might be prognostically important in patients with an LVEF of 30 to 40 percent was addressed in another analysis from MUSTT [24]. The rate of arrhythmic death at five years was significantly increased for patients with inducible VT and LVEF between 30 and 40 percent, suggesting that for patients with LVEF 30 percent only, electrophysiology testing may have useful predictive value. CABG Patch trial The Coronary Artery Bypass Graft (CABG) Patch trial evaluated the efficacy of an epicardial ICD implanted at the time of coronary artery bypass graft surgery among 900 patients with severe coronary artery disease (CAD), reduced LVEF <36 percent, abnormal signal averaged ECG, and no prior sustained VT or syncope [25]. Epicardial ICD systems were predominantly used. Compared with standard medical therapy over an average of 32 months, there was no significant difference in overall or cardiovascular mortality among patients with an ICD (hazard ratio [HR] 1.07 for overall mortality compared with standard medical therapy, 95% CI 0.81-1.42) ( figure 5). This negative trial is a primary reason why current guidelines recommend against primary prevention ICD implantation for patients who have recently undergone coronary revascularization, as revascularization itself may reduce the future risk of malignant arrhythmias and SCD. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 8/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate MADT-II trial The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) enrolled 1232 patients with a prior MI more than 30 days prior to enrollment (and more than three months if bypass surgery was performed) and reduced LVEF ( 30 percent); NSVT and inducible VT during EPS were not required [26]. The study, which randomly assigned patients to a prophylactic ICD or conventional medical therapy, was stopped early due to benefit of ICD therapy after an average follow-up of 20 months. Patients in the ICD group had reduced all- cause mortality (14.2 versus 19.8 percent for conventional therapy; HR 0.65, 95% CI 0.51-0.93) ( figure 6). SCD-HeFT trial The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), which evaluated ICD and amiodarone therapies in patients with both ischemic (52 percent) or nonischemic (48 percent) cardiomyopathy, enrolled patients with NYHA class II or III heart failure (CHF) for at least three months prior to randomization, reduced LVEF ( 35 percent), and treated with angiotensin converting enzyme (ACE) inhibitor and beta-blocker, if tolerated [27]: NYHA class II or III HF. Reduced. Congestive heart failure (CHF) present for at least three months prior to randomization and treated with ACE inhibitor and beta blocker, if tolerated. Among 2521 patients who were randomly assigned to ICD implantation, amiodarone, or placebo, and followed for a median of 46 months, total mortality at five years was significantly reduced with ICD therapy (29 versus 36 percent with placebo; HR 0.77, 95% CI 0.62-0.96). The benefit of an ICD was comparable among patients with either an ischemic or nonischemic cardiomyopathy. A long-term analysis of SCD-HeFT participants, published in July 2020, showed continued survival benefit in the ICD arm over placebo arm at a median follow-up of 11 years (HR 0.87, 95% CI 0.76-0.98) [28]. Long-term benefit was most evident for patients with ischemic cardiomyopathy and those with NYHA functional class II symptoms at enrollment. These results suggest that an ICD is beneficial in patients with chronic HF and a diminished LVEF ( 35 percent), despite appropriate medical therapy for at least three months. In contrast, amiodarone provided no benefit over placebo. DINAMIT trial The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), which evaluated the role of prophylactic ICD implantation compared with standard medical therapy, enrolled 674 patients with MI in the preceding 6 to 40 days (mean of 18 days), reduced LVEF ( 35 percent), and reduced heart rate variability or elevated resting heart rate ( 80 beats/minute) [29]. Patients with sustained VT >48 hours post-MI, NYHA class IV HF, or CABG or three-vessel https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 9/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate percutaneous coronary intervention post-MI were excluded. After a mean follow-up of 30 months, there was no significant difference in annual all-cause mortality between the patients with and without an ICD (7.5 versus 6.9 percent annual mortality; HR 1.08, 95% CI 0.76-1.55). This negative trial provides an important rationale for the current guideline recommendation that ICD implantation should be deferred until at least 40 days after an MI. IRIS trial The Immediate Risk Stratification Improves Survival (IRIS) trial also evaluated the efficacy of ICD therapy versus standard therapy early post-MI and enrolled patients with an MI in the preceding 5 to 31 days and at least one of the following: reduced LVEF ( 40 percent) with a resting heart rate 90 beats/minute or NSVT at a rate of 150 beats/minute or both [30]. Among 898 randomized patients who were followed for an average of 37 months, there was no difference in all-cause mortality between patients randomly assigned to ICD therapy and those assigned to medical therapy (HR 1.04 for ICD therapy, 95% CI 0.81-1.35). Nonischemic dilated cardiomyopathy Our approach for patients with nonischemic dilated cardiomyopathy We recommend ICD therapy for primary prevention of SCD in the following groups of patients with nonischemic dilated cardiomyopathy: For patients meeting SCD-HeFT criteria, including an LVEF 35 percent and NYHA class II to III ( table 2) HF, we suggest ICD implantation rather than guideline-directed optimal medical therapy alone [2]. For most patients with LVEF 35 percent, class III or IV HF, and a QRS duration 120 milliseconds (especially if left bundle branch block [LBBB] QRS morphology), we recommend implantation of a combined CRT-D device (biventricular pacing combined with an ICD). Additionally, many patients with specific non-ischemic cardiomyopathies (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, cardiac amyloidosis, etc) may be candidates for primary prevention ICD based on disease-specific risk markers. The approaches to selection of appropriate patients in a variety of conditions are discussed in the individual UpToDate topics. Ventricular arrhythmias are common in patients with HF and a nonischemic cardiomyopathy. While some small early trials suggested no benefit of ICD therapy in patients with nonischemic cardiomyopathy, subsequent larger trials and a 2004 meta-analysis have demonstrated greater overall survival following prophylactic ICD implantation in selected patients. While ICDs effectively reduce mortality from SCD, the benefit on total mortality appears diminished in the https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 10/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate setting of optimal guideline-directed medical therapy and CRT. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".) Trials of primary prevention ICDs in nonischemic dilated cardiomyopathy DEFINITE trial The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial evaluated the efficacy of an ICD versus standard medical therapy, in 458 patients with nonischemic dilated cardiomyopathy, reduced LVEF ( 35 percent), and premature ventricular beats or NSVT [31]. After mean follow-up of 29 months, there was a trend toward reduction in the primary endpoint of all-cause mortality in patients treated with an ICD (7.9 versus 14.1 percent with medical therapy alone; HR 0.65, 95% CI 0.40-1.06). Fewer sudden deaths occurred in the ICD arm, although the numbers were very small (3 deaths versus 14 deaths in the medical therapy arm; HR 0.20, 95% CI 0.06-0.71). The all-cause mortality rate in the "medical therapy only" arm of DEFINITE (14.1 percent at two years) was lower than had been anticipated when the study was designed, potentially contributing to the trial being underpowered for its primary endpoint. SCD-HeFT trial The Sudden Cardiac Death in Heart Failure trial (SCD-HeFT), which evaluated ICD and amiodarone therapies in patients with both ischemic (52 percent) or nonischemic (48 percent) cardiomyopathy, identified a significant reduction in overall mortality with ICD therapy (29 versus 36 percent with placebo; HR 0.77, 95% CI 0.62-0.96) [27]. The benefit of an ICD was comparable among patients with either an ischemic or nonischemic cardiomyopathy. (See 'Trials of primary prevention ICDs in ischemic cardiomyopathy' above.) COMPANION trial of ICD combined with CRT For most patients with LVEF 35 percent, class III or IV HF, and a QRS duration 120 milliseconds, we recommend implantation of a combined CRT-D device (biventricular pacing combined with an ICD) [32,33]. The benefit appears to be greatest in patients with a left bundle branch block and QRS duration 150 milliseconds [34-36]. Patients with right bundle branch block and a QRS duration <150 ms are much less likely to benefit from CRT. The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial evaluated optimal medical therapy versus CRT with or without an ICD among 682 patients with nonischemic dilated cardiomyopathy, reduced LVEF ( 35 percent), and NYHA class III or IV HF symptoms requiring hospitalization within the prior year [33]. After median follow-up of 16 months, there was a significant reduction in the incidence of the combined endpoint of all-cause mortality and all-cause hospitalization in the two arms receiving CRT compared with the medical therapy only arm (56 versus 68 percent). The CRT-D arm, but not the CRT-P arm, experienced a significant improvement in the secondary endpoint of all-cause mortality alone. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 11/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate DANISH trial The Danish Study to Assess the Efficacy of ICDs in Patients with Non- Ischemic Systolic Heart Failure on Mortality (DANISH) randomly assigned 1116 patients with symptomatic systolic HF (LVEF 35 percent) not caused by ischemic heart disease to an ICD with guideline-directed optimal medical therapy or medical therapy alone [37]. Over a median follow- up of 5.6 years, no significant difference was noted in the primary outcome of total mortality (120 deaths [21.6 percent] in the ICD group compared with 131 deaths [23.4 percent] in the group without an ICD; HR 0.87, 95% CI 0.68-1.12). A significant reduction was noted in the prespecified secondary outcome of SCD in the group receiving ICDs (24 deaths [4.3 percent] compared with 46 sudden deaths [8.2 percent] in the no ICD group; HR 0.50, 95% CI 0.31-0.82), as well as nonsignificant trends toward reduction in total cardiovascular mortality and increased device infections in the ICD group. Compared with prior primary prevention ICD trials, the overall mortality rate of patients in the DANISH trial was low, likely due to improved medical therapy for HF (notably a much higher utilization of ACE-I/ARB and beta blockers than in the older trials) and the use of CRT, which was not available during the older primary prevention trials. Because of this, the DANISH trial may have been underpowered to show a mortality benefit of ICD therapy. Finally, as there are competing causes of death with increasing age, one might not expect the same benefit of ICD therapy in older patients, who may have greater comorbidities which could contribute to nonarrhythmic causes of death. Our experts feel that it would be premature to use data from the DANISH study as the sole basis to withhold potentially life-saving ICD therapy from all patients with nonischemic cardiomyopathy. Instead, the results actually support the use of ICDs in younger patients who have a cardiomyopathy not caused by ischemic heart disease. For those patients who are likely to have a strong response to CRT or who are not considered good candidates for ICD therapy, a CRT-P device may be more suitable and compatible with therapeutic goals. Meta-analyses of ICD trials in nonischemic cardiomyopathy Several updated meta- analyses have been published that include patients with nonischemic cardiomyopathy receiving an ICD for primary prevention from the same original five ICD trials (CAT, AMIOVIRT, DEFINITE, SCD-HeFT, and COMPANION) as well as patients from the DANISH trial [38-46]. When considering all six trials collectively, each of the meta-analyses demonstrated a significant benefit of the ICD on all-cause mortality in patients with nonischemic cardiomyopathy (19 to 24 percent hazard reduction compared with medical therapy alone). When only patients who also received CRT in the COMPANION and DANISH trials were analyzed, there was a nonsignificant trend toward reduction in all-cause mortality among patients with an ICD (approximately 25 to 30 percent hazard reduction with nonsignificant confidence intervals) [38,40,43]. Despite the lack of a significant incremental benefit of the ICD in the two trials that included CRT, it is currently https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 12/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate premature to withhold ICD therapy in all patients with nonischemic cardiomyopathy who require concomitant CRT. Adequately powered randomized studies are needed before recommending a change in current practice guidelines. GUIDELINE-DIRECTED MEDICAL THERAPY For patients who meet criteria for insertion of an implantable cardioverter-defibrillator (ICD) for the primary prevention of SCD, in the absence of a contraindication, we recommend optimizing guideline-directed medical therapy prior to ICD implantation. Heart failure therapy Several of the components of appropriate medical therapy after a myocardial infarction (MI) reduce SCD as well as overall mortality. While these data are derived from trials in patients with ischemic heart disease, we can infer that many of the same benefits should apply to SCD risk reduction in patients with nonischemic cardiomyopathy. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the management of heart failure with reduced ejection fraction in adults".) Beta blockers In addition to reducing overall mortality in patients with an acute MI, beta blockers also reduced the risk of SCD [47,48]. The SCD benefit is better established in patients with chronic HF. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy", section on 'Heart failure therapy'.) Post-MI patients with an ICD also appear to derive a benefit from beta blockers. In a cohort of 691 patients with ischemic cardiomyopathy who received an ICD in the MADIT-II trial, the 433 patients treated with a beta blocker had significantly lower mortality (hazard ratio [HR] 0.43) compared with those not taking beta blockers; additionally, patients in the highest quartile of beta blocker dose had a significant reduction in the risk of ventricular tachyarrhythmias requiring ICD discharge (HR 0.48) [49]. ACE inhibitors A meta-analysis of 15,104 patients in 15 trials of acute MI found that angiotensin-converting enzyme (ACE) inhibitor therapy reduced the risk of SCD (odds ratio 0.80, 95% CI 0.70-0.92, absolute benefit approximately 1.4 percent) as well as overall and cardiovascular mortality [50]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".) Angiotensin II receptor blockers Angiotensin II receptor blockers (ARBs) are often used for patients who cannot tolerate ACE inhibitors. At appropriate doses, it is likely that ARBs https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 13/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate reduce the risk of SCD to the same degree as ACE inhibitors [51]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".) Angiotensin receptor-neprilysin inhibitor The combination of an ARB and neprilysin inhibitor, known as angiotensin receptor-neprilysin inhibitor or ARNI, is another therapy for use in patients with HF and reduced LVEF (HFrEF). A randomized double-blind trial (PARADIGM-HF) in patients with HFrEF found that sacubitril-valsartan reduced cardiovascular mortality and hospitalization for HF as well as all-cause mortality compared with a standard dose of the ACE inhibitor enalapril [52]. The ARNI combination is administered in conjunction with other HF therapies, in place of an ACE inhibitor or ARB.

months, there was a significant reduction in the incidence of the combined endpoint of all-cause mortality and all-cause hospitalization in the two arms receiving CRT compared with the medical therapy only arm (56 versus 68 percent). The CRT-D arm, but not the CRT-P arm, experienced a significant improvement in the secondary endpoint of all-cause mortality alone. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 11/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate DANISH trial The Danish Study to Assess the Efficacy of ICDs in Patients with Non- Ischemic Systolic Heart Failure on Mortality (DANISH) randomly assigned 1116 patients with symptomatic systolic HF (LVEF 35 percent) not caused by ischemic heart disease to an ICD with guideline-directed optimal medical therapy or medical therapy alone [37]. Over a median follow- up of 5.6 years, no significant difference was noted in the primary outcome of total mortality (120 deaths [21.6 percent] in the ICD group compared with 131 deaths [23.4 percent] in the group without an ICD; HR 0.87, 95% CI 0.68-1.12). A significant reduction was noted in the prespecified secondary outcome of SCD in the group receiving ICDs (24 deaths [4.3 percent] compared with 46 sudden deaths [8.2 percent] in the no ICD group; HR 0.50, 95% CI 0.31-0.82), as well as nonsignificant trends toward reduction in total cardiovascular mortality and increased device infections in the ICD group. Compared with prior primary prevention ICD trials, the overall mortality rate of patients in the DANISH trial was low, likely due to improved medical therapy for HF (notably a much higher utilization of ACE-I/ARB and beta blockers than in the older trials) and the use of CRT, which was not available during the older primary prevention trials. Because of this, the DANISH trial may have been underpowered to show a mortality benefit of ICD therapy. Finally, as there are competing causes of death with increasing age, one might not expect the same benefit of ICD therapy in older patients, who may have greater comorbidities which could contribute to nonarrhythmic causes of death. Our experts feel that it would be premature to use data from the DANISH study as the sole basis to withhold potentially life-saving ICD therapy from all patients with nonischemic cardiomyopathy. Instead, the results actually support the use of ICDs in younger patients who have a cardiomyopathy not caused by ischemic heart disease. For those patients who are likely to have a strong response to CRT or who are not considered good candidates for ICD therapy, a CRT-P device may be more suitable and compatible with therapeutic goals. Meta-analyses of ICD trials in nonischemic cardiomyopathy Several updated meta- analyses have been published that include patients with nonischemic cardiomyopathy receiving an ICD for primary prevention from the same original five ICD trials (CAT, AMIOVIRT, DEFINITE, SCD-HeFT, and COMPANION) as well as patients from the DANISH trial [38-46]. When considering all six trials collectively, each of the meta-analyses demonstrated a significant benefit of the ICD on all-cause mortality in patients with nonischemic cardiomyopathy (19 to 24 percent hazard reduction compared with medical therapy alone). When only patients who also received CRT in the COMPANION and DANISH trials were analyzed, there was a nonsignificant trend toward reduction in all-cause mortality among patients with an ICD (approximately 25 to 30 percent hazard reduction with nonsignificant confidence intervals) [38,40,43]. Despite the lack of a significant incremental benefit of the ICD in the two trials that included CRT, it is currently https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 12/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate premature to withhold ICD therapy in all patients with nonischemic cardiomyopathy who require concomitant CRT. Adequately powered randomized studies are needed before recommending a change in current practice guidelines. GUIDELINE-DIRECTED MEDICAL THERAPY For patients who meet criteria for insertion of an implantable cardioverter-defibrillator (ICD) for the primary prevention of SCD, in the absence of a contraindication, we recommend optimizing guideline-directed medical therapy prior to ICD implantation. Heart failure therapy Several of the components of appropriate medical therapy after a myocardial infarction (MI) reduce SCD as well as overall mortality. While these data are derived from trials in patients with ischemic heart disease, we can infer that many of the same benefits should apply to SCD risk reduction in patients with nonischemic cardiomyopathy. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the management of heart failure with reduced ejection fraction in adults".) Beta blockers In addition to reducing overall mortality in patients with an acute MI, beta blockers also reduced the risk of SCD [47,48]. The SCD benefit is better established in patients with chronic HF. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy", section on 'Heart failure therapy'.) Post-MI patients with an ICD also appear to derive a benefit from beta blockers. In a cohort of 691 patients with ischemic cardiomyopathy who received an ICD in the MADIT-II trial, the 433 patients treated with a beta blocker had significantly lower mortality (hazard ratio [HR] 0.43) compared with those not taking beta blockers; additionally, patients in the highest quartile of beta blocker dose had a significant reduction in the risk of ventricular tachyarrhythmias requiring ICD discharge (HR 0.48) [49]. ACE inhibitors A meta-analysis of 15,104 patients in 15 trials of acute MI found that angiotensin-converting enzyme (ACE) inhibitor therapy reduced the risk of SCD (odds ratio 0.80, 95% CI 0.70-0.92, absolute benefit approximately 1.4 percent) as well as overall and cardiovascular mortality [50]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".) Angiotensin II receptor blockers Angiotensin II receptor blockers (ARBs) are often used for patients who cannot tolerate ACE inhibitors. At appropriate doses, it is likely that ARBs https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 13/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate reduce the risk of SCD to the same degree as ACE inhibitors [51]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".) Angiotensin receptor-neprilysin inhibitor The combination of an ARB and neprilysin inhibitor, known as angiotensin receptor-neprilysin inhibitor or ARNI, is another therapy for use in patients with HF and reduced LVEF (HFrEF). A randomized double-blind trial (PARADIGM-HF) in patients with HFrEF found that sacubitril-valsartan reduced cardiovascular mortality and hospitalization for HF as well as all-cause mortality compared with a standard dose of the ACE inhibitor enalapril [52]. The ARNI combination is administered in conjunction with other HF therapies, in place of an ACE inhibitor or ARB. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.) Statins Statins given to patients who have had an acute MI improve overall mortality. Although data are limited and inconclusive, part of the benefit may result from a lower rate of SCD, which may reflect a direct effect of statin therapy [53-55]. (See "Low density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome".) Mineralocorticoid receptor antagonists Among post-MI patients who have left ventricular (LV) dysfunction and HF and/or diabetes, eplerenone significantly reduced both overall mortality and SCD (relative risk for SCD 0.79, 95% CI 0.64-0.97) [56]. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.) Sodium glucose co-transporter 2 inhibitors (SGLT-2 inhibitors) Evidence as to whether SGLT-2 inhibitors reduced SCD and/or ventricular arrhythmias in patients with HF is mixed and has not been directly studied. In a post-hoc analysis of the DAPA-HF trial of persons with New York Heart Association (NYHA) class II to IV HF and LVEF <40 percent, the SGLT-2 inhibitor dapagliflozin reduced occurrence of the composite outcome of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death compared with placebo [57]. Among participants randomized to dapagliflozin, 140 of 2373 patients (5.9 percent) experienced the composite outcome compared with 175 of 2371 patients (7.4 percent) in the placebo group (HR 0.79, 95% CI 0.63-0.99). The effect was consistent across each of the composite outcome components. While a prior meta-analysis of 34 randomly controlled trials in participants with type 2 diabetes mellitus or HF also showed that SGLT-2 inhibitors reduced SCD compared with placebo or active control (OR 0.72 95% CI 0.54-0.97), this result just achieved statistical significance, and there was no significant difference in incident ventricular arrhythmia or cardiac arrest [58]. (See "Primary pharmacologic therapy https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 14/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate for heart failure with reduced ejection fraction", section on 'Sodium-glucose co-transporter 2 inhibitors'.) Despite the proven benefits, some patients are not receiving guideline-directed medical therapy at the time of ICD implantation. In a 2011 study analyzing 175,757 first-time ICD recipients, using data from the National Cardiovascular Data Registry, 25.7 percent of ICD recipients without a documented contraindication were reported as not receiving optimal medical therapy at the time of ICD implantation, including 18.7 percent who were reported as not receiving an ACE inhibitor or ARB and 10.7 percent who were reported as not receiving a beta blocker [59]. While some of these gaps may reflect issues of coding and documentation, these data suggest an opportunity for significant improvement in the treatment of patients with evidence-based, cost-effective therapies that could potentially result in improvement in cardiomyopathy and avoidance of an ICD. Although current guidelines suggest at least three months of guideline- directed medical therapy in patients with symptomatic HF and left ventricular ejection fraction (LVEF) 35 percent, the ideal duration of guideline-directed medical therapy prior to prophylactic ICD implantation remains uncertain. However, data demonstrate that a relevant proportion of patients with newly diagnosed HF may show recovery of LVEF >35 percent beyond three months after initiation of HF therapy, allowing left ventricular reverse remodeling to occur during intensified treatment [60]. Antiarrhythmic drugs Randomized clinical trials do not support the routine use of prophylactic antiarrhythmic drug therapy, other than beta blockers, to prevent SCD in patients with HF [1,61-64]. The lack of overall benefit from prophylactic antiarrhythmic drug therapy is due to both incomplete suppression of ventricular arrhythmias and the risk of proarrhythmia [62,63,65-69]. Given the established superiority of an ICD in high-risk patients, class I and class III antiarrhythmic drugs no longer have an established role for the primary prevention of SCD. Among the antiarrhythmic drugs, amiodarone has the advantage of a relatively low rate of proarrhythmia, less negative inotropic effect, and higher efficacy for suppression of tachyarrhythmias. While amiodarone is not approved for use in the primary prevention of arrhythmias, this was a common off-label use of the drug [22]. In addition, amiodarone is frequently used for the treatment of atrial fibrillation as it is considered relatively "safe," from a cardiac standpoint, with low risk for proarrhythmia in the setting of HF [70]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Antiarrhythmic drugs' and "Amiodarone: Clinical uses", section on 'Amiodarone for ventricular arrhythmias'.) SPECIAL POPULATIONS https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 15/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Class IV heart failure Class IV HF is a state that may be transitory and therefore associated with heterogeneous prognosis. Once class IV HF is refractory (stage D HF), life expectancy is generally less than one year unless cardiac transplantation is performed or a left ventricular assist device is implanted. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Cardiac transplantation'.) The role of implantable cardioverter-defibrillator (ICD) therapy for primary prevention of SCD in patients with New York Heart Association (NYHA) class IV HF with a narrow QRS complex has not been studied. NYHA class IV patients were generally excluded from randomized primary prevention ICD trials due to high expected mortality rate from pump failure, and only a small number were included in cardiac resynchronization therapy combined with ICD (CRT-D) trials. However, a nonrandomized series of patients awaiting cardiac transplantation suggested a higher likelihood of survival to transplantation with ICD therapy, regardless of whether the ICD indication was well established [71]. Given these considerations, for ambulatory patients with NYHA class IV HF, a left ventricular ejection fraction (LVEF) 35 percent and a narrow QRS complex (ie, no dyssynchrony), who are awaiting cardiac transplantation outside the hospital, ICD implantation may be considered as a bridge to transplantation. However, there are very limited data to support this recommendation [2,71]. According to the 2017 Guideline for the Management of Patients with Ventricular Arrhythmias, "in patients with HFrEF who are awaiting heart transplant and who otherwise would not qualify for an ICD (eg, NYHA class IV and/or use of inotropes) with a plan to discharge home, an ICD is reasonable (class IIa recommendation, B-NR)." A wearable defibrillator vest may be considered as an alternative in selected patients [72,73]. Older adults and patients with comorbidities Because of the competing risks of arrhythmic and nonarrhythmic death, some investigators have expressed concern that older adults and those with multiple or severe comorbidities might be less likely to derive benefit from an ICD [74-77]. The mean age of patients in randomized primary prevention ICD trials ranged from 60 to 67 years, and patients over 75 to 80 years comprised a relatively small proportion of these cohorts. Because most older adult patients as well as those patients with severe comorbidities (such as advanced kidney disease) were excluded from most of the major ICD trials, the survival benefit from ICD implantation in such populations is less well defined. The decision to recommend an ICD should be made on a case-by-case basis based on shared decision making, taking into account patient values and preferences. Age or comorbidity alone should not be a sole exclusion for ICD implantation. As part of the 2017 AHA/ACC/HRS guideline for management of ventricular arrhythmias and prevention of SCD, a systematic review was performed to specifically assess the impact of https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 16/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate primary prevention ICD therapy among older patients and patients with significant morbidities [78]. The following findings were noted: Older adults While the systematic review identified 10 studies of primary prevention ICD use among older adults, because of concerns about overlapping patients between some of the studies, the final "minimal overlap" meta-analysis included four studies with unique patient populations. Compared with patients without ICD implantation, patients who received a primary prevention ICD had a 25 percent reduction in total mortality (hazard ratio [HR] 0.75, 95% CI 0.67-0.83). Patients with comorbidities Among 10 studies of primary prevention ICD use in patients with a variety of comorbidities (including renal disease, chronic obstructive pulmonary disease, and diabetes, among others), ICD implantation for primary prevention was associated with a 28 percent reduction in total mortality (HR 0.72, 95% CI 0.65-0.79), with similar findings in the "minimal overlap" meta-analysis, which included only five studies (HR 0.71, 95% CI 0.61-0.82). Patients with renal disease Patients with chronic kidney disease requiring dialysis have increased mortality and reported high rates of SCD. Among five studies (two post-hoc analyses of randomized trial data and three observational studies) specifically looking at patients with varying degrees of chronic renal disease, primary prevention ICD use was associated with a 29 percent reduction in total mortality (HR 0.71, 95% CI 0.60-0.85). (See "Evaluation of sudden cardiac arrest and sudden cardiac death in dialysis patients".) Following the systematic review for the 2017 AHA/ACC/HRS guidelines, additional studies have been published evaluating the role of primary prevention ICDs in older patients and those with severe kidney disease. While randomized trial data are absent, clinicians have shown a preference for using the totally subcutaneous ICD (S-ICD) in patients with severe kidney disease (in particular among patients who undergo regular hemodialysis) in order to reduce the risk of intravascular infection in this population [79]. In a retrospective multi-center cohort of 300 patients receiving a primary prevention ICD or CRT-D, which included 150 patients 80 years old (mean age 82 years, 76 percent with one or fewer comorbidities) and 150 patients <80 years old (mean age 62 years, matched for sex and type of heart disease), similar numbers of patients received an appropriate shock (19.4 percent of older patients versus 21.6 percent of younger patients) with no significant difference in complication rates over mean follow-up of three years [80]. These data suggest that, compared with younger patients, primary prevention ICDs can be safely implanted in selected patients 80 years old with few or no comorbidities. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 17/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate In patients on dialysis who did not meet standard indications for ICD therapy, the ICD2 trial was published suggesting no benefit from primary prevention ICDs [81]. In the ICD2 trial, 200 patients on dialysis who had an LVEF 35 percent without HF symptoms and no documented VT were randomized to ICD implantation with optimal medical therapy or to not receive an ICD. Following randomization of 188 patients, the trial was stopped prematurely due to futility, with no significant improvement among ICD recipients in five- year rates of SCD (9.7 versus 7.9 percent without ICD; HR 1.3, 95% CI 0.5-3.3) or overall survival (50.6 versus 54.4 percent without ICD; HR 1.0, 95% CI 0.7-1.5). While the results may be partially explained by the lower than expected observed rates of SCD in the study (annual rate of 2 percent versus expected rate of 5 to 6 percent), the data do not support extending primary prevention ICD use in dialysis beyond the standard indications. However, it should be noted that transvenous ICDs (often dual chamber systems) were utilized and significant complications occurred, including adverse events related to the ICD implantation procedure in 13 percent and ICD explantation (primarily due to bacteremia) in 7.5 percent. These results cannot necessarily be extrapolated to totally subcutaneous systems, which are frequently utilized in patients on dialysis as they appear to be associated with lower rates of bacteremia than transvenous systems. (See 'Our approach for patients with ischemic cardiomyopathy' above and 'Our approach for patients with nonischemic dilated cardiomyopathy' above and "Subcutaneous implantable cardioverter defibrillators".) GAPS IN THE GUIDELINES Possible indications not addressed by guidelines The HRS/ACC/AHA Expert Consensus Statement on the Use of ICD Therapy in Patients Who Are Not Included or Not Represented in Clinical Trials evaluated important clinical situations for which implantable cardioverter- defibrillator (ICD) therapy might be beneficial in selected populations that were not consistently included in randomized clinical trials and may not be included in guideline documents [82]. This document includes discussion related to the following topics: Use of an ICD in patients with an abnormal troponin that is not due to a myocardial infarction (MI). Use of an ICD within 40 days after a MI, such as patients with preexisting left ventricular (LV) dysfunction or those requiring non-elective permanent pacing. Use of an ICD within the first 90 days after revascularization, such as patients with preexisting LV dysfunction or those requiring non-elective permanent pacing. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 18/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Use of an ICD within the first nine months after initial diagnosis of nonischemic cardiomyopathy. Recommendations were made based on available evidence as well as consensus opinion. Many clinical scenarios where gaps in evidence exist for ICD therapy are also discussed in the 2013 Appropriate Use Criteria for Implantable Cardioverter-Defibrillators and Cardiac Resynchronization Therapy (CRT) [83]. Patients undergoing generator replacement with improved LVEF and/or no prior ICD therapies An additional clinical scenario that is not fully covered in professional society guidelines and consensus documents is the management of patients who have received a primary prevention ICD who have improved or normalized LV function, have never received appropriate ICD therapy, and have either reached the point of elective replacement for their device or require reimplantation after system extraction (ie, due to infection) [74,84-89]. Among a subset of 1273 patients from the SCD-HeFT trial (624 randomized to ICD, 649 randomized to placebo) who had repeat assessment of left ventricular ejection fraction (LVEF) at a mean of 13.5 months post-randomization, 371 patients (29 percent) showed improvement to LVEF >35 percent (186 [29.8 percent] in ICD group versus 185 [28.5 percent] in placebo group) [84]. There was a similar reduction in all-cause mortality with the ICD in both the LVEF 35 percent group (adjusted hazard ratio [HR] 0.64, 95% CI 0.48- 0.85) and the LVEF >35 percent group (adjusted HR 0.62, 95% CI 0.29-1.30). Among 752 patients from the MADIT-CRT study with mild HF symptoms, 7.3 percent had normalized LVEF to >50 percent after cardiac resynchronization therapy (CRT; so-called "super-responders"); these "super-responders" had a low rate of ventricular arrhythmias, with only 3 of 55 super-responders (5 percent) having treated VT (none requiring an ICD shock) at a mean follow-up of 2.2 years [85]. Among 231 patients with an ICD placed for primary prevention, 26 percent had shown enough improvement in LVEF to no longer meet implant criteria at the time of elective generator replacement [86]. Patients in whom LVEF improved had a lower rate of appropriate therapy after generator replacement (2.8 percent per year) than those whose LVEF remained 35 percent (10.7 percent per year). Among a prospective cohort of 538 patients from the PROSE-ICD study who received a primary prevention ICD and had subsequent reassessment of LVEF, 40 percent of patients had >5 percent improvement in LVEF (over 4.9 years of follow-up), of whom 25 percent had improvement in LVEF to >35 percent [87]. Risk of an appropriate shock was significantly lower (but not completely eliminated) in patients with improved LVEF. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 19/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Among a cohort of 1421 patients with an ICD (49 percent primary prevention, 51 percent secondary prevention) scheduled to undergo generator replacement an average of 3.5 years following initial implantation, 471 patients (33 percent) had received an appropriate shock prior to replacement [90]. Following generator replacement, 435 patients (31 percent) received an appropriate ICD therapy during mean follow-up of 2.7 years. Patients with prior appropriate ICD therapy were significantly more likely to receive additional therapy following generator replacement (HR 3.0, 95% CI 2.4-3.7). With limited observational data and no randomized trial data to guide decision making for patients with normalized LVEF, clinicians need to weigh a number of factors when planning generator replacement or system reimplantation in such patients, including original indication, possibility of relapse in LV dysfunction, overall prognosis, comorbidities, and patient preference. The 2013 ACC/HRS/AHA Appropriate Use Criteria suggest that replacement of CRT-D with CRT-P devices "may be appropriate" in selected patients who underwent initial ICD implantation for primary prevention indications if substantial improvement in LV function is noted (LVEF now >35 percent, and particularly if 50 percent), if no clinically relevant ventricular arrhythmias have occurred [83]. However, due to the paucity of prospective data on this topic, it is also considered appropriate to replace a CRT-D device with a new CRT-D device in situations where LV function has improved [83]. PROGNOSTIC SIGNIFICANCE OF ICD SHOCKS AND DEVICE PROGRAMMING Among patients with HF receiving implantable cardioverter-defibrillators (ICDs) for primary prevention in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), an appropriate shock, as compared with no appropriate shock, was associated with substantially increased all-cause mortality (hazard ratio [HR] 5.7, 95% CI 4.0-8.1) [91]. An inappropriate shock, as compared with no inappropriate shock, was also associated with a significant increase in mortality (HR 2.0, 95% CI 1.3-3.1). The most common cause of death among patients who received any ICD shock was progressive HF. Other studies have also shown that appropriate or inappropriate shocks are associated with increased mortality [92,93]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Prognosis of heart failure".) Several trials have underscored the importance of reducing both appropriate and inappropriate shocks through optimizing ICD programming. The Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) study found improved survival in ICD recipients who were randomly assigned to ICD programming with a high rate cutoff and/or long detection times, both of which were associated with fewer ICD shocks compared with conventional programming [94]. The Avoiding Defibrillator Therapies For Non-sustained https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 20/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Arrhythmias In ICD Patients (ADVANCE) III trial found a similar benefit for extended detection time in reducing both appropriate and inappropriate ICD shocks [95]. The 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter- Defibrillator Programming and Testing outlines the importance of proper ICD programming in reducing unnecessary therapy [96]. (See "Implantable cardioverter-defibrillators: Optimal programming".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Implantable cardioverter-defibrillators (The Basics)") Beyond the Basics topic (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS While implantable cardioverter-defibrillators (ICDs) are highly efficacious in the treatment of ventricular tachyarrhythmias and prevention of sudden cardiac death (SCD), they are https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 21/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate costly, require ongoing follow-up, and have acute procedural and long-term risks (eg, infection, device and lead malfunction, etc). In addition, only a subset of patients with cardiomyopathy develop sustained ventricular tachyarrhythmias or SCD. Therefore, risk stratification of patients prior to considering ICD therapy is important for targeting therapy to patients at highest risk of SCD and minimizing the number of ICD implantations in patients who are unlikely to benefit. (See 'Risk stratification strategies' above.) Recommendations for selecting the optimal patients for ICD therapy are based largely upon the entry criteria in the major trials. Prior to recommending ICD therapy for the primary prevention of SCD, there should be a reasonable expectation of survival with a good functional status for at least one year regardless of the indication for ICD therapy. For patients who meet criteria for insertion of an ICD for the primary prevention of SCD, in the absence of a contraindication, we recommend optimizing guideline-directed medical therapy with a beta blocker and either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker prior to ICD implantation (Grade 1A). (See 'Guideline-directed medical therapy' above and "Overview of the management of heart failure with reduced ejection fraction in adults".) For patients with cardiomyopathy due to ischemic heart disease, left ventricular ejection fraction (LVEF) 35 percent, and associated heart failure (HF) with New York Heart Association (NYHA) functional class II or III status, we recommend ICD therapy for primary prevention of SCD (Grade 1A). Patients should be evaluated at least 40 days post-myocardial infarction (MI) and more than three months following revascularization. (See 'Ischemic cardiomyopathy' above.) For patients with cardiomyopathy due to ischemic heart disease, LVEF 30 percent, and NYHA functional class I status, we recommend ICD therapy for primary prevention of SCD (Grade 1B). Patients should be evaluated at least 40 days post-MI and more than three months following revascularization. (See 'Ischemic cardiomyopathy' above.) For patients with nonischemic dilated cardiomyopathy, LVEF 35 percent, and associated HF with NYHA functional class II or III symptoms, we suggest ICD therapy for primary prevention of SCD rather than optimal medical therapy alone (Grade 2B). ICDs are very effective at reducing total mortality and mortality from SCD, although the benefits of an ICD on total mortality may be diminished in the setting of guideline- directed optimal medical therapy and cardiac resynchronization therapy (CRT). All patients receiving an ICD for primary prevention of SCD should be treated with at least https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 22/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate three months of guideline-directed medical therapy prior to ICD implantation. (See 'Nonischemic dilated cardiomyopathy' above.) For patients with an LVEF 35 percent, HF with NYHA functional class III or IV status, and a QRS duration 120 milliseconds, we recommend implantation of a combined CRT-D device (biventricular pacing combined with an ICD) rather than an ICD alone (Grade 1A). Strongest consideration for the CRT component should be given for those patients with left bundle branch block (LBBB) QRS morphology, those with QRS duration 150 milliseconds, and those dependent upon ventricular pacing due to atrioventricular block. (See 'Trials of primary prevention ICDs in nonischemic dilated cardiomyopathy' above and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) The role of ICD therapy for primary prevention of SCD in patients with HF and NYHA class IV status who have a narrow QRS complex has not been well-studied, as NYHA class IV patients have generally been excluded from randomized primary prevention ICD trials due to high expected mortality rate. For ambulatory patients with NYHA class IV HF, an LVEF 35 percent, and a narrow QRS complex (ie, no dyssynchrony) who are awaiting cardiac transplantation outside the hospital, it is reasonable to consider ICD implantation as a bridge to transplantation. (See 'Class IV heart failure' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, and Scott Manaker, MD, PhD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001. 2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 23/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 3. Al-Khatib SM, Hellkamp AS, Fonarow GC, et al. Association between prophylactic implantable cardioverter-defibrillators and survival in patients with left ventricular ejection fraction between 30% and 35%. JAMA 2014; 311:2209. 4. Bilchick KC, Stukenborg GJ, Kamath S, Cheng A. Prediction of mortality in clinical practice for medicare patients undergoing defibrillator implantation for primary prevention of sudden cardiac death. J Am Coll Cardiol 2012; 60:1647. 5. Hong C, Alluri K, Shariff N, et al. Usefulness of the CHA2DS2-VASc Score to Predict Mortality in Defibrillator Recipients. Am J Cardiol 2017; 120:83. 6. Zeitler EP, Hellkamp AS, Fonarow GC, et al. Primary prevention implantable cardioverter- defibrillators and survival in older women. JACC Heart Fail 2015; 3:159. 7. Zhang Y, Guallar E, Blasco-Colmenares E, et al. Clinical and serum-based markers are associated with death within 1 year of de novo implant in primary prevention ICD recipients. Heart Rhythm 2015; 12:360. 8. Nevzorov R, Goldenberg I, Konstantino Y, et al. Developing a risk score to predict mortality in the first year after implantable cardioverter defibrillator implantation: Data from the Israeli ICD Registry. J Cardiovasc Electrophysiol 2018; 29:1540. 9. Bilchick KC, Wang Y, Cheng A, et al. Seattle Heart Failure and Proportional Risk Models Predict Benefit From Implantable Cardioverter-Defibrillators. J Am Coll Cardiol 2017; 69:2606. 10. Kristensen SL, Levy WC, Shadman R, et al. Risk Models for Prediction of Implantable Cardioverter-Defibrillator Benefit: Insights From the DANISH Trial. JACC Heart Fail 2019; 7:717. 11. Levy WC, Li Y, Reed SD, et al. Does the Implantable Cardioverter-Defibrillator Benefit Vary With the Estimated Proportional Risk of Sudden Death in Heart Failure Patients? JACC Clin Electrophysiol 2017; 3:291. 12. Levy WC, Hellkamp AS, Mark DB, et al. Improving the Use of Primary Prevention Implantable Cardioverter-Defibrillators Therapy With Validated Patient-Centric Risk Estimates. JACC Clin Electrophysiol 2018; 4:1089. 13. Shadman R, Poole JE, Dardas TF, et al. A novel method to predict the proportional risk of sudden cardiac death in heart failure: Derivation of the Seattle Proportional Risk Model. Heart Rhythm 2015; 12:2069. 14. Rouleau JL, Talajic M, Sussex B, et al. Myocardial infarction patients in the 1990s their risk

costly, require ongoing follow-up, and have acute procedural and long-term risks (eg, infection, device and lead malfunction, etc). In addition, only a subset of patients with cardiomyopathy develop sustained ventricular tachyarrhythmias or SCD. Therefore, risk stratification of patients prior to considering ICD therapy is important for targeting therapy to patients at highest risk of SCD and minimizing the number of ICD implantations in patients who are unlikely to benefit. (See 'Risk stratification strategies' above.) Recommendations for selecting the optimal patients for ICD therapy are based largely upon the entry criteria in the major trials. Prior to recommending ICD therapy for the primary prevention of SCD, there should be a reasonable expectation of survival with a good functional status for at least one year regardless of the indication for ICD therapy. For patients who meet criteria for insertion of an ICD for the primary prevention of SCD, in the absence of a contraindication, we recommend optimizing guideline-directed medical therapy with a beta blocker and either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker prior to ICD implantation (Grade 1A). (See 'Guideline-directed medical therapy' above and "Overview of the management of heart failure with reduced ejection fraction in adults".) For patients with cardiomyopathy due to ischemic heart disease, left ventricular ejection fraction (LVEF) 35 percent, and associated heart failure (HF) with New York Heart Association (NYHA) functional class II or III status, we recommend ICD therapy for primary prevention of SCD (Grade 1A). Patients should be evaluated at least 40 days post-myocardial infarction (MI) and more than three months following revascularization. (See 'Ischemic cardiomyopathy' above.) For patients with cardiomyopathy due to ischemic heart disease, LVEF 30 percent, and NYHA functional class I status, we recommend ICD therapy for primary prevention of SCD (Grade 1B). Patients should be evaluated at least 40 days post-MI and more than three months following revascularization. (See 'Ischemic cardiomyopathy' above.) For patients with nonischemic dilated cardiomyopathy, LVEF 35 percent, and associated HF with NYHA functional class II or III symptoms, we suggest ICD therapy for primary prevention of SCD rather than optimal medical therapy alone (Grade 2B). ICDs are very effective at reducing total mortality and mortality from SCD, although the benefits of an ICD on total mortality may be diminished in the setting of guideline- directed optimal medical therapy and cardiac resynchronization therapy (CRT). All patients receiving an ICD for primary prevention of SCD should be treated with at least https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 22/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate three months of guideline-directed medical therapy prior to ICD implantation. (See 'Nonischemic dilated cardiomyopathy' above.) For patients with an LVEF 35 percent, HF with NYHA functional class III or IV status, and a QRS duration 120 milliseconds, we recommend implantation of a combined CRT-D device (biventricular pacing combined with an ICD) rather than an ICD alone (Grade 1A). Strongest consideration for the CRT component should be given for those patients with left bundle branch block (LBBB) QRS morphology, those with QRS duration 150 milliseconds, and those dependent upon ventricular pacing due to atrioventricular block. (See 'Trials of primary prevention ICDs in nonischemic dilated cardiomyopathy' above and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) The role of ICD therapy for primary prevention of SCD in patients with HF and NYHA class IV status who have a narrow QRS complex has not been well-studied, as NYHA class IV patients have generally been excluded from randomized primary prevention ICD trials due to high expected mortality rate. For ambulatory patients with NYHA class IV HF, an LVEF 35 percent, and a narrow QRS complex (ie, no dyssynchrony) who are awaiting cardiac transplantation outside the hospital, it is reasonable to consider ICD implantation as a bridge to transplantation. (See 'Class IV heart failure' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, and Scott Manaker, MD, PhD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001. 2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 23/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 3. Al-Khatib SM, Hellkamp AS, Fonarow GC, et al. Association between prophylactic implantable cardioverter-defibrillators and survival in patients with left ventricular ejection fraction between 30% and 35%. JAMA 2014; 311:2209. 4. Bilchick KC, Stukenborg GJ, Kamath S, Cheng A. Prediction of mortality in clinical practice for medicare patients undergoing defibrillator implantation for primary prevention of sudden cardiac death. J Am Coll Cardiol 2012; 60:1647. 5. Hong C, Alluri K, Shariff N, et al. Usefulness of the CHA2DS2-VASc Score to Predict Mortality in Defibrillator Recipients. Am J Cardiol 2017; 120:83. 6. Zeitler EP, Hellkamp AS, Fonarow GC, et al. Primary prevention implantable cardioverter- defibrillators and survival in older women. JACC Heart Fail 2015; 3:159. 7. Zhang Y, Guallar E, Blasco-Colmenares E, et al. Clinical and serum-based markers are associated with death within 1 year of de novo implant in primary prevention ICD recipients. Heart Rhythm 2015; 12:360. 8. Nevzorov R, Goldenberg I, Konstantino Y, et al. Developing a risk score to predict mortality in the first year after implantable cardioverter defibrillator implantation: Data from the Israeli ICD Registry. J Cardiovasc Electrophysiol 2018; 29:1540. 9. Bilchick KC, Wang Y, Cheng A, et al. Seattle Heart Failure and Proportional Risk Models Predict Benefit From Implantable Cardioverter-Defibrillators. J Am Coll Cardiol 2017; 69:2606. 10. Kristensen SL, Levy WC, Shadman R, et al. Risk Models for Prediction of Implantable Cardioverter-Defibrillator Benefit: Insights From the DANISH Trial. JACC Heart Fail 2019; 7:717. 11. Levy WC, Li Y, Reed SD, et al. Does the Implantable Cardioverter-Defibrillator Benefit Vary With the Estimated Proportional Risk of Sudden Death in Heart Failure Patients? JACC Clin Electrophysiol 2017; 3:291. 12. Levy WC, Hellkamp AS, Mark DB, et al. Improving the Use of Primary Prevention Implantable Cardioverter-Defibrillators Therapy With Validated Patient-Centric Risk Estimates. JACC Clin Electrophysiol 2018; 4:1089. 13. Shadman R, Poole JE, Dardas TF, et al. A novel method to predict the proportional risk of sudden cardiac death in heart failure: Derivation of the Seattle Proportional Risk Model. Heart Rhythm 2015; 12:2069. 14. Rouleau JL, Talajic M, Sussex B, et al. Myocardial infarction patients in the 1990s their risk factors, stratification and survival in Canada: the Canadian Assessment of Myocardial Infarction (CAMI) Study. J Am Coll Cardiol 1996; 27:1119. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 24/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 15. Touboul P, Andre-Fou t X, Leizorovicz A, et al. Risk stratification after myocardial infarction. A reappraisal in the era of thrombolysis. The Groupe d'Etude du Pronostic de l'Infarctus du Myocarde (GREPI). Eur Heart J 1997; 18:99. 16. Schmitt C, Barthel P, Ndrepepa G, et al. Value of programmed ventricular stimulation for prophylactic internal cardioverter-defibrillator implantation in postinfarction patients preselected by noninvasive risk stratifiers. J Am Coll Cardiol 2001; 37:1901. 17. Di Marco A, Anguera I, Schmitt M, et al. Late Gadolinium Enhancement and the Risk for Ventricular Arrhythmias or Sudden Death in Dilated Cardiomyopathy: Systematic Review and Meta-Analysis. JACC Heart Fail 2016. 18. Gutman SJ, Costello BT, Papapostolou S, et al. Reduction in mortality from implantable cardioverter-defibrillators in non-ischaemic cardiomyopathy patients is dependent on the presence of left ventricular scar. Eur Heart J 2019; 40:542. 19. https://www.centerwatch.com/clinical-trials/listings/217964/clinical-electrocardiographic-an d-cardiac-magnetic-resonance-imaging-risk-factors-associated-with-ventricular-tachyarrhyt hmias-in-nonischemic-cardiomyopathy-marven-study/ (Accessed on May 01, 2019). 20. Woods B, Hawkins N, Mealing S, et al. Individual patient data network meta-analysis of mortality effects of implantable cardiac devices. Heart 2015; 101:1800. 21. K hlkamp V, InSync 7272 ICD World Wide Investigators. Initial experience with an implantable cardioverter-defibrillator incorporating cardiac resynchronization therapy. J Am Coll Cardiol 2002; 39:790. 22. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996; 335:1933. 23. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999; 341:1882. 24. Buxton AE, Lee KL, Hafley GE, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation 2002; 106:2466. 25. Bigger JT Jr. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med 1997; 337:1569. 26. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346:877. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 25/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 27. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225. 28. Poole JE, Olshansky B, Mark DB, et al. Long-Term Outcomes of Implantable Cardioverter- Defibrillator Therapy in the SCD-HeFT. J Am Coll Cardiol 2020; 76:405. 29. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter- defibrillator after acute myocardial infarction. N Engl J Med 2004; 351:2481. 30. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med 2009; 361:1427. 31. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004; 350:2151. 32. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:1539. 33. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350:2140. 34. Stavrakis S, Lazzara R, Thadani U. The benefit of cardiac resynchronization therapy and QRS duration: a meta-analysis. J Cardiovasc Electrophysiol 2012; 23:163. 35. Sipahi I, Carrigan TP, Rowland DY, et al. Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Arch Intern Med 2011; 171:1454. 36. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012; 60:1297. 37. K ber L, Thune JJ, Nielsen JC, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med 2016; 375:1221. 38. Golwala H, Bajaj NS, Arora G, Arora P. Implantable Cardioverter-Defibrillator for Nonischemic Cardiomyopathy: An Updated Meta-Analysis. Circulation 2017; 135:201. 39. Shun-Shin MJ, Zheng SL, Cole GD, et al. Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials. Eur Heart J 2017; 38:1738. 40. Stavrakis S, Asad Z, Reynolds D. Implantable Cardioverter Defibrillators for Primary Prevention of Mortality in Patients With Nonischemic Cardiomyopathy: A Meta-Analysis of Randomized Controlled Trials. J Cardiovasc Electrophysiol 2017; 28:659. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 26/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 41. Kolodziejczak M, Andreotti F, Kowalewski M, et al. Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy: A Systematic Review and Meta-analysis. Ann Intern Med 2017; 167:103. 42. Luni FK, Singh H, Khan AR, et al. Mortality Effect of ICD in Primary Prevention of Nonischemic Cardiomyopathy: A Meta-Analysis of Randomized Controlled Trials. J Cardiovasc Electrophysiol 2017; 28:538. 43. Anantha Narayanan M, Vakil K, Reddy YN, et al. Efficacy of Implantable Cardioverter- Defibrillator Therapy in Patients With Nonischemic Cardiomyopathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. JACC Clin Electrophysiol 2017; 3:962. 44. Beggs SAS, Jhund PS, Jackson CE, et al. Non-ischaemic cardiomyopathy, sudden death and implantable defibrillators: a review and meta-analysis. Heart 2018; 104:144. 45. Alba AC, Foroutan F, Duero Posada J, et al. Implantable cardiac defibrillator and mortality in non-ischaemic cardiomyopathy: an updated meta-analysis. Heart 2018; 104:230. 46. El Moheb M, Nicolas J, Khamis AM, et al. Implantable cardiac defibrillators for people with non-ischaemic cardiomyopathy. Cochrane Database Syst Rev 2018; 12:CD012738. 47. Nuttall SL, Toescu V, Kendall MJ. beta Blockade after myocardial infarction. Beta blockers have key role in reducing morbidity and mortality after infarction. BMJ 2000; 320:581. 48. Friedman LM, Byington RP, Capone RJ, et al. Effect of propranolol in patients with myocardial infarction and ventricular arrhythmia. J Am Coll Cardiol 1986; 7:1. 49. Brodine WN, Tung RT, Lee JK, et al. Effects of beta-blockers on implantable cardioverter defibrillator therapy and survival in the patients with ischemic cardiomyopathy (from the Multicenter Automatic Defibrillator Implantation Trial-II). Am J Cardiol 2005; 96:691. 50. Domanski MJ, Exner DV, Borkowf CB, et al. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol 1999; 33:598. 51. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349:1893. 52. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371:993. 53. Mitchell LB, Powell JL, Gillis AM, et al. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 2003; 42:81. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 27/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 54. Chiu JH, Abdelhadi RH, Chung MK, et al. Effect of statin therapy on risk of ventricular arrhythmia among patients with coronary artery disease and an implantable cardioverter- defibrillator. Am J Cardiol 2005; 95:490. 55. Dickinson MG, Ip JH, Olshansky B, et al. Statin use was associated with reduced mortality in both ischemic and nonischemic cardiomyopathy and in patients with implantable defibrillators: mortality data and mechanistic insights from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Am Heart J 2007; 153:573. 56. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309. 57. Curtain JP, Docherty KF, Jhund PS, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J 2021; 42:3727. 58. Fernandes GC, Fernandes A, Cardoso R, et al. Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: A meta-analysis of 34 randomized controlled trials. Heart Rhythm 2021; 18:1098. 59. Miller AL, Wang Y, Curtis J, et al. Optimal medical therapy use among patients receiving implantable cardioverter/defibrillators: insights from the National Cardiovascular Data Registry. Arch Intern Med 2012; 172:64. 60. Duncker D, K nig T, Hohmann S, et al. Avoiding Untimely Implantable Cardioverter/Defibrillator Implantation by Intensified Heart Failure Therapy Optimization Supported by the Wearable Cardioverter/Defibrillator-The PROLONG Study. J Am Heart Assoc 2017; 6. 61. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353:9. 62. Torp-Pedersen C, M ller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999; 341:857. 63. Camm AJ, Pratt CM, Schwartz PJ, et al. Mortality in patients after a recent myocardial infarction: a randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation 2004; 109:990. 64. Singer I, Al-Khalidi H, Niazi I, et al. Azimilide decreases recurrent ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators. J Am Coll Cardiol 2004; 43:39. 65. Pratt CM, Eaton T, Francis M, et al. The inverse relationship between baseline left ventricular ejection fraction and outcome of antiarrhythmic therapy: a dangerous imbalance in the risk- benefit ratio. Am Heart J 1989; 118:433. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 28/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 66. Hallstrom A, Pratt CM, Greene HL, et al. Relations between heart failure, ejection fraction, arrhythmia suppression and mortality: analysis of the Cardiac Arrhythmia Suppression Trial. J Am Coll Cardiol 1995; 25:1250. 67. Slater W, Lampert S, Podrid PJ, Lown B. Clinical predictors of arrhythmia worsening by antiarrhythmic drugs. Am J Cardiol 1988; 61:349. 68. Gottlieb SS, Kukin ML, Medina N, et al. Comparative hemodynamic effects of procainamide, tocainide, and encainide in severe chronic heart failure. Circulation 1990; 81:860. 69. Ravid S, Podrid PJ, Lampert S, Lown B. Congestive heart failure induced by six of the newer antiarrhythmic drugs. J Am Coll Cardiol 1989; 14:1326. 70. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 71. Saba S, Atiga WL, Barrington W, et al. Selected patients listed for cardiac transplantation may benefit from defibrillator implantation regardless of an established indication. J Heart Lung Transplant 2003; 22:411. 72. Chung MK, Szymkiewicz SJ, Shao M, et al. Aggregate national experience with the wearable cardioverter-defibrillator: event rates, compliance, and survival. J Am Coll Cardiol 2010; 56:194. 73. Cantero-P rez EM, Sobrino-M rquez JM, Grande-Trillo A, et al. Implantable cardioverter defibrillator for primary prevention in patients with severe ventricular dysfunction awaiting heart transplantation. Transplant Proc 2013; 45:3659. 74. Barra S, Provid ncia R, Paiva L, et al. Implantable cardioverter-defibrillators in the elderly: rationale and specific age-related considerations. Europace 2015; 17:174. 75. Pun PH, Al-Khatib SM, Han JY, et al. Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in CKD: a meta-analysis of patient-level data from 3 randomized trials. Am J Kidney Dis 2014; 64:32. 76. Hess PL, Al-Khatib SM, Han JY, et al. Survival benefit of the primary prevention implantable cardioverter-defibrillator among older patients: does age matter? An analysis of pooled data from 5 clinical trials. Circ Cardiovasc Qual Outcomes 2015; 8:179. 77. Steinberg BA, Al-Khatib SM, Edwards R, et al. Outcomes of implantable cardioverter- defibrillator use in patients with comorbidities: results from a combined analysis of 4 randomized clinical trials. JACC Heart Fail 2014; 2:623. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 29/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 78. Kusumoto FM, Bailey KR, Chaouki AS, et al. Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:1653. 79. Friedman DJ, Parzynski CS, Varosy PD, et al. Trends and In-Hospital Outcomes Associated With Adoption of the Subcutaneous Implantable Cardioverter Defibrillator in the United States. JAMA Cardiol 2016; 1:900. 80. Zakine C, Garcia R, Narayanan K, et al. Prophylactic implantable cardioverter-defibrillator in the very elderly. Europace 2019; 21:1063. 81. Jukema JW, Timal RJ, Rotmans JI, et al. Prophylactic Use of Implantable Cardioverter- Defibrillators in the Prevention of Sudden Cardiac Death in Dialysis Patients. Circulation 2019; 139:2628. 82. Kusumoto FM, Calkins H, Boehmer J, et al. HRS/ACC/AHA expert consensus statement on the use of implantable cardioverter-defibrillator therapy in patients who are not included or not well represented in clinical trials. Circulation 2014; 130:94. 83. Russo AM, Stainback RF, Bailey SR, et al. ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation appropriate use criteria task force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2013; 61:1318. 84. Adabag S, Patton KK, Buxton AE, et al. Association of Implantable Cardioverter Defibrillators With Survival in Patients With and Without Improved Ejection Fraction: Secondary Analysis of the Sudden Cardiac Death in Heart Failure Trial. JAMA Cardiol 2017; 2:767. 85. Ruwald MH, Solomon SD, Foster E, et al. Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: results from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial. Circulation 2014; 130:2278. 86. Kini V, Soufi MK, Deo R, et al. Appropriateness of primary prevention implantable cardioverter-defibrillators at the time of generator replacement: are indications still met? J Am Coll Cardiol 2014; 63:2388. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 30/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate 87. Zhang Y, Guallar E, Blasco-Colmenares E, et al. Changes in Follow-Up Left Ventricular Ejection Fraction Associated With Outcomes in Primary Prevention Implantable Cardioverter-Defibrillator and Cardiac Resynchronization Therapy Device Recipients. J Am Coll Cardiol 2015; 66:524. 88. Madeira M, Ant nio N, Milner J, et al. Who still remains at risk of arrhythmic death at time of implantable cardioverter-defibrillator generator replacement? Pacing Clin Electrophysiol 2017; 40:1129. 89. Weng W, Sapp J, Doucette S, et al. Benefit of Implantable Cardioverter-Defibrillator Generator Replacement in a Primary Prevention Population-Based Cohort. JACC Clin Electrophysiol 2017; 3:1180. 90. Witt CM, Waks JW, Mehta RA, et al. Risk of Appropriate Therapy and Death Before Therapy After Implantable Cardioverter-Defibrillator Generator Replacement. Circ Arrhythm Electrophysiol 2018; 11:e006155. 91. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 92. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008; 51:1357. 93. Dichtl W, Wolber T, Paoli U, et al. Appropriate therapy but not inappropriate shocks predict survival in implantable cardioverter defibrillator patients. Clin Cardiol 2011; 34:433. 94. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012; 367:2275. 95. Gasparini M, Proclemer A, Klersy C, et al. Effect of long-detection interval vs standard- detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: the ADVANCE III randomized clinical trial. JAMA 2013; 309:1903. 96. Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016; 13:e50. Topic 91077 Version 39.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 31/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate GRAPHICS Modes of death based on heart failure severity As the severity of heart failure symptoms worsens, the mode of death is less likely to be arrhythmic sudden cardiac death and more likely to be due to heart failure. NYHA: New York Heart Association; CHF: congestive heart failure. Graphic 98258 Version 2.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 32/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Summary of primary prevention implantable cardioverter-defibrillator (ICD) trials Number Enrollment/follow- Ischemic/non- Med Trial of Entry criteria up ischemic CMP thera patients Ischemic CMP (late post-MI) trials MADIT-I 1991 to 1996 Mean follow-up 27 196 100%/0% Prior MI BB - NSVT on ECG ACE/A months monitoring 58% LVEF 35% MRA NYHA I/II/III AAD Inducible VT during EPS MUSTT 1990 to 1996 Mean follow-up 39 months 704 100%/0% Prior MI BB - 4 NSVT on ECG monitoring ACE/A 75% LVEF 40% MRA NYHA I/II/III AAD Inducible VT during EPS CABG-Patch 1993 to 1996 900 100%/0% <80 years old BB - Mean follow-up 32 months Scheduled for elective CABG ACE-I MRA LVEF <36% AAD Abnormal SAECG MADIT-II 1997 to 2001 Mean follow-up 20 1232 100%/0% Prior MI BB - 7 LVEF 35% ACE/A 70% months NYHA I/II/III MRA AAD Ischemic CMP (early post-MI) trials DINAMIT 1998 to 2003 674 100%/0% 6 to 40 days BB - Mean follow-up 30 post-MI ACE-I months LVEF 35% MRA https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 33/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Impaired AAD autonomic function (depressed HR variability or elevated average 24- hour HR on Holter monitoring) IRIS 1999 to 2007 Mean follow-up 37 898 100%/0% 5 to 31 days BB - post-MI ACE-I months LVEF 40% and HR 90 BPM on first MRA AAD ECG or NSVT Combined ischemic and nonischemic CMP trial SCD-HeFT 1997 to 2003 Mean follow-up 45 2521 52%/48% HF for 3 months BB - ACE/A 85% months LVEF 35% NYHA II/III MRA AAD rand to amio addit 7% cross amio Nonischemic CMP trials DEFINITE 1998 to 2003 458 0%/100% Nonischemic BB - Mean follow-up 29 months CMP ACE/A LVEF 35% 97% NYHA I/II/III MRA PVCs or NSVT AAD COMPANION 2000 to 2002 1520 55%/45% LVEF 35% BB - Median follow-up of 16 months NYHA III/IV ACE/A requiring hospitalization 69% MRA AAD https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 34/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate within prior year DANISH 2008 to 2014 Mean follow-up 68 1114 0%/100% Nonischemic BB - CMP ACE/A months LVEF 35% 97% NYHA II/III (or MRA IV if CRT planned) CRT - AAD AAD: antiarrhythmic drugs; ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta blocker; BPM: beats per minute; CABG: coronary artery bypass graft surgery; CMP: cardiomyopathy; CRT: cardiac resynchronization therapy; HF: heart failure; ECG: electrocardiogram; EPS: electrophysiologic study; ICD: implantable cardioverter-defibrillator; LVEF: left ventricular ejection fraction; MI: myocardial infarction; MRA: mineralocorticoid receptor antagonist; NR: not reported (likely near zero given early date of trial); NSVT: nonsustained ventricular tachycardia; NYHA: New York Heart Association; PVC: premature ventricular contraction; SAECG: signal averaged electrocardiogram; SCA: sudden cardiac arrest; VT: ventricular tachycardia. Epicardial ICDs were predominantly used in the CABG Patch trial, as patients were all undergoing CABG. This is not consistent with contemporary practice. Some patients with NYHA class IV functional status were enrolled in MADIT-II, but the requirement was to be NYHA class I/II/III at the time of enrollment. Graphic 98261 Version 5.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 35/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac Ordinary physical Patients can perform to disease but without activity, such as completion any activity requiring 7 metabolic equivalents (ie, can resulting limitations of physical activity. walking and climbing stairs, does not cause Ordinary physical activity does not cause angina. Angina with strenuous or rapid carry 24 lb up 8 steps; do outdoor work undue fatigue, palpitation, dyspnea, or prolonged exertion at work or recreation. [shovel snow, spade soil]; do recreational anginal pain. activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in Slight limitation of ordinary activity. Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse without stopping, garden, rake, weed, roller skate, dance foxtrot, walk at 4 mph slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal Walking or climbing stairs rapidly, walking uphill, walking or stair- climbing after meals, in cold, in wind, or when under emotional stress, or only during pain. the few hours after awakening. Walking more than 2 blocks on on level ground) but cannot and do not perform to completion activities requiring 7 metabolic equivalents. the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac disease resulting in Marked limitation of ordinary physical Patients can perform to completion any activity requiring 2 metabolic equivalents (eg, shower without stopping, strip marked limitation of activity. Walking 1 to 2 physical activity. They are comfortable at rest. blocks on the level and climbing 1 flight in Less-than-ordinary physical activity causes normal conditions. and make bed, clean windows, walk 2.5 fatigue, palpitation, mph, bowl, play golf, https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 36/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate dyspnea, or anginal dress without stopping) pain. but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac Inability to carry on any Patients cannot or do disease resulting in physical activity not perform to inability to carry on any physical activity without discomfort. Anginal syndrome may completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac be present at rest. equivalents. Cannot carry out activities insufficiency or of the anginal syndrome may listed above (specific activity scale III). be present even at rest. If any physical activity is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 37/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Pacing leads for cardiac resynchronization therapy Two leads (right atrial and right ventricular leads) permit pacing of the right atrium and right ventricle. The third lead (coronary sinus lead), which is advanced through the coronary sinus into a venous branch that runs along the free wall of the left ventricle, paces the lateral wall and enables synchronized left ventricular contraction. Graphic 79450 Version 5.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 38/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Implantable defibrillator versus conventional drug therapy Kaplan-Meier cumulative survival curves in the MADIT trial showing that selected high-risk patients (prior infarction, left ventricular ejection fraction 35 percent, nonsustained ventricular tachycardia, and an inducible sustained ventricular tachyarrhythmia not supressible with procainamide) have a better survival rate with an implantable defibrillator compared with conventional therapy with antiarrhythmic drugs (p = 0.009). The number of patients at each time period is noted at the bottom. Data from: Moss AJ, Hall WJ, Cannom DS, et al for the Multicenter Automatic De brillator Implantation Trial Investigators, N Engl J Med 1996; 335:1933. Graphic 76854 Version 2.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 39/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate ICD reduces sudden death in MUSTT The MUSTT trial enrolled 704 patients with coronary artery disease, nonsustained ventricular tachycardia (VT), and a left ventricular ejection fraction 40 percent who had sustained VT induced during electrophysiologic (EP) study. Kaplan-Meier estimates show that the incidence of cardiac arrest or death from arrhythmia is significantly lower in those receiving an implantable cardioverter-defibrillator (ICD) compared with those receiving no therapy or those with EP-guided (EPG) antiarrhythmic drug (AAD) therapy. Data from: Buxton AE, Lee KL, Fisher JD, et al. N Engl J Med 1999; 341:1882. Graphic 68247 Version 4.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 40/43 7/6/23, 3:09 PM

surgery; CMP: cardiomyopathy; CRT: cardiac resynchronization therapy; HF: heart failure; ECG: electrocardiogram; EPS: electrophysiologic study; ICD: implantable cardioverter-defibrillator; LVEF: left ventricular ejection fraction; MI: myocardial infarction; MRA: mineralocorticoid receptor antagonist; NR: not reported (likely near zero given early date of trial); NSVT: nonsustained ventricular tachycardia; NYHA: New York Heart Association; PVC: premature ventricular contraction; SAECG: signal averaged electrocardiogram; SCA: sudden cardiac arrest; VT: ventricular tachycardia. Epicardial ICDs were predominantly used in the CABG Patch trial, as patients were all undergoing CABG. This is not consistent with contemporary practice. Some patients with NYHA class IV functional status were enrolled in MADIT-II, but the requirement was to be NYHA class I/II/III at the time of enrollment. Graphic 98261 Version 5.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 35/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac Ordinary physical Patients can perform to disease but without activity, such as completion any activity requiring 7 metabolic equivalents (ie, can resulting limitations of physical activity. walking and climbing stairs, does not cause Ordinary physical activity does not cause angina. Angina with strenuous or rapid carry 24 lb up 8 steps; do outdoor work undue fatigue, palpitation, dyspnea, or prolonged exertion at work or recreation. [shovel snow, spade soil]; do recreational anginal pain. activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in Slight limitation of ordinary activity. Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse without stopping, garden, rake, weed, roller skate, dance foxtrot, walk at 4 mph slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal Walking or climbing stairs rapidly, walking uphill, walking or stair- climbing after meals, in cold, in wind, or when under emotional stress, or only during pain. the few hours after awakening. Walking more than 2 blocks on on level ground) but cannot and do not perform to completion activities requiring 7 metabolic equivalents. the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac disease resulting in Marked limitation of ordinary physical Patients can perform to completion any activity requiring 2 metabolic equivalents (eg, shower without stopping, strip marked limitation of activity. Walking 1 to 2 physical activity. They are comfortable at rest. blocks on the level and climbing 1 flight in Less-than-ordinary physical activity causes normal conditions. and make bed, clean windows, walk 2.5 fatigue, palpitation, mph, bowl, play golf, https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 36/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate dyspnea, or anginal dress without stopping) pain. but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac Inability to carry on any Patients cannot or do disease resulting in physical activity not perform to inability to carry on any physical activity without discomfort. Anginal syndrome may completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac be present at rest. equivalents. Cannot carry out activities insufficiency or of the anginal syndrome may listed above (specific activity scale III). be present even at rest. If any physical activity is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 37/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Pacing leads for cardiac resynchronization therapy Two leads (right atrial and right ventricular leads) permit pacing of the right atrium and right ventricle. The third lead (coronary sinus lead), which is advanced through the coronary sinus into a venous branch that runs along the free wall of the left ventricle, paces the lateral wall and enables synchronized left ventricular contraction. Graphic 79450 Version 5.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 38/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Implantable defibrillator versus conventional drug therapy Kaplan-Meier cumulative survival curves in the MADIT trial showing that selected high-risk patients (prior infarction, left ventricular ejection fraction 35 percent, nonsustained ventricular tachycardia, and an inducible sustained ventricular tachyarrhythmia not supressible with procainamide) have a better survival rate with an implantable defibrillator compared with conventional therapy with antiarrhythmic drugs (p = 0.009). The number of patients at each time period is noted at the bottom. Data from: Moss AJ, Hall WJ, Cannom DS, et al for the Multicenter Automatic De brillator Implantation Trial Investigators, N Engl J Med 1996; 335:1933. Graphic 76854 Version 2.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 39/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate ICD reduces sudden death in MUSTT The MUSTT trial enrolled 704 patients with coronary artery disease, nonsustained ventricular tachycardia (VT), and a left ventricular ejection fraction 40 percent who had sustained VT induced during electrophysiologic (EP) study. Kaplan-Meier estimates show that the incidence of cardiac arrest or death from arrhythmia is significantly lower in those receiving an implantable cardioverter-defibrillator (ICD) compared with those receiving no therapy or those with EP-guided (EPG) antiarrhythmic drug (AAD) therapy. Data from: Buxton AE, Lee KL, Fisher JD, et al. N Engl J Med 1999; 341:1882. Graphic 68247 Version 4.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 40/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Prophylactic ICD does not improve survival in high- risk patients after CABG The CABG-Patch trial randomized 900 patients with a low ejection fraction and a positive signal-averaged electrocardiogram to an implantable cardioverter-defibrillator or no defibrillator after coronary artery bypass graft surgery. There was no difference in mortality at a mean follow-up of 32 months. Data from: Bigger JT, for the Coronary Artery Bypass Graft (CABG) Patch Trial Investigators, N Engl J Med 1997; 337:1569. Graphic 78888 Version 4.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 41/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate ICD improves survival in MADIT II Kaplan-Meier estimates of the probability of survival in the MADIT II trial in 1232 patients who had a myocardial infarction more than 30 days prior to enrollment (and more than three months if bypass surgery was performed) and an LVEF 30 percent. The patients were randomly assigned to a prophylactic ICD or conventional medical therapy. The study was prematurely terminated after an average follow-up of 20 months because the ICD significantly reduced all- cause mortality (14.2 versus 19.8 percent for conventional therapy, hazard ratio 0.65, 95% CI 0.51-0.93). The survival benefit was largely due to a reduction in sudden death. LVEF: left ventricular ejection fraction; ICD: implantable cardioverter- defibrillator. Data from: Moss AJ, Zareba W, Hall WJ, et al. N Engl J Med 2002; 346:877. Graphic 63529 Version 4.0 https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 42/43 7/6/23, 3:09 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Contributor Disclosures Joseph E Marine, MD, FACC, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Andrea M Russo, MD, FACC, FHRS Grant/Research/Clinical Trial Support: BMS/Pfizer [Anticoagulant]; Boston Scientific [Arrhythmia]; Kestra [Arrhythmia]; Medilynx [Arrhythmia]; Medtronic [Arrhythmia]. Consultant/Advisory Boards: Abbott [Arrhythmia]; Atricure [Arrhythmia]; Biosense Webster [Arrhythmia]; Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]; PaceMate [Arrhythmia]. Speaker's Bureau: Biotronik [Arrhythmia]; Medtronic [Arrhythmia]. Other Financial Interest: ABIM [Cardiovascular board]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 43/43

7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Restoration of sinus rhythm in atrial flutter : Jordan M Prutkin, MD, MHS, FHRS : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 24, 2023. INTRODUCTION Atrial flutter is a supraventricular arrhythmia that can cause bothersome symptoms and promote atrial thrombus formation with the potential for systemic embolization. Restoration of sinus rhythm improves symptoms and decreases the risk of embolization if recurrence does not occur. (See "Overview of atrial flutter", section on 'Clinical manifestations' and "Embolic risk and the role of anticoagulation in atrial flutter", section on 'Embolic risk'.) Issues related to the indications and therapeutic options for the restoration of sinus rhythm in atrial flutter will be reviewed here. Causes of atrial flutter, rate control therapy, the maintenance of sinus rhythm after cardioversion, and the role of anticoagulation in atrial flutter are discussed separately. (See "Control of ventricular rate in atrial flutter" and "Atrial flutter: Maintenance of sinus rhythm" and "Embolic risk and the role of anticoagulation in atrial flutter".) RATIONALE Atrial flutter is a relatively common supraventricular arrhythmia that is characterized by rapid, regular atrial depolarizations at a characteristic rate of approximately 300 beats/min. (See "ECG tutorial: Atrial and atrioventricular nodal (supraventricular) arrhythmias", section on 'Atrial fibrillation and atrial flutter' and "Overview of atrial flutter".) In the absence of rate slowing drugs or atrioventricular (AV) nodal disease, most commonly, every other beat is conducted through the AV node so that the ventricular rate is usually around 150 beats per minute. Because of the rapid rate, the patient may present with symptoms of https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 1/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate palpitations, chest pain, dyspnea, fatigue, dizziness, and rarely hemodynamic shock, similar to patients with atrial fibrillation (AF) with a rapid ventricular response. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Adverse hemodynamics in AF'.) In addition to improving symptoms, the restoration of sinus rhythm prevents the potential for the development of tachycardia-mediated cardiomyopathy and somewhat reduces the risk of systemic embolization. (See "Arrhythmia-induced cardiomyopathy", section on 'Atrial fibrillation and atrial flutter' and "Embolic risk and the role of anticoagulation in atrial flutter", section on 'Embolic risk'.) Atrial flutter is often an electrically unstable rhythm, meaning that it frequently degenerates into the more disorganized atrial fibrillation (AF) or reverts to sinus rhythm within hours or days, though it can also be chronic. Spontaneous reversion to a sinus mechanism may occur after predisposing problems are improved, such as decompensated heart failure (HF) or the sequelae of cardiac surgery. In patients who do not spontaneously convert to sinus rhythm, rate slowing with drugs may be considered a therapeutic option. The ventricular rate is frequently difficult to control, however, as most medications are ineffective for rate slowing and for many patients it is not worth attempting as a long-term alternative to rhythm control. Rate control may be appropriate for patients who are reluctant to undergo cardioversion or who have no or minimal symptoms. (See "Control of ventricular rate in atrial flutter".) For those patients in whom a decision has been made to restore sinus rhythm, most can be cardioverted successfully without complication. Factors that predict spontaneous reversion to sinus rhythm or a successful cardioversion are similar to those for AF, and include a left atrial size less than 4.5 to 5 cm, little or no heart failure or left ventricular dysfunction, no underlying reversible cause such as hyperthyroidism, myocardial infarction, or pulmonary embolism, and atrial flutter of recent onset. (See "Atrial fibrillation: Cardioversion", section on 'Reasons not to perform cardioversion'.) INDICATIONS Most patients with atrial flutter who do not undergo spontaneous conversion to sinus rhythm should undergo cardioversion. The following are indications for urgent cardioversion: Patients with atrial flutter who have a rapid ventricular rate and significant hemodynamic compromise (hypotension or heart failure) should undergo urgent cardioversion. In https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 2/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate patients with atrial flutter and hemodynamic compromise, but with a controlled ventricular rate (eg, 100 beats/min), explanations for hemodynamic instability other than the atrial flutter should be sought. Restoration of sinus rhythm in these patients may not necessarily improve the clinical status. Most patients with atrial flutter who are identified as having an accessory pathway with ventricular preexcitation should undergo immediate cardioversion. (See "Wolff-Parkinson- White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis", section on 'Atrial flutter'.) For patients with minimal symptoms or signs attributable to atrial flutter, conversion to sinus rhythm may be deferred in anticipation of either spontaneous conversion or radiofrequency catheter ablation. (See 'Radiofrequency catheter ablation' below.) Among those patients who are not urgently cardioverted and who do not spontaneously revert to sinus rhythm, elective restoration of sinus rhythm is favored to decrease the risk of tachycardia-mediated cardiomyopathy. (See 'Rationale' above.) This is in contrast to atrial fibrillation (AF), in which tolerance of permanent AF may be more likely chosen since rate control is usually possible. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Control of ventricular rate in atrial flutter", section on 'Summary and recommendations'.) Circumstances in which it is reasonable to avoid cardioversion in patients with new onset atrial flutter include: Patients who are completely asymptomatic, particularly those who are elderly with multiple comorbidities or poor overall prognosis, where the risks of undergoing cardioversion and/or pharmacologic rhythm control may outweigh the benefits of restoring sinus rhythm. Patients who have a bleeding risk and cannot be anticoagulated during the peri- cardioversion and post-cardioversion periods. METHOD OF CARDIOVERSION For most patients in whom a decision is made to restore sinus rhythm urgently, we prefer electrical to pharmacologic cardioversion. Radiofrequency catheter ablation is an option for stable patients who can wait until this procedure can be performed. Electrical Cardioversion Electrical cardioversion, also called direct current (DC) cardioversion, is a routine procedure in the management of patients with cardiac arrhythmias and is the https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 3/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate preferred means for the immediate restoration of sinus rhythm. With appropriate patient selection and technique, DC cardioversion is rapid and safe. The success rate of 96 to 97 percent is higher than for any antiarrhythmic drug [1,2]. (See 'Pharmacologic cardioversion' below.) Electrical cardioversion should be performed by physicians experienced in the procedure. The patient should be fasting to allow for safe use of sedation, serum electrolytes should be normal, and drug levels, such as digoxin, should be within the therapeutic range. Cardioversion techniques are discussed in detail separately. (See "Basic principles and technique of external electrical cardioversion and defibrillation".) It is expected that normal sinus rhythm will resume once the atrial flutter terminates. Sometimes, atrial fibrillation, ectopic atrial rhythm, or a significant bradycardia may result. The approach to each of these is discussed separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Temporary cardiac pacing".) Pharmacologic enhancement of direct current cardioversion We use pharmacologic enhancement in selected patients. While the success of DC cardioversion is high for atrial flutter, antiarrhythmic drugs may be initiated prior to electrical cardioversion to increase the likelihood of successful cardioversion and long-term maintenance of sinus rhythm [3]. (See "Atrial fibrillation: Cardioversion", section on 'Preprocedural antiarrhythmic drugs'.) The decision to pretreat is often made by a physician experienced with the care of patients with one or more risk factors for cardioversion failure. (See "Atrial fibrillation: Cardioversion", section on 'Reasons not to perform cardioversion'.) The antiarrhythmic drug may restore sinus rhythm prior to DC cardioversion in some cases or may help prevent recurrent episodes of atrial flutter early after cardioversion. In addition, for patients in whom long-term antiarrhythmic therapy will be used, early initiation (prior to DC cardioversion) may allow for an evaluation of tolerability of one or more drugs. For those patients in whom a decision has been made to attempt the long- term maintenance of sinus rhythm with antiarrhythmic drug therapy, it is reasonable to preferentially select a drug for cardioversion that can also be used for long-term maintenance. Based on these considerations, we use pharmacologic enhancement in selected patients, such as those in whom ablation will not be performed. Pharmacologic cardioversion A number of antiarrhythmic drugs may be used to terminate atrial flutter and restore sinus rhythm. However, antiarrhythmic drugs are less effective than DC cardioversion and carry some degree of proarrhythmic risk. Thus, pharmacologic cardioversion is generally reserved for selected clinical scenarios. The most common reason for selecting pharmacologic cardioversion is that moderate or deep sedation is either unavailable or is expected to be poorly tolerated (for example, as in patients with hypotension). https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 4/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate Most of the available data on the efficacy of antiarrhythmic drugs for the restoration of sinus rhythm are from patients with atrial fibrillation (AF). The drugs that are effective in converting AF to sinus rhythm may also be effective in converting atrial flutter. These include flecainide, dofetilide, propafenone, ibutilide, and amiodarone. Ibutilide and dofetilide have been better studied than the other drugs discussed below. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.) Ibutilide Ibutilide, approved by the United States Food and Drug Administration for intravenous use, converts atrial flutter to sinus rhythm in approximately 60 percent of patients (compared to a 0 to 2 percent response to placebo) with a mean time to conversion of 30 minutes [4-6]. Ibutilide is more effective than procainamide for reversion of atrial flutter (64 to 76 versus 0 to 14 percent) [7,8], and is also more effective than sotalol (70 versus 19 percent) ( figure 1) [9] and amiodarone (87 versus 29 percent) [10]. (See "Therapeutic use of ibutilide".) The most serious concern with ibutilide is QT interval prolongation that can lead to torsades de pointes [4-6]. The potential for torsades de pointes is increased in patients with severe heart failure or those who are being treated with another drug that prolongs the QT interval. On the other hand, the risk of proarrhythmia does not appear to be increased when ibutilide is given with amiodarone [11]. Because of the risk of torsades de pointes, patients treated with ibutilide should be observed with continuous electrocardiogram (ECG) monitoring for at least four hours after the infusion. (See "Therapeutic use of ibutilide", section on 'Proarrhythmia'.) The addition of intravenous magnesium, in doses of 4 to 10 grams, can enhance the cardioverting effect of ibutilide and may reduce the risk of torsades de pointes as well [12,13]. Dofetilide Oral dofetilide is effective for conversion of atrial flutter and the conversion rate appears to be higher than in AF. As an example, the SAFIRE-D study randomly assigned 325 patients with AF (n = 277) or atrial flutter (n = 48) to 125, 250, and 500 g of dofetilide twice daily [14]. At a dose of 500 g, the conversion rates for AF and atrial flutter were 22 and 67 percent, respectively, compared to 1.2 percent for placebo. Conversion to sinus rhythm occurred in 70 percent within 24 hours, while 91 percent converted within 36 hours. Dofetilide has the disadvantage of requiring the patient to be hospitalized for the first six doses, as it can cause torsade de pointes and sudden death [15,16]. Intravenous dofetilide, which is not available in the United States, also appears to be effective for conversion of atrial flutter. In one study of 16 patients, 54 percent reverted to https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 5/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate sinus rhythm after dofetilide administration while in another series of 17 patients the rate of reversion was 64 percent, compared with 0 percent for placebo [17,18]. Intravenous dofetilide is more effective than intravenous amiodarone. In a randomized trial that included 31 patients with atrial flutter, the reversion rate with dofetilide was 75 percent versus 0 and 10 percent for amiodarone and placebo, respectively [19]. The following drugs are less commonly used or not recommended in this setting: Amiodarone Intravenous (IV) amiodarone is sometimes used for atrial flutter conversion, but data are limited. A small study of nine patients with atrial flutter demonstrated no patients converting with IV amiodarone [19]. Another study of 21 patients showed a success rate of 29 percent with IV amiodarone compared to 87 percent for ibutilide [10]. Class IA antiarrhythmic drugs The class IA antiarrhythmic drugs (quinidine, procainamide, and disopyramide) slow the rate of contraction of the atria but also may have a significant vagolytic effect which increases atrioventricular (AV) nodal conduction. These combined actions can result in 1:1 conduction at very rapid ventricular rates ( waveform 1). For this reason, we do not recommend their use unless patients are pretreated with a drug(s) that blocks AV nodal conduction such as beta or calcium channel blockers. Class IC antiarrhythmic drugs The class IC antiarrhythmic drugs propafenone and flecainide are less efficacious than other agents. Although they do not accelerate AV conduction, they can slow the atrial flutter rate, often to a greater extent than the class IA drugs. Slowing of the atrial flutter rate alone (eg, to 200 or 250 beats/min) can lead to 1:1 AV conduction. We do not recommend their use unless patients are pretreated with a drug(s) that blocks AV nodal conduction such as beta or calcium channel blockers. Rate control drugs Digoxin, nondihydropyridine calcium channel blockers [20-22], and beta blockers can all be effective in the control of the ventricular rate during atrial flutter. Although the hemodynamic improvement associated with a normalized ventricular rate may indirectly facilitate reversion to sinus rhythm, these drugs should be considered for the purpose of rate control, not for restoring sinus rhythm. (See "Control of ventricular rate in atrial flutter".) Vernakalant Intravenous vernakalant is approved by the European Commission for the rapid conversion of recent-onset atrial fibrillation ( 7 days duration for patients not undergoing surgery and 3 days duration for postcardiac surgery patients) to sinus rhythm. Based on one study in which the drug converted only 1 of 14 patients with atrial https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 6/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate flutter, we do not recommend its use [23]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Class III'.) Radiofrequency catheter ablation Radiofrequency catheter ablation (RFA) can be performed while a stable patient is in atrial flutter. In this setting, sinus rhythm is restored during the procedure. The use of RFA to interrupt the reentrant circuit supporting atrial flutter in order to permanently maintain normal sinus rhythm is discussed elsewhere [24,25]. (See "Atrial flutter: Maintenance of sinus rhythm".) Atrial overdrive pacing Atrial overdrive pacing may be used for cardioversion in selected patients with flutter, though it is rarely performed because of the high success rate of direct current cardioversion and/or ablation. In atrial flutter, if the atrium is paced approximately 10 percent faster than the atrial flutter rate for 15 to 30 seconds, the rate of the tachycardia increases to match that of the faster pacing rate; that is, it is entrained [26-28]. When the pacing is discontinued, one of several results may ensue: The original atrial flutter may return. The atrial flutter may cease with restoration of normal sinus rhythm ( waveform 2). The patient may convert to AF. The atrial flutter may change, possibly at a faster rate [29]. Atrial pacing can be useful in selected patients, including the following [26-28,30-32]: After cardiac surgery, since atrial pacing wires are often left in place during the early postoperative period. In patients with a pacemaker or implantable cardioverter-defibrillator where rapid pacing may be available through the device. Very rarely, a temporary pacemaker may be used: In patients who have recurrent atrial flutter due to an acute stress such as a myocardial infarction or respiratory failure; this represents a setting in which one would like to avoid repeated DC shocks and a temporary transvenous pacemaker can be used. In patients who have digitalis toxicity, a condition in which DC cardioversion may be particularly dangerous. https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 7/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate In patients in whom anesthesia is a risk and pharmacologic cardioversion is not desired or unavailable [26-28,33,34]. The success rate of rapid atrial pacing may be increased by the concurrent intravenous administration of procainamide or ibutilide [35-37]. ANTICOAGULATION We agree with recommendations from the American Heart Association/American College of Cardiology/Heart Rhythm Society guideline on atrial fibrillation, which recommend that consideration be given to managing anticoagulation during cardioversion of atrial flutter in a manner similar to that for atrial fibrillation [38-41]. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation" and "Embolic risk and the role of anticoagulation in atrial flutter", section on 'Cardioversion'.) MAINTENANCE OF SINUS RHYTHM After conversion to sinus rhythm, an attempt should be made to address all correctable causes of atrial flutter (eg, thyrotoxicosis or obesity). (See "Overview of atrial flutter", section on 'Etiology and risk factors'.) In addition to radiofrequency catheter ablation (see 'Radiofrequency catheter ablation' above), pharmacologic therapy can be used to maintain sinus rhythm. This issue is discussed in detail elsewhere. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'Pharmacologic therapy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 8/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial flutter (The Basics)") SUMMARY AND RECOMMENDATIONS Hemodynamically unstable patient For atrial flutter patients who have a rapid ventricular rate and evidence of hemodynamic instability or severe symptoms including myocardial ischemia, hypotension, angina, heart failure, or evidence of ventricular preexcitation, we recommend urgent electrical cardioversion rather than any other approach (Grade 1A). (See 'Indications' above and 'Electrical Cardioversion' above.) Stable patient For stable patients with atrial flutter, we suggest elective electrical cardioversion rather than pharmacologic cardioversion or atrial pacing in patients without atrial leads (Grade 2A). Patients who may reasonably prefer other approaches such as an attempt at pharmacologic conversion (or at rate control) include those who prefer not to undergo electrical cardioversion or those for whom moderate or deep sedation will be poorly tolerated or not available. Radiofrequency catheter ablation, if performed in a timely manner, is a reasonable alternative to electrical cardioversion. (See 'Indications' above and 'Electrical Cardioversion' above.) Available data do not support the recommendation of a specific antiarrhythmic drug if pharmacologic conversion will be attempted. Options include ibutilide, amiodarone, flecainide, propafenone, or dofetilide. We prefer ibutilide in situations where we desire acute pharmacologic cardioversion of atrial flutter. (See 'Pharmacologic cardioversion' above.) Indications for overdrive pacing For patients with atrial pacing wires in place (either as part of a permanent pacemaker, implantable-cardioverter defibrillator, or temporary https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 9/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate pacing wires after cardiac surgery), we suggest rapid atrial pacing rather than electrical cardioversion (Grade 2C). (See 'Atrial overdrive pacing' above.) As rapid atrial pacing can cause atrial flutter to degenerate into atrial fibrillation (AF), the physician should be prepared for the management of AF. Anticoagulation Anticoagulation during cardioversion of atrial flutter should be managed in a manner similar to that for atrial fibrillation. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation" and "Embolic risk and the role of anticoagulation in atrial flutter", section on 'Cardioversion'.) Method of rhythm control In addition to radiofrequency catheter ablation, pharmacologic therapy can be used to maintain sinus rhythm. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation' and "Atrial flutter: Maintenance of sinus rhythm", section on 'Pharmacologic therapy'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Gallagher MM, Guo XH, Poloniecki JD, et al. Initial energy setting, outcome and efficiency in direct current cardioversion of atrial fibrillation and flutter. J Am Coll Cardiol 2001; 38:1498. 2. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Prediction of uneventful cardioversion and maintenance of sinus rhythm from direct-current electrical cardioversion of chronic atrial fibrillation and flutter. Am J Cardiol 1991; 68:41. 3. Naccarelli GV, Dell'Orfano JT, Wolbrette DL, et al. Cost-effective management of acute atrial fibrillation: role of rate control, spontaneous conversion, medical and direct current cardioversion, transesophageal echocardiography, and antiembolic therapy. Am J Cardiol 2000; 85:36D. 4. Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation 1996; 94:1613. 5. Ellenbogen KA, Stambler BS, Wood MA, et al. Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study. J Am Coll Cardiol 1996; 28:130. 6. Abi-Mansour P, Carberry PA, McCowan RJ, et al. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Study Investigators. Am Heart J 1998; 136:632. https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 10/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate 7. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intravenous ibutilide compared with procainamide during human atrial flutter and fibrillation: electrophysiological determinants of enhanced conversion efficacy. Circulation 1997; 96:4298. 8. Volgman AS, Carberry PA, Stambler B, et al. Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation. J Am Coll Cardiol 1998; 31:1414. 9. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL- sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568. 10. Kafkas NV, Patsilinakos SP, Mertzanos GA, et al. Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset atrial fibrillation and atrial flutter. Int J Cardiol 2007; 118:321. 11. Glatter K, Yang Y, Chatterjee K, et al. Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients receiving amiodarone therapy. Circulation 2001; 103:253. 12. Patsilinakos S, Christou A, Kafkas N, et al. Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. Am J Cardiol 2010; 106:673. 13. Tercius AJ, Kluger J, Coleman CI, White CM. Intravenous magnesium sulfate enhances the ability of intravenous ibutilide to successfully convert atrial fibrillation or flutter. Pacing Clin Electrophysiol 2007; 30:1331. 14. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000; 102:2385. 15. Mounsey JP, DiMarco JP. Cardiovascular drugs. Dofetilide. Circulation 2000; 102:2665. 16. Abraham JM, Saliba WI, Vekstein C, et al. Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter. Circ Arrhythm Electrophysiol 2015; 8:772. 17. Falk RH, Pollak A, Singh SN, Friedrich T. Intravenous dofetilide, a class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. Intravenous Dofetilide Investigators. J Am Coll Cardiol 1997; 29:385. 18. N rgaard BL, Wachtell K, Christensen PD, et al. Efficacy and safety of intravenously administered dofetilide in acute termination of atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled trial. Danish Dofetilide in Atrial Fibrillation and Flutter Study Group. Am Heart J 1999; 137:1062. https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 11/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate 19. Bianconi L, Castro A, Dinelli M, et al. Comparison of intravenously administered dofetilide versus amiodarone in the acute termination of atrial fibrillation and flutter. A multicentre, randomized, double-blind, placebo-controlled study. Eur Heart J 2000; 21:1265. 20. Schamroth L, Krikler DM, Garrett C. Immediate effects of intravenous verapamil in cardiac arrhythmias. Br Med J 1972; 1:660. 21. Hagemeijer F. Verapamil in the management of supraventricular tachyarrhythmias occurring after a recent myocardial infarction. Circulation 1978; 57:751. 22. Wolfson S, Herman MV, Sullivan JM, Gorlin R. Conversion of atrial fibrillation and flutter by propranolol. Br Heart J 1967; 29:305. 23. Pratt CM, Roy D, Torp-Pedersen C, et al. Usefulness of vernakalant hydrochloride injection for rapid conversion of atrial fibrillation. Am J Cardiol 2010; 106:1277. 24. Saoudi N, Atallah G, Kirkorian G, Touboul P. Catheter ablation of the atrial myocardium in human type I atrial flutter. Circulation 1990; 81:762. 25. Da Costa A, Th venin J, Roche F, et al. Results from the Loire-Ard che-Dr me-Is re-Puy-de- D me (LADIP) trial on atrial flutter, a multicentric prospective randomized study comparing amiodarone and radiofrequency ablation after the first episode of symptomatic atrial flutter. Circulation 2006; 114:1676. 26. Waldo AL, MacLean WA, Karp RB, et al. Entrainment and interruption of atrial flutter with atrial pacing: studies in man following open heart surgery. Circulation 1977; 56:737. 27. Waldo AL, Carlson MD, Biblo LA, Henthorn RW. The role of transient entrainment in atrial flu tter. In: Atrial Arrhythmias: Current Concepts and Management, Tourboul P, Waldo AL (Eds), Mosby Year Book, St Louis 1990. p.210. 28. Greenberg ML, Kelly TA, Lerman BB, DiMarco JP. Atrial pacing for conversion of atrial flutter. Am J Cardiol 1986; 58:95. 29. Cheng J, Scheinman MM. Acceleration of typical atrial flutter due to double-wave reentry induced by programmed electrical stimulation. Circulation 1998; 97:1589. 30. Peters RW, Shorofsky SR, Pelini M, et al. Overdrive atrial pacing for conversion of atrial flutter: comparison of postoperative with nonpostoperative patients. Am Heart J 1999; 137:100. 31. Das G, Anand KM, Ankineedu K, et al. Atrial pacing for cardioversion of atrial flutter in digitalized patients. Am J Cardiol 1978; 41:308. 32. Orlando J, Cassidy J, Aronow WS. High reversion of atrial flutter to sinus rhythm after atrial pacing in patients with pulmonary disease. Chest 1977; 71:580. https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 12/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate 33. Resnekov L. Cardiac arrhythmias. 6. Present status of electroversion in the management of cardiac dysrhythmias. Circulation 1973; 47:1356. 34. Mann DL, Maisel AS, Atwood JE, et al. Absence of cardioversion-induced ventricular arrhythmias in patients with therapeutic digoxin levels. J Am Coll Cardiol 1985; 5:882. 35. Cheng J, Glatter K, Yang Y, et al. Electrophysiological response of the right atrium to ibutilide during typical atrial flutter. Circulation 2002; 106:814. 36. Olshansky B, Okumura K, Hess PG, et al. Use of procainamide with rapid atrial pacing for successful conversion of atrial flutter to sinus rhythm. J Am Coll Cardiol 1988; 11:359. 37. Stambler BS, Wood MA, Ellenbogen KA. Comparative efficacy of intravenous ibutilide versus procainamide for enhancing termination of atrial flutter by atrial overdrive pacing. Am J Cardiol 1996; 77:960. 38. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e531S. 39. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 40. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 41. Writing Group Members, January CT, Wann LS, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2019; 16:e66. Topic 1069 Version 35.0 https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 13/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate GRAPHICS Ibutilide is more effective than sotalol for acute reversion of atrial tachyarrhythmias Among 281 patients with atrial fibrillation or atrial flutter randomized to intravenous ibutilide or intravenous sotalol, both doses of ibutilide were more effective than sotalol for reverting atrial flutter. Among the patients with atrial fibrillation, only the higher dose of ibutilide was significantly more effective than sotalol for restoring sinus rhythm. p <0.05 compared with sotalol. p <0.05 compared with 1 mg ibutilide. Data from: Vos MA, Golitsyn SR, Stangl K, et al. for the Ibutilide/Sotalol Comparator Study Group, Heart 1998; 79:568. Graphic 51703 Version 3.0 https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 14/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate Type I atrial flutter The 1:1 AV conduction was induced by quinidine which both slowed the flutter wave and, via its vagolytic effect, enhanced conduction through the AV node. Courtesy of Morton Arnsdorf, MD. Graphic 55441 Version 3.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 15/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate Entrainment in typical atrial flutter with right atrial pacing with the rate of recording by the ECG machine being slowed by one-half The spontaneous rhythm, in which the flutter waves are not clearly apparent, is shown in the left side of panel A. The right atrium is then paced at just under 400 beats/min; entrainment is achieved at the asterisk when there is a sudden change in atrial morphology as the flutter rate matched the pacing rate. Cessation of pacing led to conversion to sinus rhythm (panel B). Courtesy of Morton Arnsdorf, MD. Graphic 56947 Version 3.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 16/17 7/6/23, 3:09 PM Restoration of sinus rhythm in atrial flutter - UpToDate Contributor Disclosures Jordan M Prutkin, MD, MHS, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/restoration-of-sinus-rhythm-in-atrial-flutter/print 17/17

7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy : Joseph E Marine, MD, FACC, FHRS, Andrea M Russo, MD, FACC, FHRS : Bradley P Knight, MD, FACC, Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 02, 2023. INTRODUCTION Life-threatening ventricular arrhythmias, including sustained ventricular tachycardia (VT) and ventricular fibrillation (VF), are common in patients with heart failure (HF) and cardiomyopathy and may lead to sudden cardiac death (SCD). Secondary prevention of SCD refers to medical or interventional therapy undertaken to prevent SCD in patients who have experienced symptomatic life-threatening sustained VT/VF or have been successfully resuscitated from sudden cardiac arrest. The secondary prevention of SCD in patients with HF and cardiomyopathy will be reviewed here, with emphasis on the role of implantable cardioverter-defibrillators (ICDs). The different types of ventricular arrhythmias, the effects of HF therapy on ventricular arrhythmias, and the role of electrophysiologic testing are discussed separately. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".) The approaches to the treatment of ventricular arrhythmias related to specific heart muscle diseases, such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and isolated left ventricular noncompaction, are discussed elsewhere. (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis" and "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis" and "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".) EPIDEMIOLOGY https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 1/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate While the exact percentages and mode of death in patients with HF vary with HF class and type of cardiomyopathy, progressive pump failure, unexpected SCD, and SCD during episodes of clinical worsening of HF each account for approximately one-third of deaths in HF patients [1]. Ventricular tachycardia (VT) and ventricular fibrillation (VF) are the most common arrhythmic causes of SCD, although bradyarrhythmias and pulseless electrical activity (PEA) are responsible in 5 to 33 percent of cases [2,3]. More severe HF is associated with a higher overall mortality rate and a higher absolute rate of SCD, but a decreasing proportion of SCD to total deaths. This trend was illustrated in the MERIT- HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) trial in which patients with increasing HF class (NYHA class II, III and IV) had increasing rates of SCD at one year (6.3, 10.5, and 18.6 percent, respectively), but a decreasing percentage of deaths that were classified as SCD (64, 59, and 33 percent, respectively) [4]. Patients who have received an implantable cardioverter-defibrillator (ICD) for secondary prevention have significantly higher rates of recurrent ventricular arrhythmias triggering appropriate ICD intervention than recipients of primary prevention ICDs, approximately threefold higher in one national registry from Israel [5]. Although ICD therapy improves survival of patients who suffered prior sudden cardiac arrest, mortality remains high. The mechanisms of death in such patients were illustrated in analyses from several secondary prevention ICD studies [6-8]: Nonarrhythmic cardiac death, usually progressive HF 45 to 50 percent Arrhythmic death 20 to 35 percent Noncardiac death, primarily renal and pulmonary disease 20 to 30 percent Arrhythmic death can occur despite recognition and termination of tachyarrhythmias by the ICD [9]. These deaths often result from PEA, also called electromechanical dissociation (EMD), or acute cardiac mechanical dysfunction [7-9]. PEA or bradyarrhythmias may be the mechanism of SCD in up to 40 percent of patients [7,8]. However, post-mortem interrogation of ICDs demonstrated that 25 percent of sudden deaths in ICD patients (representing 5 percent of all deaths) were caused by inability to defibrillate VF [8]. This situation may occur with VT/VF storm or refractory myocardial ischemia/infarction. SECONDARY PREVENTION OF SCD Patients with HF or cardiomyopathy who survive an episode of sudden cardiac arrest (SCA) or experience sustained ventricular tachycardia (VT) are at high risk of future sustained arrhythmic events and SCD. https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 2/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate Our approach We proceed with implantable cardioverter-defibrillator (ICD) implantation in most survivors of SCA due to sustained VT or ventricular fibrillation (VF), after completely reversible causes are excluded. (See 'Reversible causes of SCA or sustained VT' below.) Antiarrhythmic medications and/or catheter ablation should be used as adjunctive therapy to ICD implantation to suppress recurrent ventricular arrhythmias that lead to ICD therapy. These recommendations are in agreement with 2017 guidelines published by the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) [10]. In rare instances, class III antiarrhythmic drugs, such as sotalol or amiodarone, and/or catheter ablation may be selected as primary therapy for patients who refuse or who are not considered candidates for ICD therapy. Reversible causes of SCA or sustained VT In some survivors of SCA or sustained VT, a transient or reversible cause (eg, acute myocardial ischemia [MI], electrolyte disturbances, medication-related proarrhythmia, etc) can be identified which is felt to have caused the acute problem. Initial treatment should be directed at the underlying disorder. However, prior to concluding that SCA was due to a reversible cause, a thorough evaluation should be performed, usually involving a heart rhythm specialist. For example, in a patient who presents with VF and is found to have mild hypokalemia, it is generally not appropriate to assign the cause of the SCA just to the low potassium level. Correction of a reversible cause of SCA or sustained VT is most likely to be adequate in one of several settings: Polymorphic VT or VF that is preceded by clear evidence of MI or acute MI In such cases, revascularization is often adequate for the purpose of reducing the risk of SCD. However, some of these patients will later qualify for a primary prevention ICD due to severe left ventricular (LV) systolic dysfunction (MADIT II criteria) or systolic dysfunction and HF (SCD- HeFT criteria). Guideline-directed medical therapy should be applied, and follow-up evaluation with a cardiologist soon after discharge should be arranged for additional risk stratification. A repeat evaluation of LV function is recommended >40 days post-MI and >90 days after revascularization to determine if the patient qualifies for ICD implantation based on primary prevention indications [10]. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) Polymorphic VT in the setting of acquired QT prolongation In such cases, withdrawal of the offending drug and avoidance of other QT prolonging medications may be adequate to reduce the risk of SCD. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 3/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate VF occurring in the setting of Wolff-Parkinson-White syndrome in patients with a structurally normal heart These patients are adequately treated with catheter ablation of the accessory pathway. (See "Treatment of arrhythmias associated with the Wolff- Parkinson-White syndrome".) Idiopathic monomorphic VT occurring in the setting of a structurally normal heart Such patients are usually adequately treated with medical therapy or catheter ablation. (See "Ventricular tachycardia in the absence of apparent structural heart disease".) VT/VF occurring in the setting of intentional or accidental drug overdose Examples include cocaine, amphetamines, digoxin, tricyclic antidepressants, and antiarrhythmic drugs. In most other cases, life-threatening ventricular arrhythmias should not be attributed solely to a reversible disorder, and patients should be evaluated according to standard approaches to secondary prevention. Evidence for use of ICD therapy Most patients with HF or cardiomyopathy who have sustained VT or VF are candidates for ICD therapy. The indications for ICD implantation for secondary prevention of SCD are presented here ( table 1), while those for primary prevention are discussed separately. (See 'Our approach' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) AVID trial In the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, 1016 patients who presented with (a) resuscitated VF, (b) sustained VT with syncope, or (c) sustained VT with BP <80 mmHg or significant symptoms (near-syncope, CHF, or angina) suggesting hemodynamic compromise and LV ejection fraction (LVEF) 40 percent were randomized to treatment with either an ICD or antiarrhythmic drugs (primarily amiodarone [96 percent]) [11]. The following findings were noted: The trial was stopped when a significant survival benefit was observed in patients receiving the ICD compared with those treated with antiarrhythmic agents (sotalol or amiodarone). The unadjusted survival for the ICD versus drug groups was 89 versus 82 percent at one year, 82 versus 75 percent at two years, and 75 versus 65 percent at three years. The major effect of the ICD was to prevent arrhythmic death (4.7 versus 10.8 percent with antiarrhythmic drugs); nonarrhythmic cardiac death was equivalent, while patients treated with antiarrhythmic drugs had an insignificantly greater incidence of noncardiac death, primarily from renal and pulmonary causes [6]. https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 4/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate In patients with an LVEF 35 percent, there was no significant difference in survival between ICD and antiarrhythmic drugs (83.4 versus 82.7 percent at two years), while in those with an LVEF between 20 and 34 percent, survival was significantly better with the ICD (83 versus 72 percent) [12]. Among the relatively small number of patients with an LVEF <20 percent, survival tended to be better with the ICD (72 versus 64 percent), but the difference did not reach statistical significance. CASH trial In the Cardiac Arrest Survival in Hamburg (CASH) trial, 349 survivors of cardiac arrest due to documented VT or VF were randomly assigned to treatment with an ICD, metoprolol, propafenone, or amiodarone [13]. Assignment to propafenone was discontinued prematurely when interim analysis revealed a 61 percent higher mortality than that seen in patients randomized to ICD therapy. After a mean follow-up of 57 months, there was a non-significant reduction in total mortality in patients receiving an ICD compared with those treated with amiodarone or metoprolol (36.4 versus 44.9 percent). The secondary end point of SCD was significantly reduced by the ICD compared with drug therapy (13 versus 33 percent). CIDS trial In the Canadian Implantable Defibrillator Study (CIDS) 659 patients with resuscitated VT/VF or syncope deemed to be secondary to VT/VF were randomly assigned to amiodarone or ICD therapy and followed for five years [14]. In those treated with an ICD, there were non-significant reductions in total mortality (8.3 versus 10.2 percent per year) and SCD (3 versus 4.5 percent per year). Meta-analysis A significant mortality benefit with ICD therapy was noted in the AVID trial, while nonsignificant trends toward reduced mortality with ICD therapy were noted in the CASH and CIDS trials. The lack of statistical significance in the last two trials could have represented a beta error as the trials were underpowered to detect a significant difference of the magnitude observed. In addition, it is possible that patients considered by their clinicians to be good candidates for ICD therapy would be less likely to be enrolled and subjected to randomization, thus favoring the control group. In a meta-analysis of the AVID, CASH, and CIDS trials along with a fourth smaller trial, the following findings were noted [15]: Patients with an ICD had a significant reduction in total mortality compared with those receiving antiarrhythmic therapy (hazard ratio [HR] 0.75, 95% CI 0.64-0.87). Patients with an ICD had a 50 percent reduction in SCD (HR 0.50, 95% CI 0.34-0.62). https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 5/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate The absolute reduction in all-cause mortality was 7 percent, meaning that 15 patients needed to be treated to prevent one death. A second meta-analysis of AVID, CIDS, and CASH came to similar conclusions, finding a 28 percent relative risk reduction in all-cause mortality and a 50 percent reduction in arrhythmic death [16]. Patients with LVEF >35 percent had less benefit from ICD therapy than those with EF 35 percent. A subsequent meta-analysis of AVID, CIDS, and CASH further quantitated the benefit of the ICD in secondary prevention patients, finding a two-year absolute risk reduction in total mortality of 8 percent, with a number needed to treat to achieve mortality benefit of 13 [17]. Contemporary observational cohort studies The evidence supporting ICD therapy for secondary prevention rests upon randomized clinical trials that were conducted in the 1980s and 1990s. However, more contemporary observational studies or registries support these findings. In a cohort of 6996 patients with new onset ventricular arrhythmia in the setting of preexisting coronary heart disease and HF (from the National Veterans Administration database), 1442 patients had an ICD implanted [18]. At three-year follow-up, the patients who received an ICD had significant reductions in all-cause and cardiovascular mortality compared with those without an ICD (37 versus 55 percent and 23 versus 36 percent, respectively; adjusted odds ratio 0.52 for all-cause mortality and 0.56 for cardiovascular mortality), with no difference in noncardiac death. The benefit occurred despite a significantly lower frequency of use of angiotensin converting enzyme (ACE) inhibitors, beta blockers, and statins. This reduction in risk of death (28 percent) was similar to that seen in AVID (31 percent). In a smaller study of 357 patients who received an ICD for secondary prevention with much longer follow-up (mean 82 months), 208 persons (59 percent) received an ICD therapy for ventricular tachyarrhythmia, while 44 percent of participants died without receiving any ICD therapy [19]. An analysis of the NCDR ICD Registry evaluated mortality in 46,685 patients with ICDs implanted for secondary prevention indications in contemporary practice [20]. The mortality rate in this registry at one year was 10 percent compared with 8 to 11 percent among ICD patients enrolled in the secondary prevention randomized clinical trials (AVID, CIDS, CASH). Overall, the magnitude of the benefit of ICD therapy for secondary prevention in this real-world cohort was similar to or greater than that in the randomized trials, although mortality also remains high due to significant comorbidities. Effect in older patients Randomized clinical trials evaluating the role of the ICD for secondary prevention included only a minority of patients who were 75 years old. A meta- analysis of pooled individual patient data from three major randomized trials (CASH, CIDS, and AVID) comparing ICD with antiarrhythmic therapy for secondary prevention included 252 patients (out of 1866 total, or 13.5 percent) who were 75 years old [21]. This meta-analysis https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 6/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate suggested that the survival benefit from ICD therapy may be reduced in older patients compared with younger patients [21-23]. In contrast, other studies have shown older patients to benefit equally from primary or secondary prevention ICD therapy as younger patients [24,25]. While clinical trials enrolled relatively few older adult patients, the National Cardiovascular Data Registry ICD Registry provides the ability to examine outcomes in much larger numbers of patients in real-life clinical practice. In an analysis of 12,420 Medicare patients who were ages 65 years or older (mean age 75 years) who underwent initial ICD implantation between 2006 and 2009 for secondary prevention of SCD, the overall risk of death at two years was 21.8 percent [26]. However, there was a twofold difference in total mortality between patients 80 years of age and those who were ages 65 to 69 years (28.9 versus 14.7 percent; adjusted risk ratio 2.01, 95% CI 1.85-2.33). The study did not include a control group of similarly matched patients without an ICD; therefore no conclusions can be drawn about any potential total mortality benefit from placing the ICD for secondary prevention. However, nearly four in five patients over age 65 years who received an ICD for secondary prevention were alive two years later, indicating that age alone should not be the deciding criterion for ICD placement. Rather, multiple clinical factors should be considered including comorbidities, functional status, and competing risks of mortality, with the patient and family engaged in a shared decision-making process. This is highlighted in the guidelines, which state In patients with ventricular arrhythmias or at increased risk for SCD, clinicians should adopt a shared decision-making approach in which treatment decisions are based not only on the best available evidence but also on the patients health goals, preferences, and values (class I, LOE B-NR) [10]. These results suggest that ICD use in older patients should be individualized. Patients with few comorbidities may benefit, while those with significant other illnesses may be more likely to die of non-arrhythmic causes. Clinicians should consider issues of competing mortality risk, co- morbidities, risk of complications, and patient preferences for end-of-life care. Effect in heart failure Patients who are being evaluated for an ICD for secondary prevention and who have at least class II HF symptoms, significant LV systolic dysfunction, left bundle branch block, and a QRS duration 150 milliseconds should be strongly considered for an ICD that also provides cardiac resynchronization therapy (CRT). Some patients with a QRS duration of 120 to <150 milliseconds, those with non-LBBB conduction delays, and class I ischemic patients may also be candidates for CRT [27] or physiological pacing. This is discussed in greater detail elsewhere. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Use of an ICD'.) https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 7/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate Patients with syncope Some of the randomized trials of ICDs for the secondary prevention of SCD included patients with syncope and either spontaneous or induced sustained VT. For patients with HF or cardiomyopathy who have had syncope and either induced or spontaneous VT, we recommend treatment with an ICD for secondary prevention of SCD [10]. Based upon observational data from patients with nonischemic cardiomyopathy, severe LV dysfunction, and unexplained syncope, ICD implantation is also often appropriate. Most patients with ischemic cardiomyopathy and an LVEF 35 percent qualify for ICD therapy even without syncope based upon the results of the MADIT-II [28] and SCD-HeFT trials [29] . The best approach for managing patients with an LVEF >35 percent and unexplained syncope is not clear and likely varies according to the etiology of the cardiomyopathy. For such patients with an ischemic cardiomyopathy, we generally perform an invasive electrophysiology (EP) study and, if the patient has inducible VT, implant an ICD. For patients with a nonischemic cardiomyopathy, an EP study is less informative, although it may reveal conduction abnormalities or bundle branch reentrant VT. In such patients, decisions regarding ICD implantation should be individualized based upon clinical circumstances, type of heart muscle disease, and patient preference. Cardiac MRI can be a useful test to detect scarring and fibrosis; in some cardiomyopathies, the presence of these can predict arrythmia sudden cardiac death. The 2017 AHA/ACC/HRS guidelines recommend the use of an ICD in patients with significant LV dysfunction due to ischemic cardiomyopathy who have unexplained syncope [10]. However, regardless of the history of syncope, many such patients will already qualify for an ICD for primary prevention of SCD based upon SCD-HeFT criteria, and patients with ischemic cardiomyopathy and severe LV dysfunction (ie, LVEF 30 to 35 percent) generally qualify for an ICD based upon MADIT-II [28] or SCD-HeFT criteria [29]. Patients with transient or reversible disorders Patients with a life-threatening ventricular tachyarrhythmia due to a transient or reversible cause (often an ischemic event) have been thought to have a low risk for recurrent SCA after correction of the underlying precipitant. However, many such patients remain at high risk for SCA, and the full clinical context should be considered before concluding that VT/VF is entirely due to a transient or reversible cause [30,31]. As examples: While acute ischemic events occur in patients who may have had an antecedent MI or multivessel disease, the presence of scar from a prior MI and progression of CHD both increase the risk of future events. In the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, patients identified with a potentially transient or correctable cause for VT/VF (such as an ischemic event, electrolyte abnormalities, or drug reactions) remained at high https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 8/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate risk for death [30]. (See "Prognosis and outcomes following sudden cardiac arrest in adults".) In a retrospective single-center cohort study of 1433 patients with SCA between 2000 and 2012 who survived to hospital discharge, 792 patients (55 percent) were felt to have a reversible and correctable cause, which included evidence of acute MI or ischemia, significant electrolyte or metabolic abnormality, or recent antiarrhythmic medication or illicit drug use, with 207 patients (26 percent) with a reversible cause receiving an ICD [32]. Over a mean follow-up of 3.8 years, 319 patients (40 percent) died, with ICD recipients having a significantly lower mortality risk (HR 0.61 compared with patients without an ICD, 95% CI 0.47-0.80). The benefit was consistent across all subgroups with the exception of patients whose reversible cause was MI/ischemia, in whom no mortality benefit was seen. While patients with SCA in the setting of MI did not receive a mortality benefit from ICD therapy, it should be noted that all of these patients underwent coronary revascularization before being classified as having a reversible cause of SCA. Additionally, 32 of the ICD recipients (15 percent) received an appropriate ICD therapy during follow-up, including 21 percent of the group without MI/ischemia, suggesting that SCA in the setting of a perceived reversible cause may not always be related to the putative reversible cause. While this study is limited by its retrospective, nonrandomized nature, it suggests caution on the part of clinicians evaluating patients after cardiac arrest not to overestimate the potential for reversibility of arrhythmic risk, particularly outside of the setting of acute MI. The 2017 AHA/ACC/HRS guidelines for the management of ventricular arrhythmias and the prevention of sudden cardiac death recommend ICD therapy for patients who either survive SCA or experience hemodynamically unstable VT or stable VT not due to "reversible causes" if meaningful survival greater than one year is expected [10]. As defined in AVID, "potentially reversible causes" may include acute MI, transient ischemia, electrolyte imbalance, antiarrhythmic drug proarrhythmia, hypoxia, electrocution, drowning, or sepsis. Clinical judgment is needed to discern which causes are entirely transient or reversible. General opinion would support the following: Patients who experience cardiac arrest due to polymorphic VT or VF in the setting of acute ischemia or an MI should be treated with revascularization for the purpose of reducing the risk of SCD. Patients may be eligible for ICD therapy if they are considered ineligible for complete revascularization. In general, patients with polymorphic VT or VF who also have electrolyte disorders should be evaluated and treated in the same manner as other patients, including evaluation for https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 9/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate ICD therapy unless the electrolyte abnormalities are proved to be the cause of the arrhythmia. Patients who experience sustained monomorphic VT in the setting of antiarrhythmic drug use or electrolyte abnormalities should be evaluated and treated in the same manner as other patients presenting with sustained VT. Antiarrhythmic drugs or electrolyte abnormalities should not be assumed to be the sole cause of sustained monomorphic VT. Patients who experience polymorphic VT in the setting of acquired QT prolongation due to drug therapy should be advised to avoid exposure to all agents associated with QT prolongation. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) SCD despite ICD implantation In the trials of ICD therapy for the secondary prevention of SCD, approximately 20 to 35 percent of the deaths in patients with an ICD were due to SCD. These deaths may result from pulseless electrical activity (PEA), pulmonary embolus, ruptured aortic aneurysm, VT below rate detection cutoff, and, rarely, from ICD failure or under-detection of VF. Post-mortem interrogation of ICDs revealed that the most common mechanism of SCD in patients was VT/VF treated with an appropriate shock followed by PEA [8]. Increasingly frequent and refractory episodes of VT/VF may reflect the terminal stage of severe HF, and such patients may succumb from VT/VF storm despite appropriate function of the ICD. (See 'Epidemiology' above.) Other treatment options In addition to the ICD, several other pharmacologic and nonpharmacologic therapies have been evaluated in survivors of SCD. None is considered an adequate alternative to ICD therapy in most clinical circumstances, but each has a role in selected patients. Antiarrhythmic drugs Antiarrhythmic drugs may be used to improve quality of life in patients with frequent ventricular tachyarrhythmias leading to ICD shocks, or in those patients who are not candidates for or who decline ICD implantation. In the presence of HF and/or structural heart disease, antiarrhythmic drug therapy is limited to a small number of choices (ie, amiodarone, sotalol, mexiletine) [10]. In patients who require an antiarrhythmic drug, we typically prefer amiodarone in patients with HF and LV dysfunction due to its superior efficacy and demonstration of short-term safety in patients with HF and structural heart disease. Sotalol or mexiletine may be alternative drugs for selected patients with structural heart disease who have an ICD. Often, a beta blocker is coadministered with antiarrhythmic drugs, which do not have intrinsic beta-blocker activity. Beta blockers are often separately indicated in patients with ventricular arrhythmias due to coexistent HF, LV dysfunction, and/or coronary artery disease. In https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 10/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate addition, beta blockers have important antiarrhythmic action which may reduce recurrence of ventricular arrhythmias. (See 'Beta blockers' below.) In survivors of SCA, the need for adjunctive antiarrhythmic drug therapy is not uncommon, with an antiarrhythmic drug being added to ICD therapy in 22 percent at two years in the AVID trial and in 28 percent at five years in the CIDS trial [11,14]. In patients who have an ICD in place, there are two main indications for concomitant antiarrhythmic drug therapy. To reduce the frequency of ventricular arrhythmias In the AVID trial, frequent ICD shocks were the primary reason for adding an antiarrhythmic drug (64 percent) [33]. Frequent shocks impact quality of life. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Quality of life'.) To suppress supraventricular arrhythmias Arrhythmias other than VT or VF may cause symptoms or result in "inappropriate" discharges. Atrial fibrillation is by far the most common of these arrhythmias. Dofetilide may also be a useful agent for treatment of atrial fibrillation in patients with underlying structural heart disease. Amiodarone is generally the preferred antiarrhythmic choice and was shown in the OPTIC trial to be more effective than sotalol. However, this drug has more long-term side effects and drug interactions than other antiarrhythmic agents. In some circumstances, therefore, it may be more appropriate to use sotalol or mexiletine, despite the superior efficacy of amiodarone. In addition, amiodarone may result in an increase in the defibrillation threshold, which could adversely affect ICD shock efficacy and increase VT cycle length, which should be considered during device programming. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Amiodarone: Clinical uses", section on 'Drug interactions' and "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Choice of pharmacologic therapy'.) While antiarrhythmic drugs are sometimes required to reduce the frequency of shocks and improve a person's quality of life, a systematic review of 17 studies involving nearly 6000 ICD recipients showed that shock prevention using antiarrhythmic therapy resulted in no improvement in mortality [34]. (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Antiarrhythmic drugs'.) Other medical therapies Beta blockers The majority of patients who receive an ICD will be treated with a beta blocker as part of the therapy for their underlying heart disease. Beta blockers confer an https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 11/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate additional survival benefit in patients with an MI, HF, congenital long QT syndrome, or catecholaminergic polymorphic VT. Additional benefits of beta-blockers in ICD patients may include reduction in inappropriate ICD shocks from sinus tachycardia and atrial fibrillation with a rapid ventricular response. Careful attention to ICD programming, including programming a long detection delay, may also reduce unnecessary ICD therapy [35,36]. (See "Beta blockers in the management of chronic coronary syndrome".) Among survivors of SCA who were eligible but not randomized in the AVID trial, beta-blocker use was associated with improved survival in patients who were not treated with specific antiarrhythmic therapy (adjusted RR 0.47, 95% CI 0.25-0.88) [37]. Lipid-lowering therapy Most patients with CHD who have an ICD are treated with lipid- lowering therapy. However, data on the effect of lipid-lowering therapy on ventricular arrhythmia are mixed. [38,39]. Among 362 patients with CHD who received an ICD in the AVID trial, there was a significant reduction in the risk of recurrence of VT or VF in the 83 patients receiving lipid-lowering therapy (adjusted HR 0.40, 95% CI 0.15 to 0.58). Reduction in VT/VF was also seen among statin-treated patients in one primary prevention ICD trial [40]. However, there are still no randomized controlled trials to suggest that lipid-lowering therapy confers an independent antiarrhythmic effect in patients with VT/VF. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) There are mixed data on whether the administration of fish oil reduces the risk of recurrent ventricular tachyarrhythmias. A meta-analysis of three fish oil trials showed no overall effect of fish oil treatment on the risk of ICD discharge [41]. Ranolazine Initially developed as an antianginal therapy, some studies have suggested that ranolazine has antiarrhythmic properties, including one trial in which ranolazine reduced the frequency of both supraventricular and ventricular arrhythmias within seven days of an acute coronary syndrome. This prompted investigators to study the effectiveness of ranolazine in reducing ventricular arrhythmias in patients with an ICD in the RAID trial, which randomized 1012 high-risk patients with ischemic or nonischemic cardiomyopathy and an ICD to receive either ranolazine (1000 mg twice daily) or placebo in addition to usual care [42,43]. During a mean follow-up of 28 months, there was a non-significant reduction in the primary end point of death or appropriate ICD shock among patients in the ranolazine group compared with placebo (HR 0.84; 95% CI 0.67-1.05), with a pre-specified secondary analysis identifying a significant reduction in recurrent ICD therapies (ATP and shocks) in the ranolazine group (HR 0.70; 95% CI 0.51-0.96). Compliance in the study was poor, however, with 50 percent of patients receiving ranolazine and 40 percent of patients receiving placebo discontinuing the medication. Until further data become available, suggesting a benefit, ranolazine should not be used routinely to https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 12/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate prevent VT/VF in patients with an ICD, but there may be select patients (eg, those with frequent ICD therapies in spite of maximal medical therapy) in whom its use is reasonable. Catheter ablation Similar to antiarrhythmic drugs, catheter ablation may be used as adjunctive therapy to improve quality of life in patients with frequent ventricular tachyarrhythmias leading to ICD shocks, or in those patients who are not candidates for or refuse ICD placement. Catheter ablation alone without an ICD is rarely appropriate for patients who survive cardiac arrest due to VT/VF or who have VT associated with structural heart disease. Radiofrequency ablation (RFA) is often an effective treatment for VT, particularly monomorphic VT due to reentry. In patients with a prior MI, the border zone of the infarct is frequently the site of the reentrant circuit, and these sites are often amenable to endocardial catheter ablation [44]. In contrast, patients with nonischemic cardiomyopathy may have multiple endocardial reentrant circuits, epicardial or mid-myocardial circuits, or other mechanisms of VT (eg, triggered arrhythmias or polymorphic VT) [45]. Due to the presence of more complex arrhythmic substrate, endocardial RFA is less effective in patients with nonischemic cardiomyopathy, and an epicardial approach may be required [46]. Catheter ablation may also be effective in selected patients with polymorphic VT or VF associated with triggering PVCs arising in the right ventricular outflow tract or His-Purkinje system [47]. (See "Overview of catheter ablation of cardiac arrhythmias".) Catheter ablation of VT is considered in three settings: As an adjunct to an ICD in patients who have frequent ventricular arrhythmias and ICD therapies. (See "Electrical storm and incessant ventricular tachycardia", section on 'Catheter ablation'.) As an alternative to an ICD in patients who do not want or are not candidates for an ICD. As prophylactic adjunctive therapy in patients who initially presented with sustained VT and received ICD therapy. A meta-analysis of five trials showed that this approach reduces the risk of VT recurrence by 35 percent with no effect on mortality [48]. Arrhythmia surgery Ischemic cardiomyopathy Reentrant VT circuits associated with a chronic myocardial infarct scar can be surgically resected. Arrhythmia surgery was used more commonly prior to the advent of RFA, particularly in patients with an LV aneurysm and sustained monomorphic VT. The successes of ICD implantation and RFA have made surgery for ventricular arrhythmias appropriate only in rare circumstances. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Surgical therapy'.) https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 13/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate Nonischemic cardiomyopathy Surgical treatment of VT/VF in patients with nonischemic cardiomyopathy has not been well studied, but likely has a lower success rate than in ischemic cardiomyopathy, given that the underlying myocardial disease tends to be diffuse without a discrete scar or aneurysm present. In selected patients, however, there remains a role

during device programming. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Amiodarone: Clinical uses", section on 'Drug interactions' and "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Choice of pharmacologic therapy'.) While antiarrhythmic drugs are sometimes required to reduce the frequency of shocks and improve a person's quality of life, a systematic review of 17 studies involving nearly 6000 ICD recipients showed that shock prevention using antiarrhythmic therapy resulted in no improvement in mortality [34]. (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Antiarrhythmic drugs'.) Other medical therapies Beta blockers The majority of patients who receive an ICD will be treated with a beta blocker as part of the therapy for their underlying heart disease. Beta blockers confer an https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 11/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate additional survival benefit in patients with an MI, HF, congenital long QT syndrome, or catecholaminergic polymorphic VT. Additional benefits of beta-blockers in ICD patients may include reduction in inappropriate ICD shocks from sinus tachycardia and atrial fibrillation with a rapid ventricular response. Careful attention to ICD programming, including programming a long detection delay, may also reduce unnecessary ICD therapy [35,36]. (See "Beta blockers in the management of chronic coronary syndrome".) Among survivors of SCA who were eligible but not randomized in the AVID trial, beta-blocker use was associated with improved survival in patients who were not treated with specific antiarrhythmic therapy (adjusted RR 0.47, 95% CI 0.25-0.88) [37]. Lipid-lowering therapy Most patients with CHD who have an ICD are treated with lipid- lowering therapy. However, data on the effect of lipid-lowering therapy on ventricular arrhythmia are mixed. [38,39]. Among 362 patients with CHD who received an ICD in the AVID trial, there was a significant reduction in the risk of recurrence of VT or VF in the 83 patients receiving lipid-lowering therapy (adjusted HR 0.40, 95% CI 0.15 to 0.58). Reduction in VT/VF was also seen among statin-treated patients in one primary prevention ICD trial [40]. However, there are still no randomized controlled trials to suggest that lipid-lowering therapy confers an independent antiarrhythmic effect in patients with VT/VF. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) There are mixed data on whether the administration of fish oil reduces the risk of recurrent ventricular tachyarrhythmias. A meta-analysis of three fish oil trials showed no overall effect of fish oil treatment on the risk of ICD discharge [41]. Ranolazine Initially developed as an antianginal therapy, some studies have suggested that ranolazine has antiarrhythmic properties, including one trial in which ranolazine reduced the frequency of both supraventricular and ventricular arrhythmias within seven days of an acute coronary syndrome. This prompted investigators to study the effectiveness of ranolazine in reducing ventricular arrhythmias in patients with an ICD in the RAID trial, which randomized 1012 high-risk patients with ischemic or nonischemic cardiomyopathy and an ICD to receive either ranolazine (1000 mg twice daily) or placebo in addition to usual care [42,43]. During a mean follow-up of 28 months, there was a non-significant reduction in the primary end point of death or appropriate ICD shock among patients in the ranolazine group compared with placebo (HR 0.84; 95% CI 0.67-1.05), with a pre-specified secondary analysis identifying a significant reduction in recurrent ICD therapies (ATP and shocks) in the ranolazine group (HR 0.70; 95% CI 0.51-0.96). Compliance in the study was poor, however, with 50 percent of patients receiving ranolazine and 40 percent of patients receiving placebo discontinuing the medication. Until further data become available, suggesting a benefit, ranolazine should not be used routinely to https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 12/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate prevent VT/VF in patients with an ICD, but there may be select patients (eg, those with frequent ICD therapies in spite of maximal medical therapy) in whom its use is reasonable. Catheter ablation Similar to antiarrhythmic drugs, catheter ablation may be used as adjunctive therapy to improve quality of life in patients with frequent ventricular tachyarrhythmias leading to ICD shocks, or in those patients who are not candidates for or refuse ICD placement. Catheter ablation alone without an ICD is rarely appropriate for patients who survive cardiac arrest due to VT/VF or who have VT associated with structural heart disease. Radiofrequency ablation (RFA) is often an effective treatment for VT, particularly monomorphic VT due to reentry. In patients with a prior MI, the border zone of the infarct is frequently the site of the reentrant circuit, and these sites are often amenable to endocardial catheter ablation [44]. In contrast, patients with nonischemic cardiomyopathy may have multiple endocardial reentrant circuits, epicardial or mid-myocardial circuits, or other mechanisms of VT (eg, triggered arrhythmias or polymorphic VT) [45]. Due to the presence of more complex arrhythmic substrate, endocardial RFA is less effective in patients with nonischemic cardiomyopathy, and an epicardial approach may be required [46]. Catheter ablation may also be effective in selected patients with polymorphic VT or VF associated with triggering PVCs arising in the right ventricular outflow tract or His-Purkinje system [47]. (See "Overview of catheter ablation of cardiac arrhythmias".) Catheter ablation of VT is considered in three settings: As an adjunct to an ICD in patients who have frequent ventricular arrhythmias and ICD therapies. (See "Electrical storm and incessant ventricular tachycardia", section on 'Catheter ablation'.) As an alternative to an ICD in patients who do not want or are not candidates for an ICD. As prophylactic adjunctive therapy in patients who initially presented with sustained VT and received ICD therapy. A meta-analysis of five trials showed that this approach reduces the risk of VT recurrence by 35 percent with no effect on mortality [48]. Arrhythmia surgery Ischemic cardiomyopathy Reentrant VT circuits associated with a chronic myocardial infarct scar can be surgically resected. Arrhythmia surgery was used more commonly prior to the advent of RFA, particularly in patients with an LV aneurysm and sustained monomorphic VT. The successes of ICD implantation and RFA have made surgery for ventricular arrhythmias appropriate only in rare circumstances. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Surgical therapy'.) https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 13/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate Nonischemic cardiomyopathy Surgical treatment of VT/VF in patients with nonischemic cardiomyopathy has not been well studied, but likely has a lower success rate than in ischemic cardiomyopathy, given that the underlying myocardial disease tends to be diffuse without a discrete scar or aneurysm present. In selected patients, however, there remains a role for surgical treatment. In a study of eight patients in whom percutaneous ablation was not an option, successful reduction in VT was reported in six of eight nonischemic cardiomyopathy patients (75 percent) treated with surgical cryoablation [49]. Cardiac transplantation Cardiac transplantation is occasionally required for patients with incessant life-threatening ventricular arrhythmias, which cannot be controlled by medication or catheter ablation. ICD therapy is generally contraindicated in patients with uncontrollable incessant VT/VF, and such patients should proceed to mechanical support and transplantation if they are candidates. (See "Heart transplantation in adults: Indications and contraindications", section on 'Indications for transplantation'.) Another scenario involves patients who are listed for cardiac transplantation who experience cardiac arrest or symptomatic VT while on the waiting list. In such patients, there is an important role for the ICD as a bridge to transplantation [50-54]. In one study, 16 patients with a mean LVEF of 15 percent who were listed for heart transplantation underwent ICD implantation for ventricular arrhythmias refractory to medical therapy [50]. The ICD delivered appropriate shocks for tachyarrhythmias associated with near syncope in all but one of the patients. Twelve patients underwent transplantation after a mean of 156 days. In another study of 60 patients listed for heart transplantation who survived resuscitation from sustained VT/VF, ICD implantation was associated with significantly improved survival. Only 1 of 30 ICD patients (19 transplanted) versus 7 of 30 non-ICD patients (14 transplanted) died on the waiting list [55]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 14/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Heart failure (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Reversible causes In some survivors of sudden cardiac arrest (SCA) or sustained ventricular tachycardia (VT), a transient or reversible cause (eg, acute myocardial ischemia [MI], electrolyte disturbances, medication-related proarrhythmia, etc) can be identified as being responsible for the SCA. Initial treatment should be directed at the underlying disorder. However, prior to concluding that SCA was due to a reversible cause, a thorough evaluation should be performed, typically involving a heart rhythm specialist. (See 'Reversible causes of SCA or sustained VT' above.) Secondary prevention Patients with HF and cardiomyopathy who survive an episode of SCA or have hemodynamically unstable VT or stable VT are typically treated with implantable cardioverter-defibrillator (ICD) therapy for secondary prevention if meaningful survival greater than one year is expected. (See 'Secondary prevention of SCD' above.) For survivors of SCA or sustained VT without a clearly reversible cause, we recommend ICD implantation rather than antiarrhythmic drug therapy (Grade 1A). (See 'Evidence for use of ICD therapy' above.) For survivors of SCA or sustained VT who are identified as having a definite transient or reversible cause (eg, acute MI, acute infarction, severe electrolyte disturbances, medication-related proarrhythmia, etc), in particular those whose cardiac rhythm is polymorphic VT or ventricular fibrillation (VF), we do not recommend ICD implantation if the etiology is clearly understood, the underlying cause is fully treated, and the https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 15/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate condition is unlikely to recur (Grade 1B). (See 'Reversible causes of SCA or sustained VT' above and 'Patients with transient or reversible disorders' above.) For patients with HF or cardiomyopathy who have had syncope and either induced or spontaneous VT, we recommend treatment with an ICD for secondary prevention of SCD (Grade 1A). (See 'Patients with syncope' above.) For patients with nonischemic cardiomyopathy, significant LV dysfunction, and unexplained syncope, we suggest ICD implantation (Grade 2B). Most patients with an ischemic cardiomyopathy and left ventricular ejection fraction 35 percent already qualify for an ICD based upon the results of the MADIT-II and SCD-HeFT trials. (See 'Patients with syncope' above and 'Our approach' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Antiarrhythmic drugs These may be used to improve quality of life in patients with frequent ventricular tachyarrhythmias leading to ICD shocks, or in those patients who are not candidates for or who decline ICD implantation. In patients who require an antiarrhythmic drug, we typically prefer amiodarone in patients with HF and LV dysfunction due to its superior efficacy and demonstration of short-term safety in such patients. Sotalol and mexiletine may be useful alternative drugs for selected patients. (See 'Antiarrhythmic drugs' above.) Catheter ablation Similar to antiarrhythmic drugs, catheter ablation may be used as adjunctive therapy to improve quality of life in patients with frequent ventricular tachyarrhythmias leading to ICD shocks, or in those patients who are not candidates for or refuse ICD placement. Catheter ablation alone without an ICD is rarely appropriate for patients who survive cardiac arrest due to VT/VF or who have VT associated with structural heart disease. (See 'Catheter ablation' above.) The majority of patients who receive an ICD will be treated with a beta blocker as part of the therapy for their underlying heart disease. (See 'Beta blockers' above.) ACKNOWLEDGMENT The authors and UpToDate thank Dr. Phillip Podrid, Dr. Jie Cheng, Dr. Scott Manaker, and Dr. Leonard Ganz, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 16/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate REFERENCES 1. Narang R, Cleland JG, Erhardt L, et al. Mode of death in chronic heart failure. A request and proposition for more accurate classification. Eur Heart J 1996; 17:1390. 2. Cleland JG, Erhardt L, Murray G, et al. Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators. Eur Heart J 1997; 18:41. 3. Greenberg H, Case RB, Moss AJ, et al. Analysis of mortality events in the Multicenter Automatic Defibrillator Implantation Trial (MADIT-II). J Am Coll Cardiol 2004; 43:1459. 4. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001. 5. Sabbag A, Suleiman M, Laish-Farkash A, et al. Contemporary rates of appropriate shock therapy in patients who receive implantable device therapy in a real-world setting: From the Israeli ICD Registry. Heart Rhythm 2015; 12:2426. 6. Causes of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Am Coll Cardiol 1999; 34:1552. 7. Grubman EM, Pavri BB, Shipman T, et al. Cardiac death and stored electrograms in patients with third-generation implantable cardioverter-defibrillators. J Am Coll Cardiol 1998; 32:1056. 8. Mitchell LB, Pineda EA, Titus JL, et al. Sudden death in patients with implantable cardioverter defibrillators: the importance of post-shock electromechanical dissociation. J Am Coll Cardiol 2002; 39:1323. 9. Pires LA, Lehmann MH, Steinman RT, et al. Sudden death in implantable cardioverter- defibrillator recipients: clinical context, arrhythmic events and device responses. J Am Coll Cardiol 1999; 33:24. 10. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 11. Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997; 337:1576. 12. Domanski MJ, Sakseena S, Epstein AE, et al. Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias. AVID https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 17/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate Investigators. Antiarrhythmics Versus Implantable Defibrillators. J Am Coll Cardiol 1999; 34:1090. 13. Kuck KH, Cappato R, Siebels J, R ppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest : the Cardiac Arrest Study Hamburg (CASH). Circulation 2000; 102:748. 14. Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000; 101:1297. 15. Lee DS, Green LD, Liu PP, et al. Effectiveness of implantable defibrillators for preventing arrhythmic events and death: a meta-analysis. J Am Coll Cardiol 2003; 41:1573. 16. Connolly SJ, Hallstrom AP, Cappato R, et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg . Canadian Implantable Defibrillator Study. Eur Heart J 2000; 21:2071. 17. Betts TR, Sadarmin PP, Tomlinson DR, et al. Absolute risk reduction in total mortality with implantable cardioverter defibrillators: analysis of primary and secondary prevention trial data to aid risk/benefit analysis. Europace 2013; 15:813. 18. Chan PS, Hayward RA. Mortality reduction by implantable cardioverter-defibrillators in high- risk patients with heart failure, ischemic heart disease, and new-onset ventricular arrhythmia: an effectiveness study. J Am Coll Cardiol 2005; 45:1474. 19. Schaer B, K hne M, Reichlin T, et al. Incidence of and predictors for appropriate implantable cardioverter-defibrillator therapy in patients with a secondary preventive implantable cardioverter-defibrillator indication. Europace 2016; 18:227. 20. Katz DF, Peterson P, Borne RT, et al. Survival After Secondary Prevention Implantable Cardioverter-Defibrillator Placement: An Analysis From the NCDR ICD Registry. JACC Clin Electrophysiol 2017; 3:20. 21. Healey JS, Hallstrom AP, Kuck KH, et al. Role of the implantable defibrillator among elderly patients with a history of life-threatening ventricular arrhythmias. Eur Heart J 2007; 28:1746. 22. Panotopoulos PT, Axtell K, Anderson AJ, et al. Efficacy of the implantable cardioverter- defibrillator in the elderly. J Am Coll Cardiol 1997; 29:556. 23. Narasimhan C, Dhala A, Axtell K, et al. Comparison of outcome of implantable cardioverter defibrillator implantation in patients with severe versus moderately severe left ventricular dysfunction secondary to atherosclerotic coronary artery disease. Am J Cardiol 1997; 80:1305. https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 18/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate 24. Huang DT, Sesselberg HW, McNitt S, et al. Improved survival associated with prophylactic implantable defibrillators in elderly patients with prior myocardial infarction and depressed ventricular function: a MADIT-II substudy. J Cardiovasc Electrophysiol 2007; 18:833. 25. Duray G, Richter S, Manegold J, et al. Efficacy and safety of ICD therapy in a population of elderly patients treated with optimal background medication. J Interv Card Electrophysiol 2005; 14:169. 26. Betz JK, Katz DF, Peterson PN, et al. Outcomes Among Older Patients Receiving Implantable Cardioverter-Defibrillators for Secondary Prevention: From the NCDR ICD Registry. J Am Coll Cardiol 2017; 69:265. 27. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. 28. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346:877. 29. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225. 30. Wyse DG, Friedman PL, Brodsky MA, et al. Life-threatening ventricular arrhythmias due to transient or correctable causes: high risk for death in follow-up. J Am Coll Cardiol 2001; 38:1718. 31. Viskin S, Halkin A, Olgin JE. Treatable causes of sudden death: not really "treatable" or not really the cause? J Am Coll Cardiol 2001; 38:1725. 32. Ladejobi A, Pasupula DK, Adhikari S, et al. Implantable Defibrillator Therapy in Cardiac Arrest Survivors With a Reversible Cause. Circ Arrhythm Electrophysiol 2018; 11:e005940. 33. Steinberg JS, Martins J, Sadanandan S, et al. Antiarrhythmic drug use in the implantable defibrillator arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study. Am Heart J 2001; 142:520. 34. Ha AH, Ham I, Nair GM, et al. Implantable cardioverter-defibrillator shock prevention does not reduce mortality: a systemic review. Heart Rhythm 2012; 9:2068. 35. Gasparini M, Proclemer A, Klersy C, et al. Effect of long-detection interval vs standard- detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: the ADVANCE III randomized clinical trial. JAMA 2013; 309:1903. https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 19/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate 36. Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016; 13:e50. 37. Exner DV, Reiffel JA, Epstein AE, et al. Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 1999; 34:325. 38. Mitchell LB, Powell JL, Gillis AM, et al. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 2003; 42:81. 39. De Sutter J, Tavernier R, De Buyzere M, et al. Lipid lowering drugs and recurrences of life- threatening ventricular arrhythmias in high-risk patients. J Am Coll Cardiol 2000; 36:766. 40. Vyas AK, Guo H, Moss AJ, et al. Reduction in ventricular tachyarrhythmias with statins in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol 2006; 47:769. 41. Jenkins DJ, Josse AR, Beyene J, et al. Fish-oil supplementation in patients with implantable cardioverter defibrillators: a meta-analysis. CMAJ 2008; 178:157. 42. Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST- segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007; 116:1647. 43. Zareba W, Daubert JP, Beck CA, et al. Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial. J Am Coll Cardiol 2018; 72:636. 44. Wissner E, Stevenson WG, Kuck KH. Catheter ablation of ventricular tachycardia in ischaemic and non-ischaemic cardiomyopathy: where are we today? A clinical review. Eur Heart J 2012; 33:1440. 45. Soejima K, Stevenson WG, Sapp JL, et al. Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low- voltage scars. J Am Coll Cardiol 2004; 43:1834. 46. Yamada T, Kay GN. Optimal ablation strategies for different types of ventricular tachycardias. Nat Rev Cardiol 2012; 9:512. 47. Knecht S, Sacher F, Wright M, et al. Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study. J Am Coll Cardiol 2009; 54:522. https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 20/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate 48. Mallidi J, Nadkarni GN, Berger RD, et al. Meta-analysis of catheter ablation as an adjunct to medical therapy for treatment of ventricular tachycardia in patients with structural heart disease. Heart Rhythm 2011; 8:503. 49. Anter E, Hutchinson MD, Deo R, et al. Surgical ablation of refractory ventricular tachycardia in patients with nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol 2011; 4:494. 50. Jeevanandam V, Bielefeld MR, Auteri JS, et al. The implantable defibrillator: an electronic bridge to cardiac transplantation. Circulation 1992; 86:II276. 51. Grimm M, Wieselthaler G, Avanessian R, et al. The impact of implantable cardioverter- defibrillators on mortality among patients on the waiting list for heart transplantation. J Thorac Cardiovasc Surg 1995; 110:532. 52. Bolling SF, Deeb GM, Morady F, et al. Automatic internal cardioverter defibrillator: a bridge to heart transplantation. J Heart Lung Transplant 1991; 10:562. 53. Lorga-Filho A, Geelen P, Vanderheyden M, et al. Early benefit of implantable cardioverter defibrillator therapy in patients waiting for cardiac transplantation. Pacing Clin Electrophysiol 1998; 21:1747. 54. Saba S, Atiga WL, Barrington W, et al. Selected patients listed for cardiac transplantation may benefit from defibrillator implantation regardless of an established indication. J Heart Lung Transplant 2003; 22:411. 55. Grimm M, Grimm G, Zuckermann A, et al. ICD therapy in survivors of sudden cardiac death awaiting heart transplantation. Ann Thorac Surg 1995; 59:916. Topic 946 Version 38.0 https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 21/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate GRAPHICS [1] Summary of secondary prevention ICD trials NCDR [2] [3] [4] Study AVID CASH CIDS [5] Cohort Years 1993 to 1997 1987 to 1998 1990 to 1997 2006 to 2009 Patients 1016 191 659 46,685 Mean age (years) 65 11 58 11 63 9 66 14 Male (%) 78 79 85 73 Follow-up (months) 18 12 57 34 36 None CAD (%) 81 73 83 64 Nonischemic (%) 15 12 10 23 LVEF 32 13 46 19 34 14 36 15 Presenting arrhythmia (%) VF 45 100 45 51 VT with LOC 21 0 16 NR VT without LOC 34 0 24 27 Syncope 0 0 15 22 BB (%) 42 0 33 84 ACE-I/ARB (%) 69 45 NR 72 One-year mortality (%): Control/ICD 17.7/10.7 15.2/8.1 11.2/9.5 NA/10.4 Two-year mortality (%): 25.3/18.4 27.2/17.2 21.0/14.8 NA/16.4 Control/ICD ICD: implantable cardioverter-defibrillator; CAD: coronary artery disease; LVEF: left ventricular ejection fraction; VF: ventricular fibrillation; VT: ventricular tachycardia; LOC: loss of consciousness; BB: beta blocker; ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; NR: not recorded; NA: not applicable. References: 1. Borne R, Katz D, Betz J, et al. Implantable Cardioverter-De brillators for Secondary Prevention of Sudden Cardiac Death: A Review. J Am Heart Assoc 2017; 6:e005515. https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 22/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate 2. Antiarrhythmics versus Implantable De brillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable de brillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997; 337:1576. 3. Kuck KH, Cappato R, Siebels J, R ppel R. Randomized comparison of antiarrhythmic drug therapy with implantable de brillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation 2000; 102:748. 4. Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable de brillator study (CIDS): a randomized trial of the implantable cardioverter de brillator against amiodarone. Circulation 2000; 101:1297. 5. Katz DF, Peterson P, Borne RT, et al. Survival after secondary prevention ICD placement: an analysis from the NCDR ICD Registry. JACC Clin Electrophysiol 2017; 3:20. Graphic 116653 Version 1.0 https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 23/24 7/6/23, 3:10 PM Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy - UpToDate Contributor Disclosures Joseph E Marine, MD, FACC, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Andrea M Russo, MD, FACC, FHRS Grant/Research/Clinical Trial Support: BMS/Pfizer [Anticoagulant]; Boston Scientific [Arrhythmia]; Kestra [Arrhythmia]; Medilynx [Arrhythmia]; Medtronic [Arrhythmia]. Consultant/Advisory Boards: Abbott [Arrhythmia]; Atricure [Arrhythmia]; Biosense Webster [Arrhythmia]; Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]; PaceMate [Arrhythmia]. Speaker's Bureau: Biotronik [Arrhythmia]; Medtronic [Arrhythmia]. Other Financial Interest: ABIM [Cardiovascular board]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/secondary-prevention-of-sudden-cardiac-death-in-heart-failure-and-cardiomyopathy/print 24/24

7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Supportive data for advanced cardiac life support in adults with sudden cardiac arrest : Mark S Link, MD : Richard L Page, MD, Ron M Walls, MD, FRCPC, FAAEM : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 09, 2021. INTRODUCTION Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden cessation of cardiac activity with hemodynamic collapse, often due to sustained ventricular tachycardia/ventricular fibrillation. Other causes of SCA and SCD are asystole and pulseless electrical activity. These events most commonly occur in patients with structural heart disease (that may not have been previously diagnosed), particularly coronary heart disease. (See "Pathophysiology and etiology of sudden cardiac arrest".) The event is referred to as SCA (or aborted SCD) if an intervention (eg, defibrillation) results in the return of spontaneous circulation (ROSC) and restored circulation. The event is called SCD if the patient dies. However, the use of SCD to describe both fatal and nonfatal cardiac arrest persists by convention. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Definitions'.) The treatment of SCA consists of emergency resuscitation followed, in survivors, by immediate post-resuscitative care and attempted long-term prevention of recurrence using pharmacologic and nonpharmacologic interventions. Over time, the frequency of cardiopulmonary resuscitation (CPR) performed by bystanders has increased, and the interval between collapse and defibrillation has decreased, both of which are particularly important in survival [1,2]. Despite these improvements as well as advances in the treatment of heart disease, the outcome https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 1/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate of patients experiencing SCA remains poor. (See "Prognosis and outcomes following sudden cardiac arrest in adults".) In reality, there are only two out of hospital therapies of resuscitation that have been shown to be associated with improved survival: excellent, prompt chest compressions and early defibrillation. Resuscitation should focus on providing these two elements with the highest quality. This is not to say that advanced cardiac life support (ACLS) therapies should be withheld if indicated; however, shockable rhythms should first be defibrillated, and excellent CPR (either compressions only, or compressions and mouth to mouth breathing) should be performed. Any other interventions should be delayed until these first-line therapies are implemented. In general, the performance of the second-line interventions (as part of ACLS) should rarely interfere with defibrillation and excellent CPR. The only other therapy has shown to be associated with a neurologically favorable survival advantage is targeted temperature management (TTM) in the post-arrest care. This is discussed in greater detail separately. (See 'Targeted temperature management' below and "Initial assessment and management of the adult post-cardiac arrest patient", section on 'Temperature management'.) The data supporting advanced cardiac life support (ACLS) recommendations for the management of SCA will be reviewed here. The performance of ACLS, controversies surrounding cardiopulmonary resuscitation, and issues related to the prevention of recurrent SCA in survivors are discussed separately. (See "Advanced cardiac life support (ACLS) in adults" and "Adult basic life support (BLS) for health care providers" and "Therapies of uncertain benefit in basic and advanced cardiac life support" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Pharmacologic therapy in survivors of sudden cardiac arrest".) VF AND PULSELESS VT The management of ventricular fibrillation (VF) and pulseless ventricular tachycardia (pVT) is the same ( algorithm 1) [3]. Survival depends upon prompt, high-quality cardiopulmonary resuscitation (CPR) with chest compressions and the earliest defibrillation possible to reestablish organized electrical activity with a stable sinus or supraventricular rhythm. Excellent CPR is a priority and should be maintained throughout the resuscitative effort; pauses should only occur during rhythm analysis and defibrillation (as soon as possible for the first defibrillation and then at two-minute intervals, and when required to deliver ventilations in an un-intubated patient by bag-mask ventilation at a ratio of 30:2). Other procedures, such as vascular access, vasopressor https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 2/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate administration, and intubation, should not be performed in the initial resuscitation efforts (ie, first few minutes) unless they can be performed without interrupting CPR and defibrillation. Multiple studies have reported that intubation should not be attempted in adults until return of spontaneous circulation (ROSC) unless bag-mask ventilation is ineffective or there has been a prolonged period of resuscitation [4-6]. Any adjunctive procedure requiring discontinuation of CPR should occur during rhythm checks, as this minimizes interruptions in perfusion and the build-up necessary to reach threshold perfusion pressures once compressions are restarted. Interruptions should be brief and should never create prolonged delays in resumption of CPR. (See "Advanced cardiac life support (ACLS) in adults".) Specific issues relating to the management of VF and pVT, including technical aspects of defibrillation, are discussed below. The use of automated external defibrillators (AED) for the treatment of cardiac arrest is presented separately. (See "Automated external defibrillators".) Defibrillation The only effective approach for the treatment of VF and pVT is defibrillation, with earlier efforts yielding better outcomes. VF rarely, if ever, terminates spontaneously or after delivery of an antiarrhythmic drug. (See "Cardioversion for specific arrhythmias", section on 'Ventricular fibrillation'.) Timing The success of defibrillation and patient survival depends upon the duration of the arrhythmia and the promptness of defibrillation [2,7-9]: When VF has been present for seconds to a few minutes and the fibrillatory waves are coarse, the success rate for terminating VF with defibrillation is high. As VF continues, the fibrillatory waves become finer ( waveform 1) [10]. When VF continues for more than four minutes, especially if not accompanied by excellent CPR, irreversible damage to the central nervous system and other organs begins, which can reduce survival even if defibrillation is successful [11-13]. There is strong evidence that longer interruptions in chest compressions reduce the likelihood of successful defibrillation and lower the odds of survival [14-18]. In a prospective observational cohort of 506 adult patients with out-of-hospital cardiac arrest, patients with the highest chest compression fractions (61 to 80 percent and 81 to 100 percent), defined as the proportion of time in cardiac arrest without spontaneous circulation during which chest compressions were being performed, had the greatest chance of survival to hospital discharge (adjusted odds ratios [OR] 3.01, 95% CI 1.37-6.58 and 2.33, 95% CI 0.96-5.63, respectively). As there are data indicating that shortening the duration between stopping compressions and delivering the defibrillatory shock has a survival advantage, defibrillators should be fully charged prior to cessation of https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 3/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate compressions, after which immediate rhythm identification and shock delivery is performed as indicated (this should typically occur in no more than three to five seconds) [18,19]. In a series of over 12,000 patients treated by Emergency Medical Services, 4546 had witnessed VF [2]. For these patients with witnessed VF, a shorter defibrillation response interval was significantly correlated with an increased chance of survival to hospital discharge. The analysis yielded an odds ratio for survival of 0.88 for every one-minute increase in response time, which corresponds to a 3 to 5 percent drop in survival for each minute of delay to defibrillation [2]. There is debate about whether CPR should be performed prior to defibrillation. Outcomes may be improved by performing CPR before defibrillation, in particular if the patient has been in SCA for a longer time period. This was illustrated in a retrospective report that compared outcomes in patients with out-of-hospital VF in two time periods: when an initial shock was given as soon as possible; and when the initial shock was delayed until 90 seconds of CPR had been performed [20]. Survival to hospital discharge was significantly increased with routine CPR before defibrillation (30 versus 24 percent without prior CPR); this benefit was primarily seen in patients in whom the initial response interval was four minutes or longer (27 versus 17 percent without prior CPR). Yet in a randomized controlled trial, there was no difference in outcome. In this RCT, in which 200 patients presenting with out-of-hospital VF were assigned to immediate defibrillation or CPR for three minutes prior to the first defibrillation attempt, there was no difference in outcome between the two groups for patients with an EMS response time 5 minutes [21]. For those with response times >5 minutes, patients undergoing CPR first were significantly more likely to survive to hospital discharge (22 versus 4 percent). Subsequent larger randomized controlled studies, however, have not confirmed that performing CPR prior to defibrillation improves survival to hospital discharge [22-24]. As one example, in a randomized trial of 9933 patients with out-of-hospital cardiac arrest who were assigned to either 30 to 60 seconds of CPR versus 180 seconds of CPR prior to initial cardiac rhythm analysis, there was no significant difference in survival to hospital discharge [24]. Practically, however, in nearly all cardiac arrest, rescuers should perform excellent compressions before the arrival and deployment of an AED or while a monitor/defibrillator is being placed and charged. Thus, CPR should generally be performed prior to defibrillation in these situations. Early defibrillation of VT/VF in patients with in-hospital cardiac arrest has also been shown to improve survival, in both the short term and long term. Among a cohort of 8119 with in-hospital cardiac arrest with VT/VF, patients who were defibrillated within two minutes of cardiac arrest had significantly better survival (compared with initial defibrillation at >2 minutes) at one year https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 4/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate (26 versus 16 percent), three years (19 versus 11 percent), and five years (15 versus 9 percent) [25]. Based upon the above studies, the 2020 American Heart Association (AHA) guidelines for cardiopulmonary resuscitation and emergency cardiovascular care suggest the initiation of CPR while awaiting the arrival of a defibrillator [26-29]. Once the defibrillator is attached to the patient, CPR should be briefly stopped to allow for a rhythm check and shock, if indicated (cessation of compressions should not occur until the defibrillator is fully charged), followed by immediate resumption of CPR for two minutes prior to any additional rhythm checks. Defibrillatory waveforms Defibrillators manufactured prior to 2000 deliver a monophasic wave of direct electrical current. Since then, "biphasic" devices have been developed, which reverse current polarity 5 to 10 milliseconds after discharge begins ( figure 1). Biphasic waveforms defibrillate more effectively and at lower energies than monophasic waveforms. They have a much higher likelihood of first shock efficacy, which is the basis for the current recommendation to deliver a single shock compared with earlier recommendations that three shocks be delivered in rapid succession [3]. Data comparing the use of monophasic and biphasic waveforms in the treatment of VF are presented separately. (See "Basic principles and technique of external electrical cardioversion and defibrillation", section on 'Monophasic versus biphasic waveforms'.) There have been case reports in the literature on the successful use of double sequence defibrillation for VF not terminated by maximal energy from a single defibrillator [30,31]. Importantly, this procedure is not warranted for those whose VF terminates with shock and then reinitiates. This procedure employs two external defibrillators used simultaneously or sequentially (one right after the other) to deliver higher energy with the intent to convert VF to a perfusing rhythm. Despite these case reports, two retrospective studies with small patient populations of OHCA showed disparate results; one reported no difference [30,31]. More and better research is needed on the efficacy of this therapy prior to making any recommendations. VF or VT arrest and vasopressors Despite conflicting data on survival, the 2020 guidelines concluded that it is appropriate to administer epinephrine (1 mg IV/IO every three to five minutes) for patients presenting with cardiac arrest [3,29,32]. Routine use of high-dose epinephrine is not supported by data and is not recommended. Additionally, the 2020 guidelines state that vasopressin alone or in combination with epinephrine may be considered during resuscitation from cardiac arrest but offers no advantage over epinephrine alone. Accordingly, we recommend that epinephrine be used as the sole vasopressor during resuscitation from cardiac arrest and that vasopressin no longer be used [3]. https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 5/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate The totality of the evidence assessing the efficacy of epinephrine for out-of-hospital cardiac arrest suggest that, although ROSC and even overall survival may be increased with the use of epinephrine, meaningful survival with favorable neurologic outcome is not improved [33-36]. Whether improvement in post-ROSC care will be able to transform those without meaningful neurologic outcome is not clear. Thus, as the data are quite mixed in outcome, they do not support the routine use of epinephrine in the treatment of all patients, but should serve as an impetus for additional randomized controlled trials of this issue targeting subgroups who are more likely to benefit. Pending review and updating of ACLS protocols, it is reasonable to include epinephrine in resuscitation protocols as an option for resuscitation personnel, and the decision whether to administer it can occur on a case-by-case basis. Epinephrine has been studied in two randomized, double-blind, placebo-controlled trials, with mixed survival results [33,34]. In the trial of 8014 patients in the United Kingdom with out-of-hospital cardiac arrest (PARAMEDIC-2) who were randomized to either epinephrine (1 mg doses, mean total dose 4.9 mg) or placebo, the primary outcome (30-day survival) was significantly higher in the group who received epinephrine (130 patients [3.2 percent] versus 94 patients [2.4 percent]; adjusted OR 1.47; 95% CI 1.09-1.97) [33]. Subgroup analysis showed a significant survival benefit for patients with a nonshockable initial rhythm (OR 2.10; 95% CI 1.11-3.98) that was not seen in patients with an initial shockable rhythm. However, patients receiving epinephrine had no significant improvement in survival with favorable neurologic outcome (score between 0 and 3 on modified Rankin scale) but among survivors were more likely to have severe neurologic impairment (modified Rankin scale score 4 or 5; 31 versus 18 percent of survivors). In a trial of 601 patients with out-of-hospital cardiac arrest who were randomized to either epinephrine (1 mg doses, mean total dose 5 mg) or placebo, patients who received epinephrine were more likely to have ROSC (24 versus 8 percent, OR 3.4, 95% CI 2.0-5.6) and survival to hospital admission, but there was no significant improvement in survival to hospital discharge (4 versus 1.9 percent, OR 2.2, 95% CI 0.7-6.3) [34]. A 2019 meta-analysis, which combined the data from these two randomized trials, reported increased survival to hospital discharge for patients with nonshockable initial rhythms receiving epinephrine, with the results largely driven by the PARAMEDIC-2 data [35]. No significant improvement in survival to hospital discharge was seen in patients with an initial shockable rhythm. https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 6/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate The benefits of epinephrine (and other vasopressors) in the treatment of cardiac arrest have been questioned in numerous nonrandomized studies: In a prospective observational study of 417,188 adults with out-of-hospital cardiac arrest, investigators compared ROSC, survival, and neurologic outcome in patients who received epinephrine (15,030 patients, 3.6 percent) with those who did not receive epinephrine (402,158 patients, 96.4 percent) [37]. While there was a significantly greater ROSC in the epinephrine group (18.5 versus 5.7 percent using raw data, 18.3 versus 10.5 percent using propensity analysis), this did not translate into improved outcomes. In fact, using propensity analysis, patients receiving epinephrine had significantly lower rates of survival at one month (5.1 versus 7.0 percent); survival with moderate or good cerebral performance (1.3 versus 3.1 percent); and survival with no, mild, or moderate neurological disability (1.3 versus 3.1 percent). Similar results were reported from a study of 1646 patients presenting to a single center between 2000 and 2012 following out-of-hospital cardiac arrest with ROSC, in which the chance of survival was significantly lower among patients who received epinephrine and decreased further as the cumulative dose of epinephrine during resuscitation increased [38]. The early administration of epinephrine within two minutes following the initial defibrillation for VF/VT may be detrimental. In a prospective cohort study of 2978 patients with in-hospital cardiac arrest and a shockable rhythm (1510 patients with epinephrine administered within two minutes of defibrillation and 1468 propensity score matched patients without early epinephrine administration), patients who received early epinephrine had a significantly decreased likelihood of survival (OR 0.70, 95% CI 0.59-0.82) [39]. (See "Advanced cardiac life support (ACLS) in adults", section on 'Pulseless ventricular tachycardia and ventricular fibrillation'.) In a 2019 Cochrane Database systematic review which looked only at randomized controlled trials (26 trials with 21,704 patients) in which standard-dose epinephrine was compared to placebo, high-dose epinephrine, or vasopressin (alone or in combination with epinephrine), the following findings were reported among patients receiving epinephrine compared with placebo [40]: Moderate quality evidence of ROSC (relative risk [RR] 2.86; 95% CI 2.21-3.71) Moderate quality evidence of survival to hospital discharge (RR 1.44; 95% CI 1.11-1.86) No significant difference in survival with favorable neurologic outcomes (RR 1.21; 95% CI 0.90-1.62) https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 7/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate Although the 2020 guidelines still allow vasopressin to be "considered" (ie, 2b) alone or in combination with epinephrine, we recommend that vasopressin no longer be used for SCA29. Although a single randomized controlled trial found higher rates of successful resuscitation and 24-hour survival with vasopressin compared with epinephrine, subsequent randomized trials and a meta-analysis failed to show an improvement in initial ROSC or survival to hospital discharge [41-44]. Furthermore, in a multicenter trial of 1442 patients, treatment of out-of- hospital cardiac arrest with a combination of epinephrine and vasopressin did not improve outcomes compared with treatment with epinephrine alone [45]. Because of this lack of benefit of vasopressin over epinephrine, the 2015 AHA guidelines removed vasopressin from the treatment protocol (allowing for EMS and hospitals to remove it from resuscitation supplies) for patients with VF or pVT [3]. Because vasopressors given in the setting of ROSC may be detrimental, it is now strongly suggested that resuscitation be performed using quantitative waveform capnography so that ROSC may be more readily identified during ongoing compressions [46-48]. As soon as ROSC is obtained, no further vasopressors should generally be administered. (See "Advanced cardiac life support (ACLS) in adults", section on 'Airway management' and "Carbon dioxide monitoring (capnography)".) Antiarrhythmic drugs VF or VT may persist despite electrical countershock or recur after successful electrical countershock. The 2020 AHA guidelines state that IV/IO antiarrhythmic drug therapy may be considered in such cases, in particular for witnessed cardiac arrest in which the time to drug administration is shorter, although benefit from this therapy remains uncertain [3,29,49-51]. Antiarrhythmic drugs that may be used include amiodarone and lidocaine, with no guideline-based preference of a preferred agent. Some post-hoc nonrandomized data suggest that outcomes are better for both amiodarone and lidocaine administered intravenously (compared with intraosseously), but this has not been assessed in an RCT [52,53]. The performance of ACLS, including the details of antiarrhythmic drug therapy, is discussed elsewhere. (See "Advanced cardiac life support (ACLS) in adults".) Amiodarone Intravenous amiodarone increases ROSC and survival to hospital admission compared with lidocaine in patients with refractory VF and pVT, However, there is no significant difference between amiodarone and lidocaine in terms of the patient-important outcomes of survival to hospital discharge and neurologically intact survival [49,54]. In the ALIVE trial of 347 patients with out-of-hospital sudden cardiac arrest (SCA) and persistent or recurrent VF despite three defibrillation shocks, IV/IO epinephrine, and a further attempt at defibrillation, survival to hospital admission was significantly higher in https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 8/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate patients receiving amiodarone (23 versus 12 percent for lidocaine, OR 2.17, 95% CI 1.21- 3.83) [55]. Among patients who had the ROSC prior to antiarrhythmic administration, amiodarone led to an even higher rate of survival to admission (42 versus 27 percent with lidocaine). Despite these benefits, the in-hospital death rates in the two groups were 78 and 75 percent, similar to those in other studies, and there was no significant difference in survival to hospital discharge (nine and five patients in the amiodarone and lidocaine groups, respectively). In the ARREST trial of 504 patients with SCA due to VF or pVT who were not resuscitated after at least three defibrillation shocks, patients were randomly assigned to intravenous bolus amiodarone (300 mg) or placebo [56]. While the mean time to resuscitation and the total number of shocks delivered were similar in the two groups, survival to hospital admission was significantly greater in the amiodarone group (44 versus 34 percent with placebo), especially in patients who had the ROSC during defibrillation prior to receiving amiodarone (64 versus 41 percent placebo). Amiodarone, however, was associated with more adverse effects, including hypotension (59 versus 48 percent) and bradycardia requiring therapy (41 versus 25 percent). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) The ARREST trial was not sufficiently powered to detect differences in survival to hospital discharge, which did not differ significantly between the two groups, similar to the findings in the ALIVE trial. Intravenous amiodarone is also effective for the acute suppression of life-threatening, hemodynamically significant ventricular tachyarrhythmias that recur despite therapy with other agents. Amiodarone can prevent recurrence of sustained spontaneous VT or VF in more than 50 percent of patients, and it has been approved for the acute treatment and prevention of VF and for hemodynamically significant VT that is refractory to other agents [57,58]. Lidocaine There is no significant difference between lidocaine and amiodarone in terms of the patient-important outcomes of survival to hospital discharge and neurologically intact survival. The 2020 AHA guidelines state that either lidocaine or amiodarone can be administered during cardiac arrest for VT/VF refractory to shocks and epinephrine [29,50,51]. (See 'Amiodarone' above and "Advanced cardiac life support (ACLS) in adults", section on 'Pulseless patient in sudden cardiac arrest'.) Comparison of amiodarone and lidocaine In 2016, the first randomized trial (the ALPS study) was published that compared amiodarone, lidocaine, and placebo in patients with pVT or https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 9/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate VF refractory to defibrillation and initial vasopressor therapy [59]. This study was the first to evaluate the effect of a new preparation of amiodarone that employs a solvent that is not associated with hypotension. In this trial of 3026 patients, there was no significant difference in the primary outcome (survival to hospital discharge) among the three groups, with no statistically significant improvement in survival for either the amiodarone or lidocaine groups compared with placebo (24.4 versus 23.7 versus 21.0 percent, respectively). Similarly, there was no significant improvement in the prespecified secondary outcome of favorable neurologic function at discharge among those who received amiodarone or lidocaine. Subgroup analysis identified a nonsignificant mortality decrease of 5 percent for either drug therapy in patients with bystander-witnessed arrest (in whom CPR and activation of emergency medical systems likely occur earlier than in non-witnessed patients). A prespecified analysis from the ALPS study was performed on a cohort of 1063 patients with cardiac arrest initially due to a nonshockable rhythm (ie, pulseless electrical activity or asystole) that subsequently evolved to a shockable rhythm during resuscitation efforts [60]. As with the primary cohort from the ALPS study (patients presenting with cardiac arrest due to pVT or VF), patients were randomized to amiodarone, lidocaine, or placebo. Similar to the findings among patients presenting with an initial shockable rhythm, for patients who evolved from a nonshockable to a shockable rhythm during resuscitation, there was no significant difference in the primary outcome (survival to hospital discharge) among the amiodarone, lidocaine, and placebo groups (4.1 versus 3.1 versus 1.9 percent, respectively). These randomized trial data further support the approach as stated in the 2018 AHA focused update to the 2015 AHA guidelines, in which amiodarone and lidocaine "may be considered" for patients with VF or pVT which is refractory to initial treatments, especially when arrest is witnessed [50,51]. Magnesium sulfate Data from randomized trials do NOT support the routine use of magnesium sulfate for the treatment of cardiac arrest [50,51]. However, observational data from a small number of patients suggest that intravenous magnesium sulfate is beneficial for the treatment of a VF or pVT arrest due to drug-induced prolonged QT interval associated with torsades de pointes [61]. Magnesium's primary benefit is in the prevention of recurrent episodes of VF, not in the termination of such. Defibrillation is generally necessary for termination. The 2020 AHA guidelines state that torsades de pointes is the only arrhythmia for which administration of magnesium sulfate should be considered [29,50,51]. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) Targeted temperature management The induction of mild to moderate hypothermia (target temperature 32 to 34 C for 24 hours) has been shown to improve survival in patients https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 10/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate successfully resuscitated after a cardiac arrest who are comatose. Improved neurologic outcome and reduced mortality have been demonstrated in multiple series of patients with VF arrest in whom spontaneous circulation was restored, even when the patient remained comatose after resuscitation. More recently, a large randomized controlled trial, which involved 939 patients with ROSC following cardiac arrest and compared target temperatures of 32 to 34 degrees with targeted temperatures of 34 to 36 degrees, showed no significant difference in survival between the groups [62]. It is still unclear whether the benefits of targeted temperature management are related to actual cooling or the prevention of post-ROSC fever. Targeted temperature management is discussed in greater detail elsewhere. (See "Advanced cardiac life support (ACLS) in adults", section on 'Post-resuscitation care' and "Initial assessment and management of the adult post-cardiac arrest patient", section on 'Temperature management'.) PULSELESS ELECTRICAL ACTIVITY In contrast to ventricular fibrillation or pulseless ventricular tachycardia, there is no role for defibrillation in the management of pulseless electrical activity (PEA) or asystole ( algorithm 1). Excellent cardiopulmonary resuscitation (CPR), vasopressor therapy, and rapid treatment of reversible causes are the mainstays of PEA management. However, because CPR is ineffective in cardiac arrest due to cardiac tamponade and tension pneumothorax, the rapid identification and treatment of these eminently reversible causes must be of primary importance. Reversible causes include the five H's and T's (hypoxia, hypovolemia, hydrogen ion (acidosis), hypo-/hyperkalemia, hypothermia, toxins [especially narcotics and benzodiazepines], tamponade [cardiac], tension pneumothorax, thrombosis [pulmonary], thrombosis [coronary]) as defined by the 2015 AHA guidelines ( table 1) [3]. While CPR with excellent chest compressions is performed, other rescuers should not be afraid to perform "heroic" procedures, even if no definitive confirmatory studies are available, for plausibly suspected causes of PEA. CPR should be provided throughout the resuscitative effort, except during brief pauses at two- minute intervals to analyze the rhythm and assess for return of spontaneous circulation (ROSC). In a cohort of 3960 patients with out-of-hospital cardiac arrest and a nonshockable cardiac rhythm, 1774 patients were treated with ACLS before and 2186 patients were treated with ACLS after the revised 2005 guidelines, which increased the emphasis on chest compressions during resuscitation [63]. Patients treated after 2005 with an increased emphasis on chest compressions had significantly greater ROSC (34 versus 27 percent), one month survival (6.2 versus 4.1 percent), and favorable neurologic outcomes (5.1 versus 3.4 percent). (See "Advanced cardiac life support (ACLS) in adults", section on 'Asystole and pulseless electrical activity'.) https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 11/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate PEA and vasopressors The efficacy of epinephrine (1 mg IV/IO push every three to five minutes) for PEA remains uncertain, but it remains a part of the 2015 AHA guidelines for the treatment of cardiac arrest with PEA [3,37]. In a secondary analysis of a cardiac arrest registry, among a cohort of 32,101 patients with out-of-hospital cardiac arrest and a nonshockable initial rhythm (published after the 2015 AHA guidelines), earlier administration of epinephrine was associated with improved survival, with a 4 percent decreased likelihood of survival for each additional minute of delay in epinephrine administration [64]. Improvements in one-year survival following in-hospital cardiac arrest have also been reported with early administration of epinephrine [25]. (See 'VF or VT arrest and vasopressors' above.) PEA and atropine Atropine is not recommended in the 2020 guidelines for PEA because of its lack of therapeutic benefit [3,29]. The administration of atropine (1 mg IV/IO every three to five minutes) may be considered for PEA when the rate is slow, ie, absolute bradycardia with a rate <50 beats/minute or a relative bradycardia (rate less than expected relative to the underlying condition) [26,27]. Atropine's effect is on vagally-mediated bradycardia, which is rarely a cause of cardiac arrest, and treatment successes are reportable. In a cohort study of 1029 patients with PEA published after the 2010 AHA guidelines, 30-day neurologic outcomes were no different in the groups treated with epinephrine and atropine versus epinephrine alone [65]. In addition, survival was significantly lower in the group treated with epinephrine and atropine (3.2 percent versus 7.1 percent in epinephrine only group; OR 0.43, 95% CI 0.19 to 0.91), suggesting that atropine may actually be harmful when used to treat PEA. Registry data on over 20,000 in-hospital cardiac arrests with a non-shockable rhythm, collected between 2006 and 2015, showed no difference in survival before and after atropine was removed from the treatment protocol in the 2010 AHA guidelines [66]. ASYSTOLE Sudden cardiac arrest in which asystole is the initial rhythm is associated with an extremely poor prognosis (0 to 2 percent survival to hospital discharge). Asystole is usually a secondary event, resulting from prolonged ventricular fibrillation or pulseless electrical activity (PEA) with subsequent loss of all electrical activity. It may also occur as a result of prolonged hypoxia, acidosis, and death of myocardial tissue ( waveform 1). (See "Prognosis and outcomes following sudden cardiac arrest in adults", section on 'Asystole'.) True asystole should be confirmed by checking the ECG and defibrillator cable connections, making certain that the gain is turned up and the monitor is working. Confirmation of asystole in another lead is recommended. The 2015 AHA guidelines recommend that asystole be treated https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 12/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate in the same manner as PEA, with excellent cardiopulmonary resuscitation (CPR), vasopressors, and the consideration of possible reversible causes ( table 1) [3]. Atropine is no longer recommended as therapy in asystole. CPR, with an emphasis on excellent chest compressions, should be provided throughout the resuscitative effort, stopping only at two-minute intervals during which brief rhythm analysis and defibrillation is provided if the patient has reverted to a shockable rhythm [63]. There is no benefit to defibrillation in patients with asystole. (See 'Pulseless electrical activity' above and "Advanced cardiac life support (ACLS) in adults", section on 'Asystole and pulseless electrical activity'.) Because randomized controlled trials and other data have not shown a survival benefit with the use of temporary pacing in asystole, its routine use is not recommended by the 2020 AHA guidelines [3,29,67-71]. Prolonged resuscitative efforts of patients in asystole are generally futile. Termination of resuscitation is discussed elsewhere. (See "Advanced cardiac life support (ACLS) in adults", section on 'Termination of resuscitative efforts'.) Asystole and vasopressors Epinephrine Epinephrine (1 mg IV/IO push every three to five minutes) is recommended in patients with asystole, although its benefit has not been clearly demonstrated in prospective trials [3,37]. In a secondary analysis of a cardiac arrest registry, among a cohort of 32,101 patients with out-of-hospital cardiac arrest and a nonshockable initial rhythm (published after the 2015 AHA guidelines), earlier administration of epinephrine was associated with improved survival, with a 4 percent decreased likelihood of survival for each additional minute of delay in epinephrine administration [64]. Improvements in one-year survival following in-hospital cardiac arrest have also been reported with early administration of epinephrine [25]. In a separate registry study that included more than 41,000 patients (not all of whom were in asystole), delay to epinephrine administration was also associated reduced survival [72]. (See 'VF or VT arrest and vasopressors' above.) Routine use of high-dose epinephrine is not supported by data and is not recommended [73,74]. In a randomized trial comparing repeated high doses and standard doses of epinephrine for out-of-hospital cardiac arrest, survival to hospital discharge was similar with high-dose and standard dose epinephrine [74]. Although high-dose epinephrine improved the rate of successful resuscitation in patients with asystole, it did not improve survival to hospital discharge. Vasopressin Vasopressin has been studied as a potential alternative to epinephrine. In one trial comparing vasopressin with epinephrine in 1186 patients with out-of-hospital arrest, the

reversible causes are the mainstays of PEA management. However, because CPR is ineffective in cardiac arrest due to cardiac tamponade and tension pneumothorax, the rapid identification and treatment of these eminently reversible causes must be of primary importance. Reversible causes include the five H's and T's (hypoxia, hypovolemia, hydrogen ion (acidosis), hypo-/hyperkalemia, hypothermia, toxins [especially narcotics and benzodiazepines], tamponade [cardiac], tension pneumothorax, thrombosis [pulmonary], thrombosis [coronary]) as defined by the 2015 AHA guidelines ( table 1) [3]. While CPR with excellent chest compressions is performed, other rescuers should not be afraid to perform "heroic" procedures, even if no definitive confirmatory studies are available, for plausibly suspected causes of PEA. CPR should be provided throughout the resuscitative effort, except during brief pauses at two- minute intervals to analyze the rhythm and assess for return of spontaneous circulation (ROSC). In a cohort of 3960 patients with out-of-hospital cardiac arrest and a nonshockable cardiac rhythm, 1774 patients were treated with ACLS before and 2186 patients were treated with ACLS after the revised 2005 guidelines, which increased the emphasis on chest compressions during resuscitation [63]. Patients treated after 2005 with an increased emphasis on chest compressions had significantly greater ROSC (34 versus 27 percent), one month survival (6.2 versus 4.1 percent), and favorable neurologic outcomes (5.1 versus 3.4 percent). (See "Advanced cardiac life support (ACLS) in adults", section on 'Asystole and pulseless electrical activity'.) https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 11/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate PEA and vasopressors The efficacy of epinephrine (1 mg IV/IO push every three to five minutes) for PEA remains uncertain, but it remains a part of the 2015 AHA guidelines for the treatment of cardiac arrest with PEA [3,37]. In a secondary analysis of a cardiac arrest registry, among a cohort of 32,101 patients with out-of-hospital cardiac arrest and a nonshockable initial rhythm (published after the 2015 AHA guidelines), earlier administration of epinephrine was associated with improved survival, with a 4 percent decreased likelihood of survival for each additional minute of delay in epinephrine administration [64]. Improvements in one-year survival following in-hospital cardiac arrest have also been reported with early administration of epinephrine [25]. (See 'VF or VT arrest and vasopressors' above.) PEA and atropine Atropine is not recommended in the 2020 guidelines for PEA because of its lack of therapeutic benefit [3,29]. The administration of atropine (1 mg IV/IO every three to five minutes) may be considered for PEA when the rate is slow, ie, absolute bradycardia with a rate <50 beats/minute or a relative bradycardia (rate less than expected relative to the underlying condition) [26,27]. Atropine's effect is on vagally-mediated bradycardia, which is rarely a cause of cardiac arrest, and treatment successes are reportable. In a cohort study of 1029 patients with PEA published after the 2010 AHA guidelines, 30-day neurologic outcomes were no different in the groups treated with epinephrine and atropine versus epinephrine alone [65]. In addition, survival was significantly lower in the group treated with epinephrine and atropine (3.2 percent versus 7.1 percent in epinephrine only group; OR 0.43, 95% CI 0.19 to 0.91), suggesting that atropine may actually be harmful when used to treat PEA. Registry data on over 20,000 in-hospital cardiac arrests with a non-shockable rhythm, collected between 2006 and 2015, showed no difference in survival before and after atropine was removed from the treatment protocol in the 2010 AHA guidelines [66]. ASYSTOLE Sudden cardiac arrest in which asystole is the initial rhythm is associated with an extremely poor prognosis (0 to 2 percent survival to hospital discharge). Asystole is usually a secondary event, resulting from prolonged ventricular fibrillation or pulseless electrical activity (PEA) with subsequent loss of all electrical activity. It may also occur as a result of prolonged hypoxia, acidosis, and death of myocardial tissue ( waveform 1). (See "Prognosis and outcomes following sudden cardiac arrest in adults", section on 'Asystole'.) True asystole should be confirmed by checking the ECG and defibrillator cable connections, making certain that the gain is turned up and the monitor is working. Confirmation of asystole in another lead is recommended. The 2015 AHA guidelines recommend that asystole be treated https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 12/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate in the same manner as PEA, with excellent cardiopulmonary resuscitation (CPR), vasopressors, and the consideration of possible reversible causes ( table 1) [3]. Atropine is no longer recommended as therapy in asystole. CPR, with an emphasis on excellent chest compressions, should be provided throughout the resuscitative effort, stopping only at two-minute intervals during which brief rhythm analysis and defibrillation is provided if the patient has reverted to a shockable rhythm [63]. There is no benefit to defibrillation in patients with asystole. (See 'Pulseless electrical activity' above and "Advanced cardiac life support (ACLS) in adults", section on 'Asystole and pulseless electrical activity'.) Because randomized controlled trials and other data have not shown a survival benefit with the use of temporary pacing in asystole, its routine use is not recommended by the 2020 AHA guidelines [3,29,67-71]. Prolonged resuscitative efforts of patients in asystole are generally futile. Termination of resuscitation is discussed elsewhere. (See "Advanced cardiac life support (ACLS) in adults", section on 'Termination of resuscitative efforts'.) Asystole and vasopressors Epinephrine Epinephrine (1 mg IV/IO push every three to five minutes) is recommended in patients with asystole, although its benefit has not been clearly demonstrated in prospective trials [3,37]. In a secondary analysis of a cardiac arrest registry, among a cohort of 32,101 patients with out-of-hospital cardiac arrest and a nonshockable initial rhythm (published after the 2015 AHA guidelines), earlier administration of epinephrine was associated with improved survival, with a 4 percent decreased likelihood of survival for each additional minute of delay in epinephrine administration [64]. Improvements in one-year survival following in-hospital cardiac arrest have also been reported with early administration of epinephrine [25]. In a separate registry study that included more than 41,000 patients (not all of whom were in asystole), delay to epinephrine administration was also associated reduced survival [72]. (See 'VF or VT arrest and vasopressors' above.) Routine use of high-dose epinephrine is not supported by data and is not recommended [73,74]. In a randomized trial comparing repeated high doses and standard doses of epinephrine for out-of-hospital cardiac arrest, survival to hospital discharge was similar with high-dose and standard dose epinephrine [74]. Although high-dose epinephrine improved the rate of successful resuscitation in patients with asystole, it did not improve survival to hospital discharge. Vasopressin Vasopressin has been studied as a potential alternative to epinephrine. In one trial comparing vasopressin with epinephrine in 1186 patients with out-of-hospital arrest, the https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 13/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate 528 patients with asystole who received vasopressin were significantly more likely to survive until hospital admission (29 versus 20 percent with epinephrine, odds ratio [OR] 0.6, 95% CI 0.4- 0.9) and hospital discharge (4.7 versus 1.5 percent, OR 0.3, 95% CI 0.1-1.0) [43]. However, a subsequent meta-analysis, which included data from this and four smaller studies (1519 patients overall), found no significant benefit of vasopressin compared with epinephrine among patients with asystole, or any other initial cardiac rhythm [44]. Based upon these data, the 2020 AHA guidelines removed vasopressin as an option for the treatment of patients with asystole [3,29]. A more recent placebo-controlled randomized trial of 501 patients with in-hospital cardiac arrest showed that vasopressin given with methylprednisolone after epinephrine administration was associated with a higher rate of return of spontaneous circulation (42 versus 33 percent) but no difference in 30-day mortality or neurologic recovery [75]. These new data are unlikely to modify the 2020 guideline recommendation regarding vasopressin. Asystole and atropine Due to a paucity of data supporting the use of atropine for asystole, the 2020 AHA guidelines no longer recommend the routine use of atropine for the management of asystole [3,29]. In a cohort study of 6419 patients with asystole, return of spontaneous circulation was significantly greater in patients receiving epinephrine and atropine (33 versus 19 percent with epinephrine alone) [65]. However, overall survival and 30-day neurologic outcomes were no different in the two groups. Registry data on over 20,000 in-hospital cardiac arrests with a non-shockable rhythm, collected between 2006 and 2015, showed no difference in survival before and after atropine was removed from the treatment protocol in the 2010 AHA guidelines [66]. INEFFECTIVE THERAPIES A number of therapies have been shown to be generally ineffective in patients who present with sudden cardiac arrest, and therefore are not part of routine management: Sodium bicarbonate, except in patients with hyperkalemia (calcium is first-line therapy) or tricyclic antidepressant overdose Fibrinolytic therapy Cardiac pacing for asystole or pulseless electrical activity (PEA) Magnesium sulfate, except in patients who have drug-induced QT prolongation and develop torsades de pointes (see 'Magnesium sulfate' above) https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 14/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate Vasopressin for SCA of any cause Atropine for PEA The relevant data regarding these therapies are presented separately. (See "Therapies of uncertain benefit in basic and advanced cardiac life support".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Basic and advanced cardiac life support in adults".) SUMMARY AND RECOMMENDATIONS In patients with sudden cardiac arrest (SCA), survival depends upon prompt resuscitative efforts, including excellent cardiopulmonary resuscitation (CPR) with chest compressions and, when indicated, defibrillation to reestablish organized electrical activity with a stable rhythm. Chest compressions should not be stopped until the defibrillator is fully charged and the patient is ready for defibrillation. (See 'Introduction' above.) Excellent CPR should be provided throughout the resuscitative effort until return of spontaneous circulation or termination of resuscitative efforts. Brief (10 second) pauses in CPR should only occur at two-minute intervals for rhythm analysis and defibrillation, if indicated. (See "Advanced cardiac life support (ACLS) in adults" and 'Introduction' above.) The only definitively effective treatment of ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) is defibrillation, as VF and VT rarely, if ever, terminate spontaneously or after delivery of an antiarrhythmic drug. The chances of successful defibrillation, and survival, are greatest when defibrillation is performed early after the onset of VF or VT. However, while awaiting the arrival and setup of a defibrillator, CPR should be performed. (See "Advanced cardiac life support (ACLS) in adults" and 'VF and pulseless VT' above and 'Defibrillation' above.) In shockable rhythms, the priority remains early defibrillation and excellent CPR. If return of spontaneous circulation is not achieved after the second defibrillation, epinephrine 1 mg IV/IO should be administered every three to five minutes while excellent CPR and defibrillation are continued. (See "Advanced cardiac life support (ACLS) in adults" and 'VF or VT arrest and vasopressors' above.) https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 15/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate VF and VT often persist despite defibrillation, or recur promptly after successful defibrillation. In such cases, intravenous antiarrhythmic drug therapy should be used, with amiodarone or lidocaine being the preferred antiarrhythmic drugs. Notably in the management of cardiac arrest, amiodarone did not provide any benefit when assessing the clinically relevant outcome of neurologically favorable survival as compared with lidocaine or placebo. (See "Advanced cardiac life support (ACLS) in adults" and 'Antiarrhythmic drugs' above.) In patients with recurrent VF or pVT thought to be due to torsades de pointes with a prolonged QT interval, the administration of intravenous magnesium sulfate should be considered. (See 'Magnesium sulfate' above.) In contrast to SCA caused by VF or pVT, there is no role for defibrillation in the management of pulseless electrical activity (PEA) or asystole. While CPR is ongoing, epinephrine should be administered as soon as possible (and repeated every three to five minutes). However, before vascular access and epinephrine administration are considered, excellent CPR must be in progress, and epinephrine should only administered after early identification and management of other etiologies of non-shockable rhythms ( table 1). (See "Advanced cardiac life support (ACLS) in adults" and 'Pulseless electrical activity' above and 'Asystole' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Charles Pozner, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Herlitz J, Andersson E, B ng A, et al. Experiences from treatment of out-of-hospital cardiac arrest during 17 years in G teborg. Eur Heart J 2000; 21:1251. 2. Rea TD, Eisenberg MS, Becker LJ, et al. Temporal trends in sudden cardiac arrest: a 25-year emergency medical services perspective. Circulation 2003; 107:2780. 3. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132:S444. https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 16/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate 4. McMullan J, Gerecht R, Bonomo J, et al. Airway management and out-of-hospital cardiac arrest outcome in the CARES registry. Resuscitation 2014; 85:617. 5. Hasegawa K, Hiraide A, Chang Y, Brown DF. Association of prehospital advanced airway management with neurologic outcome and survival in patients with out-of-hospital cardiac arrest. JAMA 2013; 309:257. 6. Benoit JL, Gerecht RB, Steuerwald MT, McMullan JT. Endotracheal intubation versus supraglottic airway placement in out-of-hospital cardiac arrest: A meta-analysis. Resuscitation 2015; 93:20. 7. Winkle RA, Mead RH, Ruder MA, et al. Effect of duration of ventricular fibrillation on defibrillation efficacy in humans. Circulation 1990; 81:1477. 8. De Maio VJ, Stiell IG, Wells GA, et al. Optimal defibrillation response intervals for maximum out-of-hospital cardiac arrest survival rates. Ann Emerg Med 2003; 42:242. 9. Larsen MP, Eisenberg MS, Cummins RO, Hallstrom AP. Predicting survival from out-of- hospital cardiac arrest: a graphic model. Ann Emerg Med 1993; 22:1652. 10. Niemann JT, Cairns CB, Sharma J, Lewis RJ. Treatment of prolonged ventricular fibrillation. Immediate countershock versus high-dose epinephrine and CPR preceding countershock. Circulation 1992; 85:281. 11. Baum RS, Alvarez H 3rd, Cobb LA. Survival after resuscitation from out-of-hospital ventricular fibrillation. Circulation 1974; 50:1231. 12. Callans DJ. Out-of-hospital cardiac arrest the solution is shocking. N Engl J Med 2004; 351:632. 13. Thompson RJ, McCullough PA, Kahn JK, O'Neill WW. Prediction of death and neurologic outcome in the emergency department in out-of-hospital cardiac arrest survivors. Am J Cardiol 1998; 81:17. 14. Eftest l T, Sunde K, Steen PA. Effects of interrupting precordial compressions on the calculated probability of defibrillation success during out-of-hospital cardiac arrest. Circulation 2002; 105:2270. 15. Eftestol T, Sunde K, Ole Aase S, et al. Predicting outcome of defibrillation by spectral characterization and nonparametric classification of ventricular fibrillation in patients with out-of-hospital cardiac arrest. Circulation 2000; 102:1523. 16. Eftest l T, Wik L, Sunde K, Steen PA. Effects of cardiopulmonary resuscitation on predictors of ventricular fibrillation defibrillation success during out-of-hospital cardiac arrest. Circulation 2004; 110:10. https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 17/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate 17. Christenson J, Andrusiek D, Everson-Stewart S, et al. Chest compression fraction determines survival in patients with out-of-hospital ventricular fibrillation. Circulation 2009; 120:1241. 18. Yu T, Weil MH, Tang W, et al. Adverse outcomes of interrupted precordial compression during automated defibrillation. Circulation 2002; 106:368. 19. Steen S, Liao Q, Pierre L, et al. The critical importance of minimal delay between chest compressions and subsequent defibrillation: a haemodynamic explanation. Resuscitation 2003; 58:249. 20. Cobb LA, Fahrenbruch CE, Walsh TR, et al. Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation. JAMA 1999; 281:1182. 21. Wik L, Hansen TB, Fylling F, et al. Delaying defibrillation to give basic cardiopulmonary resuscitation to patients with out-of-hospital ventricular fibrillation: a randomized trial. JAMA 2003; 289:1389. 22. Baker PW, Conway J, Cotton C, et al. Defibrillation or cardiopulmonary resuscitation first for patients with out-of-hospital cardiac arrests found by paramedics to be in ventricular fibrillation? A randomised control trial. Resuscitation 2008; 79:424. 23. Jacobs IG, Finn JC, Oxer HF, Jelinek GA. CPR before defibrillation in out-of-hospital cardiac arrest: a randomized trial. Emerg Med Australas 2005; 17:39. 24. Stiell IG, Nichol G, Leroux BG, et al. Early versus later rhythm analysis in patients with out- of-hospital cardiac arrest. N Engl J Med 2011; 365:787. 25. Patel KK, Spertus JA, Khariton Y, et al. Association Between Prompt Defibrillation and Epinephrine Treatment With Long-Term Survival After In-Hospital Cardiac Arrest. Circulation 2018; 137:2041. 26. Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S729. 27. Field JM, Hazinski MF, Sayre MR, et al. Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S640. 28. Neumar RW, Shuster M, Callaway CW, et al. Part 1: Executive Summary: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132:S315. 29. Panchal AR, Bartos JA, Caba as JG, et al. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2020; 142:S366. https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 18/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate 30. Emmerson AC, Whitbread M, Fothergill RT. Double sequential defibrillation therapy for out- of-hospital cardiac arrests: The London experience. Resuscitation 2017; 117:97. 31. Cortez E, Krebs W, Davis J, et al. Use of double sequential external defibrillation for refractory ventricular fibrillation during out-of-hospital cardiac arrest. Resuscitation 2016; 108:82. 32. Soar J, Maconochie I, Wyckoff MH, et al. 2019 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces. Circulation 2019; 140:e826. 33. Perkins GD, Ji C, Deakin CD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med 2018; 379:711. 34. Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation 2011; 82:1138. 35. Perkins GD, Kenna C, Ji C, et al. The effects of adrenaline in out of hospital cardiac arrest with shockable and non-shockable rhythms: Findings from the PACA and PARAMEDIC-2 randomised controlled trials. Resuscitation 2019; 140:55. 36. Vargas M, Buonanno P, Iacovazzo C, Servillo G. Epinephrine for out of hospital cardiac arrest: A systematic review and meta-analysis of randomized controlled trials. Resuscitation 2019; 136:54. 37. Hagihara A, Hasegawa M, Abe T, et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012; 307:1161. 38. Dumas F, Bougouin W, Geri G, et al. Is epinephrine during cardiac arrest associated with worse outcomes in resuscitated patients? J Am Coll Cardiol 2014; 64:2360. 39. Andersen LW, Kurth T, Chase M, et al. Early administration of epinephrine (adrenaline) in patients with cardiac arrest with initial shockable rhythm in hospital: propensity score matched analysis. BMJ 2016; 353:i1577. 40. Finn J, Jacobs I, Williams TA, et al. Adrenaline and vasopressin for cardiac arrest. Cochrane Database Syst Rev 2019; 1:CD003179. 41. Lindner KH, Dirks B, Strohmenger HU, et al. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 1997; 349:535. 42. Stiell IG, H bert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet 2001; 358:105. https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 19/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate 43. Wenzel V, Krismer AC, Arntz HR, et al. A comparison of vasopressin and epinephrine for out- of-hospital cardiopulmonary resuscitation. N Engl J Med 2004; 350:105. 44. Aung K, Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis. Arch Intern Med 2005; 165:17. 45. Gueugniaud PY, David JS, Chanzy E, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med 2008; 359:21. 46. Grmec S, Lah K, Tusek-Bunc K. Difference in end-tidal CO2 between asphyxia cardiac arrest and ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest in the prehospital setting. Crit Care 2003; 7:R139. 47. Grmec S, Klemen P. Does the end-tidal carbon dioxide (EtCO2) concentration have prognostic value during out-of-hospital cardiac arrest? Eur J Emerg Med 2001; 8:263. 48. Kolar M, Krizmaric M, Klemen P, Grmec S. Partial pressure of end-tidal carbon dioxide successful predicts cardiopulmonary resuscitation in the field: a prospective observational study. Crit Care 2008; 12:R115. 49. Ali MU, Fitzpatrick-Lewis D, Kenny M, et al. Effectiveness of antiarrhythmic drugs for shockable cardiac arrest: A systematic review. Resuscitation 2018; 132:63. 50. Panchal AR, Berg KM, Kudenchuk PJ, et al. 2018 American Heart Association Focused Update on Advanced Cardiovascular Life Support Use of Antiarrhythmic Drugs During and Immediately After Cardiac Arrest: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2018; 138:e740. 51. Soar J, Donnino MW, Maconochie I, et al. 2018 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary. Resuscitation 2018; 133:194. 52. Daya MR, Leroux BG, Dorian P, et al. Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest. Circulation 2020; 141:188. 53. Mody P, Brown SP, Kudenchuk PJ, et al. Intraosseous versus intravenous access in patients with out-of-hospital cardiac arrest: Insights from the resuscitation outcomes consortium continuous chest compression trial. Resuscitation 2019; 134:69. 54. McLeod SL, Brignardello-Petersen R, Worster A, et al. Comparative effectiveness of antiarrhythmics for out-of-hospital cardiac arrest: A systematic review and network meta- analysis. Resuscitation 2017; 121:90. https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 20/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate 55. Dorian P, Cass D, Schwartz B, et al. Amiodarone as compared with lidocaine for shock- resistant ventricular fibrillation. N Engl J Med 2002; 346:884. 56. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999; 341:871. 57. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995; 92:3264. 58. Kowey PR, Levine JH, Herre JM, et al. Randomized, double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995; 92:3255. 59. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, Lidocaine, or Placebo in Out-of- Hospital Cardiac Arrest. N Engl J Med 2016; 374:1711. 60. Kudenchuk PJ, Leroux BG, Daya M, et al. Antiarrhythmic Drugs for Nonshockable-Turned- Shockable Out-of-Hospital Cardiac Arrest: The ALPS Study (Amiodarone, Lidocaine, or Placebo). Circulation 2017; 136:2119. 61. Tzivoni D, Banai S, Schuger C, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation 1988; 77:392. 62. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 C versus 36 C after cardiac arrest. N Engl J Med 2013; 369:2197. 63. Kudenchuk PJ, Redshaw JD, Stubbs BA, et al. Impact of changes in resuscitation practice on survival and neurological outcome after out-of-hospital cardiac arrest resulting from nonshockable arrhythmias. Circulation 2012; 125:1787. 64. Hansen M, Schmicker RH, Newgard CD, et al. Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults. Circulation 2018; 137:2032. 65. Survey of Survivors After Out-of-hospital Cardiac Arrest in KANTO Area, Japan (SOS-KANTO) Study Group. Atropine sulfate for patients with out-of-hospital cardiac arrest due to asystole and pulseless electrical activity. Circ J 2011; 75:580. 66. Holmberg MJ, Moskowitz A, Wiberg S, et al. Guideline removal of atropine and survival after adult in-hospital cardiac arrest with a non-shockable rhythm. Resuscitation 2019; 137:69. 67. Hedges JR, Syverud SA, Dalsey WC, et al. Prehospital trial of emergency transcutaneous cardiac pacing. Circulation 1987; 76:1337. https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 21/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate 68. Barthell E, Troiano P, Olson D, et al. Prehospital external cardiac pacing: a prospective, controlled clinical trial. Ann Emerg Med 1988; 17:1221. 69. Cummins RO, Graves JR, Larsen MP, et al. Out-of-hospital transcutaneous pacing by emergency medical technicians in patients with asystolic cardiac arrest. N Engl J Med 1993; 328:1377. 70. Ornato JP, Peberdy MA. The mystery of bradyasystole during cardiac arrest. Ann Emerg Med 1996; 27:576. 71. Quan L, Graves JR, Kinder DR, et al. Transcutaneous cardiac pacing in the treatment of out- of-hospital pediatric cardiac arrests. Ann Emerg Med 1992; 21:905. 72. Okubo M, Komukai S, Callaway CW, Izawa J. Association of Timing of Epinephrine Administration With Outcomes in Adults With Out-of-Hospital Cardiac Arrest. JAMA Netw Open 2021; 4:e2120176. 73. Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. N Engl J Med 1992; 327:1051. 74. Gueugniaud PY, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group. N Engl J Med 1998; 339:1595. 75. Andersen LW, Isbye D, Kj rgaard J, et al. Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA 2021; 326:1586. Topic 1028 Version 43.0 https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 22/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate GRAPHICS Adult cardiac arrest algorithm https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 23/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 24/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate Reprinted with permission. Highlights of the 2020 American Heart Association Guidelines for CPR and ECC. Copyright 2020 American Association, Inc. Graphic 129983 Version 9.0 https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 25/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate Continuous electrocardigraphic (ECG) strip during an episode of ventricular fibrillation (VF) that progresses to fine VF and then asystole At the onset of ventricular fibrillation (VF), the QRS complexes are regular, widened, and of tall amplitude, suggesting a more organized ventricular tachyarrhythmia. Over a brief period of time, the rhythm becomes more disorganized with high amplitude fibrillatory waves; this is coarse VF. After a longer period of time, the fibrillatory waves become fine, culminating in asystole. Graphic 67777 Version 3.0 https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 26/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate Defibrillation waveforms in implantable cardioverter- defibrillators Figure A shows the monophasic, exponentially decaying pulse was the waveform used in the first generation of ICDs. Figure B shows the biphasic waveform, which is generated with a single capacitor by switching the output polarity during discharge. Each division is 2 milliseconds. ICD: implantable cardioverter-defibrillator. Graphic 51842 Version 3.0 https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 27/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate Treatable conditions associated with cardiac arrest Condition Common associated clinical settings Acidosis Diabetes, diarrhea, drug overdose, renal dysfunction, sepsis, shock Anemia Gastrointestinal bleeding, nutritional deficiencies, recent trauma Cardiac Post-cardiac surgery, malignancy, post-myocardial infarction, pericarditis, trauma tamponade Hyperkalemia Drug overdose, renal dysfunction, hemolysis, excessive potassium intake, rhabdomyolysis, major soft tissue injury, tumor lysis syndrome Hypokalemia* Alcohol abuse, diabetes mellitus, diuretics, drug overdose, profound gastrointestinal losses Hypothermia Alcohol intoxication, significant burns, drowning, drug overdose, elder patient, endocrine disease, environmental exposure, spinal cord disease, trauma Hypovolemia Significant burns, diabetes, gastrointestinal losses, hemorrhage, malignancy, sepsis, trauma Hypoxia Upper airway obstruction, hypoventilation (CNS dysfunction, neuromuscular disease), pulmonary disease Myocardial infarction Cardiac arrest Poisoning History of alcohol or drug abuse, altered mental status, classic toxidrome (eg, sympathomimetic), occupational exposure, psychiatric disease Pulmonary embolism Immobilized patient, recent surgical procedure (eg, orthopedic), peripartum, risk factors for thromboembolic disease, recent trauma, presentation consistent with acute pulmonary embolism Tension Central venous catheter, mechanical ventilation, pulmonary disease (eg, asthma, pneumothorax chronic obstructive pulmonary disease), thoracentesis, thoracic trauma CNS: central nervous system. Hypomagnesemia should be assumed in the setting of hypokalemia, and both should be treated. Adapted from: Eisenberg MS, Mengert TJ. Cardiac resuscitation. N Engl J Med 2001; 344:1304. Graphic 52416 Version 8.0 https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 28/29 7/6/23, 3:10 PM Supportive data for advanced cardiac life support in adults with sudden cardiac arrest - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard L Page, MD No relevant financial relationship(s) with ineligible companies to disclose. Ron M Walls, MD, FRCPC, FAAEM Other Financial Interest: Airway Management Education Center [Health care provider education and resources]; First Airway [Health care provider education and resources]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/supportive-data-for-advanced-cardiac-life-support-in-adults-with-sudden-cardiac-arrest/print 29/29

7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. The management of atrial fibrillation in patients with heart failure : Brian Olshansky, MD : Wilson S Colucci, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 30, 2022. INTRODUCTION Atrial fibrillation (AF) is common among patients with heart failure (HF). This topic will focus on the acute and long-term management and prognosis of AF in patients with HF, including those with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). Our recommendations are similar to those made in the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline, its 2019 focused update, the 2021 guideline for AF management in HFrEF, and the joint European Heart Rhythm Association/Heart Failure Association consensus document on AF [1-5]. The general management of patients with HFrEF and HFpEF is discussed separately: (See "Overview of the management of heart failure with reduced ejection fraction in adults".) (See "Treatment and prognosis of heart failure with preserved ejection fraction".) The management of AF in HF for patients with specific cardiomyopathies and valvular disease are discussed separately: Hypertrophic cardiomyopathy. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Treatment'.) Amyloid cardiomyopathy. (See "Amyloid cardiomyopathy: Treatment and prognosis".) https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 1/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Valvular heart disease. (See "Rheumatic mitral stenosis: Overview of management", section on 'Management of atrial fibrillation' and "Medical management of asymptomatic aortic stenosis in adults", section on 'Atrial fibrillation' and "Indications for intervention for chronic severe primary mitral regurgitation".) EPIDEMIOLOGY The prevalence of AF in patients with HF varies from less than 10 to 57 percent, depending in part upon the severity of HF [6-11]. For instance, the prevalence of AF increases from 4 to 50 percent as the New York Heart Association functional class increases from I to IV [12-19]. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'NYHA functional class'.) However, AF was recently associated with heart failure with reduced ejection fraction (HFrEF) and HF with preserved EF (HFpEF) events, with no significant difference in the strength of association among these subtypes, and many comorbidities (eg, anemia, renal failure, hypertension, valvular disease, coronary artery disease, etc) may also contribute to the development of AF in HF patients [20]. The presence of either HF or AF increases the likelihood that the other will develop over time [21]. The temporal associations of AF and HF were studied in over 10,000 individuals in the Framingham Heart Study [22]: Among 1737 persons with new AF, 37 percent had HF. Among 1166 persons with new HF, 57 percent had AF. Of these, 41 percent had HFpEF and 44 percent had HFrEF (15 percent could not be classified). The presence of both AF and HF predicted greater mortality risk compared with having neither condition, particularly among individuals with HFrEF. (See 'Prognosis' below.) In the investigation from the Framingham Heart Study, prevalent AF was more strongly associated with incident HFpEF than HFrEF (hazard ratios [HRs] 2.34 versus 1.48) [21]. However, a more recent study of over 25,000 participants in the REGARDS cohort did not show differential associations between AF and the development of HFpEF compared with HFrEF (HR 1.87 and 1.67 respectively, p interaction = 0.58) [20]. MECHANISMS OF CARDIAC DYSFUNCTION https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 2/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate AF can impair myocardial function by multiple mechanisms that cause or worsen HF [23]. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Specific mechanisms include: Tachycardia, bradycardia, abrupt heart rate change, and irregular rhythm may decrease cardiac output. Persistent tachycardia may lead to arrhythmia-induced cardiomyopathy or can worsen a preexisting cardiomyopathy [24-26]. (See "Arrhythmia-induced cardiomyopathy" and "Arrhythmia-induced cardiomyopathy", section on 'Atrial fibrillation and atrial flutter'.) Loss of atrial systole prevents optimal ventricular filling. Patients with diastolic HF are especially symptomatic in AF since left ventricular (LV) filling is more dependent on atrial contraction. (See "Pathophysiology of heart failure with preserved ejection fraction".) AF can lead to maladaptive vasoconstriction from angiotensin II, norepinephrine, and other procoagulant biochemicals. The left atrial remodeling that occurs in AF can lead to atrial fibrosis, dilation and dysfunction (this is sometimes referred to as an atriopathy ). This can cause mitral and/or tricuspid regurgitation, which exacerbate HF. HF is also a risk factor for AF, possibly mediated by left atrial stretch. (See "Mechanisms of atrial fibrillation", section on 'Triggers of AF'.) GOALS OF THERAPY For patients with AF and HF, we set the following goals of therapy: Manage acute HF exacerbation Control symptoms; prevent cardiac dysfunction and subsequent HF and/or hemodynamic compromise Prevent arterial thromboembolism, particularly stroke Reduce mortality and cardiac hospitalization ACUTE DECOMPENSATION The general approach to managing acute HF decompensation with AF involves anticoagulation, treating the acute HF exacerbation, rate control to <120 beats per minute, correction of https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 3/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate reversible causes, and (only in rare instances) cardioversion. To manage acute decompensated HF with uncontrolled rates in AF, hospitalization is generally required. AF can precede an acute HF exacerbation, and uncontrolled HF can accelerate the ventricular response of AF or precipitate AF in patients in sinus rhythm. Symptoms Patients can present with sudden pulmonary congestion and an increase in the ventricular rate of AF, causing palpitations and shortness of breath and hypotension leading to dizziness or even syncope. Anticoagulation Prior to or concurrent with treating the acute HF exacerbation, we anticoagulate patients with AF and HF; if the patient has acute HF symptoms, we prioritize HF treatment. Because of the high risk of thromboembolism in these patients, we anticoagulate irrespective of ejection fraction (EF), whether or not a long-term rate or rhythm control management strategy is employed, and even if patient has a CHA DS -VASc score of 1 [27]. 2 2 However, if a patient has contraindications to anticoagulation such as a high risk of bleeding, we do not anticoagulate them. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) In addition, effective anticoagulation is required prior to, during, and after cardioversion, whether it be pharmacological or electrical. Details regarding anticoagulation and the role of transesophageal echocardiography prior to cardioversion in patients with AF are discussed separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Acute heart failure management We treat HF with diuretics, vasodilators, and other measures as appropriate. This is discussed separately. (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Initial therapy'.) As part of acute HF management in patients with AF, we also slow the ventricular response. Acute rate control We aim to reduce the ventricular rate to <120 beats per minute. We do not rate control to lower ventricular rates until the acute HF exacerbation is stabilized, as patients may need a higher heart rate to maintain their cardiac output. Our specific approach to acute rate control differs for patients with HFrEF and HFpEF. HF with reduced EF (HFrEF) For patients with HFrEF, we use intravenous (IV) amiodarone, IV digoxin, (and rarely IV diltiazem) to acutely control the heart rate. After starting the medication, we continually reassess the heart rate and titrate the medication https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 4/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate to achieve the goal heart rate of <120 beats per minute. Usually, we try the medication for one to two days, and if the heart rate remains elevated, we attempt another agent. The choice of medications is usually influenced by practitioner familiarity. Amiodarone has very little negative inotropic activity and is usually more effective than digoxin. However, amiodarone and IV diltiazem can both cause hypotension. Amiodarone is associated with conversion to sinus rhythm in a small percent of patients, which is of concern if the patient is not anticoagulated. We usually avoid diltiazem due to its negative inotropic effect that might further compromise cardiac contractility. (See "Amiodarone: Clinical uses".) Amiodarone dosing for AF rate control in all patients and among critically ill patients is presented separately. Dosing is similar for AF in patients with HF. (See "Amiodarone: Clinical uses", section on 'Ventricular rate control in critically ill patients with atrial fibrillation and rapid ventricular response'.) Digoxin dosing for AF rate control usually includes IV loading followed by a maintenance oral dose. Oral loading is also possible. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Rapid digoxin loading'.) Diltiazem dosing in the acute setting is discussed separately. We generally avoid beta blocker therapy in patients with AF and acute decompensated HF. In such patients, the negative inotropic properties of a beta blocker may worsen the clinical condition. The use of beta blockers for long-term control of heart rate in AF is discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Urgent therapy' and 'Rate control in heart failure with reduced ejection fraction' below and 'Rate control in heart failure with preserved ejection fraction' below and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) HF with preserved EF (HFpEF) In HFpEF patients who present with congestion or hypotension, rate control can be attempted first with IV diltiazem (which may be better tolerated in patients with borderline hypotension) or IV beta blockade. We consider these agents to be equally effective at rate control of AF in patients with HFpEF. With both medications, hypotension is a potential side effect. Diltiazem dosing in the acute setting is discussed separately. For the acute control of ventricular rate, IV beta blockade with metoprolol, propranolol, or esmolol can be effective. Specific dosing information for these medications is presented separately. Specific dosing information is discussed separately. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 5/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Correction of reversible causes In some patients, there is a reversible cause of AF, HF, or both. These are reviewed separately. (See "Pathophysiology of heart failure with preserved ejection fraction", section on 'Decompensated HFpEF' and "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Management of causes and associated conditions' and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Triggers'.) Etiologies that are specific to AF and HF include: If a patient with existing AF develops new HF, a possible diagnosis to consider is arrythmia- induced cardiomyopathy from inadequate rate control. (See "Arrhythmia-induced cardiomyopathy".) If a patient develops new-onset AF and HF concurrently, thyrotoxicosis should be considered as a diagnostic possibility. (See "Cardiovascular effects of hyperthyroidism", section on 'Heart failure' and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) Role of cardioversion We rarely consider an initial cardioversion for treatment of patients with acute decompensated HF; there is a low probability of successful or durable cardioversion unless the HF decompensation is first corrected. However, cardioversion (generally electrical) may be helpful in the following circumstances: Initial attempts to decrease pulmonary congestion with diuretics, vasodilators, and rate control have failed. AF is thought to be the cause of acute HF decompensation, ie, the onset of AF has recently preceded the HF exacerbation. In such patients, even if the rate is well controlled, cardioversion may be helpful in managing HF. Patients with persistent evidence of myocardial ischemia. This scenario assumes that the patient does not require urgent reperfusion or other stabilizing therapies for acute coronary syndrome. (See "Overview of the acute management of ST-elevation myocardial infarction", section on 'Choosing and initiating reperfusion with PCI or fibrinolysis' and "Overview of the acute management of non-ST-elevation acute coronary syndromes", section on 'Choosing a revascularization strategy'.) In patients with HFpEF, it can be difficult to tell if the HF is predominantly due to AF or some other cause. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 6/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate An important potential harm of cardioversion in this setting is the risk of a thromboembolic event in nonanticoagulated patients. We almost always avoid cardioversion (even in patients with hemodynamic instability or cardiogenic shock) if the patient is not adequately anticoagulated (ie, has not been on therapeutic, uninterrupted, chronic anticoagulation for at least one month prior). For patients in whom urgent cardioversion is being considered despite inadequate anticoagulation, a transesophageal echocardiogram should be considered to evaluate for a left atrial or left atrial appendage thrombus. (See 'Anticoagulation' above and "Role of echocardiography in atrial fibrillation", section on 'Transesophageal echocardiography'.) We avoid cardioversion in patients with long-standing persistent or permanent AF, who have failed cardioversion, or who have had early recurrence of AF after cardioversion with additional antiarrhythmic therapy. LONG-TERM MANAGEMENT Long-term anticoagulation We continue anticoagulation that was started during acute management, transitioning to oral anticoagulation as appropriate. If anticoagulation was not started during the acute management phase, and if there are no contraindications, we start anticoagulation. Because of the high risk of thromboembolism in these patients, we anticoagulate irrespective of ejection fraction (EF), whether or not a long-term rate or rhythm control management strategy is employed, and even if a patient has a CHA DS -VASc score of 1 2 2 [27]. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Novel oral anticoagulants, instead of warfarin, are often used for effective anticoagulation. There is increased risk of bleeding when these anticoagulants are used concomitantly with amiodarone or other medications [28-31]. Preference for rhythm over rate control Although the first management approach in acute decompensated AF with HF is often rate control, rhythm control is our preferred long-term management strategy for most patients. This includes patients with recent-onset AF, persistent HF even when rate controlled, or inadequate rate control. (See 'Acute decompensation' above.) Potential exceptions to this approach are noted below. (See 'Exceptions' below.) Evidence for cardiovascular benefit Specific reasons for returning the patient to sinus rhythm are to establish a symptom-rhythm correlation; this helps to establish if AF is a specific trigger or contributing factor for a patient's HF symptoms and/or worsening HF. A return to sinus rhythm can also improve cardiac function, increase exercise tolerance, and alleviate HF symptoms. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 7/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Some evidence suggests that early rhythm control (ie, within one year) is beneficial for improved five-year cardiovascular outcomes in patients with HF (either HF with preserved EF [HFpEF] or reduced EF [HFrEF]). In a prespecified subanalysis of the EAST-AFNET 4 randomized trial, over 750 patients with symptomatic HF were randomly assigned to early rhythm control or usual care (which included rhythm control for symptoms) [32]. The following was observed: The composite outcome of cardiovascular death, stroke, or hospitalization for HF or acute coronary syndrome occurred less often in patients in the early rhythm control versus usual care group (5.7 versus 7.9 per 100 patient-years; hazard ratio [HR] 0.74, 95% CI 0.56-0.97). Kaplan-Meier curves showed that event rates in the two treatment groups began to separate at six months. The two treatment groups had similar rates of all-cause mortality (9.9 versus 11.8 percent). Left ventricular EF (LVEF) improved in both groups (approximately 5 percent increase). The primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) was similar between treatment groups (17.9 versus 21.6 percent, HR 0.85, 95% CI 0.62-1.17). Some limitations of EAST-AFNET 4 should be mentioned. The usual care assigned to the control group in EAST-AFNET 4 may not be generalizable, as it may not reflect standard treatment of AF in patients with HF. Also, patients assigned to rhythm control received a variety of therapies; only 19 percent received catheter ablation (CA). In the subsequent RAFT-AF trial, results were similar, although the trial was stopped early for futility and did not have statistically significant findings. Four hundred and eleven patients with HF and a high burden of AF were randomly assigned to either CA-based rhythm control or rate control and followed for mortality and HF events [33]. Patients assigned to rhythm control had a lower mortality and HF events compared with the rate control group, but the results were not statistically significant (23.4 versus 32.5 percent; HR 0.71, 95% CI 0.49-1.03). Patients in the rhythm control group also had greater improvements in LVEF (increase of 10 versus 4 percent), six-minute walk test, and HF- and AF-related quality of life. The CA-related adverse event rate was high at 11 percent. An additional limitation of this study was the lack of statistical power to detect a potential protective effect of therapy; the study was unable to recruit the anticipated number of participants due to restrictions on clinical research during the COVID-19 pandemic. Four small randomized trials, each with methodological limitations, and one observational study have compared CA with rate control in patients with HF and also found benefit [34-38]. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy' and 'Catheter ablation' below.) https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 8/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate A previous trial (AF-CHF) did not find a significant benefit for long-term pharmacologic rhythm control compared with rate control in patients with HFrEF and AF [39,40]. It is important to recognize that CA was not a strategy tested in the AF-CHF trial, whereas 19 percent of patients in the rhythm control arm had CA in the EAST-AFNET 4 trial. Furthermore, in AF-CHF, the patients all had severe LV systolic dysfunction. These key differences may underline why the results in AF- CHF were null in contrast to the EAST-AFNET 4 trial described above, in which early rhythm control was beneficial. Exceptions A rate control strategy may be preferred in patients with longstanding AF or severe left atrial enlargement. In these cases, the cardioversion is much less likely to be successful or durable. Also, for patients with severe valvular disease (such as severe mitral regurgitation), cardioversion is less likely to be successful in maintaining sinus rhythm and reducing symptoms. A rate control strategy may also be reasonable in an older patient who is unwilling to undergo the burdens of a rhythm control strategy, particularly if they tolerate AF well. Some patients will not want to be placed on antiarrhythmic medications or undergo invasive procedures. In these patients, a rate control strategy may be pursued. If a patient has a contraindication to anticoagulation, a rate control strategy may also be preferred. Heart failure with reduced ejection fraction Rhythm control Conversion to and maintenance of sinus rhythm can be achieved with electrical cardioversion, antiarrhythmic drug therapy, CA, or surgical ablation [21]. Generally, we approach attempts at rhythm control in a step-wise fashion as outlined in the sections that follow. (See 'Preference for rhythm over rate control' above.) Rhythm control is less effective in patients with persistent AF (which is common among patients with HF) or with severe left atrial enlargement (a marker of AF chronicity). Electrical cardioversion For nearly all patients, we first try electrical cardioversion (this can be done in conjunction with antiarrhythmic medication, which can increase the likelihood of maintaining sinus rhythm, or it can be performed without such a medication). We generally perform the initial electrical cardioversion without an antiarrhythmic medication if this is the first episode of AF, if AF is well tolerated, if HF is not difficult to manage, and if there is no hemodynamically significant mitral regurgitation or left atrial enlargement. Patients require appropriate anticoagulation prior to, during, and after cardioversion. (See 'Anticoagulation' above.) https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 9/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Electrical cardioversion is not appropriate in those who have short episodes of paroxysmal AF and for those in whom HF exacerbation is unlikely to be due to the AF. However, we use cardioversion if paroxysmal AF episodes last days, if there is precipitous change in condition, and if patients do not respond to an antiarrhythmic drug. After initial cardioversion, the majority of patients will have recurrent AF unless it was due to an acute precipitant that is no longer present (eg, acute pulmonary edema, myocardial infarction, pulmonary embolus, cardiac surgery). If a patient reverts to AF after cardioversion, we may try another cardioversion, this time with an antiarrhythmic medication (initiated prior to cardioversion) in order to help the patient maintain sinus rhythm. In some patients, we attempt cardioversion multiple times. Considerations include the likelihood of maintaining sinus rhythm, the time course of AF recurrence, patient symptom burden, and need for improvement of patient hemodynamics. We also try to balance these with the patient's overall preference to be in sinus rhythm. For example, if AF seems to be related to acute HF decompensation or other adverse event, repeat cardioversions are appropriate. If repeat cardioversions are not successful, we may use antiarrhythmic drugs and/or CA to maintain sinus rhythm. Antiarrhythmic drugs In nearly all patients with HFrEF who have recurrent AF after cardioversion, we use an antiarrhythmic drug to help maintain sinus rhythm or to facilitate cardioversion if the cardioversion is not successful in achieving sinus rhythm. We always ensure the patient is appropriately anticoagulated. (See 'Anticoagulation' above.) We use dofetilide, sotalol, or amiodarone as the initial antiarrhythmic medication in patients with persistent AF and HF. Some experts prefer to try dofetilide first, especially in patients who are younger and have preserved kidney dysfunction. Other experts prefer to use amiodarone, given its ease of use. Dofetilide is more likely to cause the potentially life-threatening ventricular arrhythmia "torsades de pointes" in patients with HF with severe systolic dysfunction than amiodarone and in those with acute decompensation. Therefore, dofetilide is safer to use in patients with HF and milder systolic dysfunction, as well as those patients who have an implantable cardiac defibrillator, as these devices can prevent sudden cardiac arrest from ventricular arrhythmia. Prior to using dofetilide, during its initiation, and subsequent to initiation, measurements of QT intervals are necessary. (See "Clinical use of dofetilide", section on 'Safety' and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Sotalol can worsen HF in those with HFrEF due to the beta-blocking effects and is not recommended for patients with markedly impaired LV function and acute decompensated https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 10/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate HF. Sotalol can cause the potentially life-threatening arrythmia torsade de pointes, and thus prior to using the drug and after it is initiated, measurements of QT intervals are necessary. If the baseline QTc is greater than 450 msec, sotalol is contraindicated. Other details regarding sotalol initiation and QTc monitoring are discussed separately. (See "Clinical uses of sotalol", section on 'Dosing' and "Clinical uses of sotalol", section on 'Proarrhythmia'.) We avoid propafenone, dronedarone, and flecainide because of worse outcomes in HFrEF patients. The following provides evidence for the efficacy of specific pharmacotherapy in AF and HF: Dofetilide Dofetilide, a class III antiarrhythmic drug, can be effective and safe for preventing recurrent persistent AF in patients with HF. It may also be used to convert patients to sinus rhythm. The recommended dose of dofetilide is 500 micrograms twice daily in the absence of renal insufficiency, but it is adjusted based on renal function. Patients need to be hospitalized for dofetilide initiation. Further information regarding the initiation protocol and safety of dofetilide is discussed separately. (See "Clinical use of dofetilide".) In the DIAMOND-CHF trial, 390 patients with AF and symptomatic HF were randomly assigned to dofetilide or placebo [41]. Dofetilide was more likely to be associated with conversion to sinus rhythm at one month (12 versus 1 percent) and maintenance of sinus rhythm at one year (44 versus 13 percent; HR 0.35, 95% CI 0.22-0.57). Mortality did not differ between treatment groups (41 versus 42 percent; HR 0.95, 95% CI 0.81-1.11). In a separate investigation, among 500 patients with HFrEF and AF in the DIAMOND-HF and DIAMOND-MI studies, dofetilide was more likely than placebo to lead to conversion to sinus rhythm (59 versus 34 percent) and to maintain sinus rhythm at one year (79 versus 42 percent; relative risk 0.30, 95% CI 0.19-0.48) [42]. (See "Clinical use of dofetilide".) The most important side effect of dofetilide was torsades de pointes, which was seen in 25 cases (3.3 percent); three-quarters of episodes occurred within the first three days while the patient was in the hospital [42]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Definitions'.) Amiodarone When used for preventing recurrence of AF, advantages of low-dose amiodarone include no negative inotropic effect and little or no proarrhythmia. Advantages of amiodarone compared with dofetilide include the ability to start therapy as an outpatient (for AF), once-a-day dosing, and a lower risk of torsades de pointes. In addition, https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 11/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate since amiodarone has non-competitive beta-blocking and calcium channel antagonist activity, the ventricular rate is usually slow and well tolerated if AF does recur. The recommended dose of amiodarone is 400 mg/day. Occasionally, less than 200 mg/day is used (eg, for patients at high risk of side effects or toxicities). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse drug interactions'.) Its use in HF patients does not necessarily require hospitalization, but careful monitoring of the prothrombin time international normalized ratio is necessary, as amiodarone can potentiate the effects of warfarin. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse drug interactions'.) The efficacy of amiodarone in AF and HF was illustrated in a subset analysis from the CHF- STAT trial of over 660 patients in which 15 percent of patients had AF at baseline [43]. Among these 103 patients, 51 were randomly assigned to amiodarone and 52 to placebo. Patients assigned to amiodarone had a higher likelihood of converting to sinus rhythm (31 versus 8 percent). Patients who converted to sinus rhythm with amiodarone had a lower mortality than those who did not. However, it is not clear if reductions in mortality were because patients who converted were less sick to begin with or if restoration of sinus rhythm was causative. Complications associated with amiodarone loading and long-term therapy in patients with HFrEF and AF include bradycardia requiring permanent pacemaker, hypothyroidism, and neurotoxicity [44]. Side effects with maintenance therapy are less likely with lower doses but still occur. Sotalol Sotalol should be used with caution in patients with HF who have poor LV function (LVEF <30 percent) based on increased risk for torsades de pointes [45]. This is especially true if there are marked fluctuations in electrolyte levels, acute or decompensated HF, or renal dysfunction. (See "Drugs that should be avoided or used with caution in patients with heart failure", section on 'Antiarrhythmic agents' and "Clinical uses of sotalol", section on 'Heart failure'.) Sotalol can be used if the QT is not prolonged, if there is no renal dysfunction, if there are normal electrolytes (specifically normal potassium), if there is no acute decompensation, and if the LVEF is no more than modestly impaired (ie, if LVEF is >30 percent). However, sotalol can cause marked bradycardia and worsen HF in HFrEF in some instances. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 12/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Beta blockers Chronic beta blocker therapy may reduce the likelihood of development of AF in patients with HF due to systolic dysfunction. Likewise, in people with paroxysmal AF, beta blockers may help maintain sinus rhythm. Using beta blockers as antiarrhythmic therapy can serve a dual purpose because these medications are also an important component of optimal medical therapy for HF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Beta blockers'.) Medications we do not suggest using in AF and HF patients include: Dronedarone In general, dronedarone has no role in the management of AF in a HF patient. In particular, dronedarone should not be used in patients with New York Heart Association class III to IV HF or LV systolic dysfunction (LVEF <0.40), as efficacy is low, and safety is a concern. It should also not be used in patients with longstanding persistent AF. This recommendation is consistent with that made by the European Medicines Agency in September of 2011 and the U S Food and Drug Administration in December of 2011. Strong evidence for an adverse effect of dronedarone use in patients with HFrEF comes from the ANDROMEDA trial (patients in this study had an LVEF 35 percent) [46] . The trial was discontinued early due to a significant increase in the incidence of death in the patients assigned to dronedarone versus placebo (8.1 versus 3.8 percent; HR 2.13, 95% CI 1.07-4.25). The primary cause of death among patients receiving dronedarone was worsening HF [46]. Dronedarone is likely less efficacious than amiodarone at AF rhythm control [47]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Class IC drugs Class IC drugs (flecainide, propafenone) are associated with an increased risk for proarrhythmia and sudden cardiac death and should not be used in patients with AF and HF ( table 1). Ibutilide We do not use this medication in decompensated HF due to the substantial risks of torsades de pointes. (See "Therapeutic use of ibutilide", section on 'Proarrhythmia'.) Catheter ablation For patients with symptomatic AF who have HFrEF that is not decompensated and recurrent AF despite electrical cardioversion and antiarrhythmic drug therapy (or side effect or intolerance to antiarrhythmic therapy), we perform CA of AF rather than continued attempts at cardioversion with or without antiarrhythmic drug therapy. In some patients, repeat CA is pursued if the first CA is unsuccessful. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 13/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Rarely, if a patient has a contraindication to all antiarrhythmic medications and there is new AF and/or paroxysmal AF, we will pursue CA as the initial therapy. An example is a patient with HF and AF who has a contraindication to dofetilide and/or sotalol (eg, kidney disease, a long QT interval) and propensity to develop amiodarone toxicity (eg, underlying thyroid, lung, or liver disease). Patients HFrEF and AF who are unlikely to benefit from CA If the patient has one or more of the following factors, they may be unsuitable for CA: Some patients with advanced HF (including those with LV assist device destination therapy or on ionotropic support). Severe comorbidities or medical instability. Patients asymptomatic on optimal HF therapy. Longstanding AF that is unrelated to progressive symptoms or concerns. Older-aged persons including those with frailty. We do not generally perform CA in persons >age 80 years of age. Markedly enlarged left atrial size and longstanding persistent and drug-resistant AF. There is no evidence that suggests a specific left atrial dimension cut point beyond which CA may not be useful. Patients with complete heart block (either spontaneous or related to an atrioventricular node ablation) and permanent ventricular pacing. If the patient is deemed unsuitable for CA for one or more of these reasons and has failed other attempts at rhythm control, we pursue a rate control strategy. (See 'Rate control in heart failure with reduced ejection fraction' below.) Efficacy of CA versus medical therapy The CASTLE-AF trial randomly assigned 363 patients with implantable cardioverter-defibrillators, symptomatic paroxysmal or persistent AF, New York Heart Association class II or higher, and an LVEF 35 percent to CA or medical therapy [48]. Death from any cause or hospitalization for HF occurred in fewer patients in the CA compared with medical therapy group (29 versus 45 percent; HR 0.62; 95% CI 0.43- 0.87). The time in AF was also lower with CA versus medical therapy (25 versus 60 percent). Several important limitations of the CASTLE-AF trial include patients lost to follow-up (particularly in the group assigned implantable cardioverter-defibrillator), lack of blinding, small sample size, and limited generalizability given that 85 percent of participants were https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 14/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate male (females have less successful CAs) and that all patients had defibrillators and/or cardiac resynchronization therapy. A greater number of patients in the ablation group than in the medical therapy group crossed over to the other treatment group (15.6 versus 9.8). Finally, although medical therapy (for both AF and HF) was managed per study protocol, it is possible that a nontraditional or more aggressive approach to medical management might have influenced the trial results. In a 2019 meta-analysis of six trials (775 patients), of which CASTLE-AF was the largest [49], CA reduced all-cause mortality compared with drug therapy (9 versus 18 percent). Studies have also shown that CA can increase exercise ability, LVEF, quality of life, and is associated with a decrease in pro-brain natriuretic peptide levels [34,36,37,50]. Efficacy of CA versus atrioventricular node ablation with biventricular pacing In a randomized trial of 81 patients with HF and symptomatic, drug-refractory AF, CA was associated with modest improvements in LVEF (35 versus 28 percent), six-minute walk distance (340 versus 297 meters), and score on the Minnesota Living With Heart Failure questionnaire [35]. The role of atrioventricular ablation and biventricular pacing in patients with AF is discussed in detail elsewhere. (See 'Atrioventricular node ablation with pacing' below and "Cardiac resynchronization therapy in atrial fibrillation", section on 'Cardiac resynchronization therapy outcomes in patients with atrial fibrillation'.) Rate control in heart failure with reduced ejection fraction Indications We pursue a rate control strategy for patients in whom rhythm control is not tolerated or has been unsuccessful. A rate control strategy is sometimes the preferred initial

heart failure", section on 'Antiarrhythmic agents' and "Clinical uses of sotalol", section on 'Heart failure'.) Sotalol can be used if the QT is not prolonged, if there is no renal dysfunction, if there are normal electrolytes (specifically normal potassium), if there is no acute decompensation, and if the LVEF is no more than modestly impaired (ie, if LVEF is >30 percent). However, sotalol can cause marked bradycardia and worsen HF in HFrEF in some instances. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 12/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Beta blockers Chronic beta blocker therapy may reduce the likelihood of development of AF in patients with HF due to systolic dysfunction. Likewise, in people with paroxysmal AF, beta blockers may help maintain sinus rhythm. Using beta blockers as antiarrhythmic therapy can serve a dual purpose because these medications are also an important component of optimal medical therapy for HF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Beta blockers'.) Medications we do not suggest using in AF and HF patients include: Dronedarone In general, dronedarone has no role in the management of AF in a HF patient. In particular, dronedarone should not be used in patients with New York Heart Association class III to IV HF or LV systolic dysfunction (LVEF <0.40), as efficacy is low, and safety is a concern. It should also not be used in patients with longstanding persistent AF. This recommendation is consistent with that made by the European Medicines Agency in September of 2011 and the U S Food and Drug Administration in December of 2011. Strong evidence for an adverse effect of dronedarone use in patients with HFrEF comes from the ANDROMEDA trial (patients in this study had an LVEF 35 percent) [46] . The trial was discontinued early due to a significant increase in the incidence of death in the patients assigned to dronedarone versus placebo (8.1 versus 3.8 percent; HR 2.13, 95% CI 1.07-4.25). The primary cause of death among patients receiving dronedarone was worsening HF [46]. Dronedarone is likely less efficacious than amiodarone at AF rhythm control [47]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Class IC drugs Class IC drugs (flecainide, propafenone) are associated with an increased risk for proarrhythmia and sudden cardiac death and should not be used in patients with AF and HF ( table 1). Ibutilide We do not use this medication in decompensated HF due to the substantial risks of torsades de pointes. (See "Therapeutic use of ibutilide", section on 'Proarrhythmia'.) Catheter ablation For patients with symptomatic AF who have HFrEF that is not decompensated and recurrent AF despite electrical cardioversion and antiarrhythmic drug therapy (or side effect or intolerance to antiarrhythmic therapy), we perform CA of AF rather than continued attempts at cardioversion with or without antiarrhythmic drug therapy. In some patients, repeat CA is pursued if the first CA is unsuccessful. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 13/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Rarely, if a patient has a contraindication to all antiarrhythmic medications and there is new AF and/or paroxysmal AF, we will pursue CA as the initial therapy. An example is a patient with HF and AF who has a contraindication to dofetilide and/or sotalol (eg, kidney disease, a long QT interval) and propensity to develop amiodarone toxicity (eg, underlying thyroid, lung, or liver disease). Patients HFrEF and AF who are unlikely to benefit from CA If the patient has one or more of the following factors, they may be unsuitable for CA: Some patients with advanced HF (including those with LV assist device destination therapy or on ionotropic support). Severe comorbidities or medical instability. Patients asymptomatic on optimal HF therapy. Longstanding AF that is unrelated to progressive symptoms or concerns. Older-aged persons including those with frailty. We do not generally perform CA in persons >age 80 years of age. Markedly enlarged left atrial size and longstanding persistent and drug-resistant AF. There is no evidence that suggests a specific left atrial dimension cut point beyond which CA may not be useful. Patients with complete heart block (either spontaneous or related to an atrioventricular node ablation) and permanent ventricular pacing. If the patient is deemed unsuitable for CA for one or more of these reasons and has failed other attempts at rhythm control, we pursue a rate control strategy. (See 'Rate control in heart failure with reduced ejection fraction' below.) Efficacy of CA versus medical therapy The CASTLE-AF trial randomly assigned 363 patients with implantable cardioverter-defibrillators, symptomatic paroxysmal or persistent AF, New York Heart Association class II or higher, and an LVEF 35 percent to CA or medical therapy [48]. Death from any cause or hospitalization for HF occurred in fewer patients in the CA compared with medical therapy group (29 versus 45 percent; HR 0.62; 95% CI 0.43- 0.87). The time in AF was also lower with CA versus medical therapy (25 versus 60 percent). Several important limitations of the CASTLE-AF trial include patients lost to follow-up (particularly in the group assigned implantable cardioverter-defibrillator), lack of blinding, small sample size, and limited generalizability given that 85 percent of participants were https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 14/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate male (females have less successful CAs) and that all patients had defibrillators and/or cardiac resynchronization therapy. A greater number of patients in the ablation group than in the medical therapy group crossed over to the other treatment group (15.6 versus 9.8). Finally, although medical therapy (for both AF and HF) was managed per study protocol, it is possible that a nontraditional or more aggressive approach to medical management might have influenced the trial results. In a 2019 meta-analysis of six trials (775 patients), of which CASTLE-AF was the largest [49], CA reduced all-cause mortality compared with drug therapy (9 versus 18 percent). Studies have also shown that CA can increase exercise ability, LVEF, quality of life, and is associated with a decrease in pro-brain natriuretic peptide levels [34,36,37,50]. Efficacy of CA versus atrioventricular node ablation with biventricular pacing In a randomized trial of 81 patients with HF and symptomatic, drug-refractory AF, CA was associated with modest improvements in LVEF (35 versus 28 percent), six-minute walk distance (340 versus 297 meters), and score on the Minnesota Living With Heart Failure questionnaire [35]. The role of atrioventricular ablation and biventricular pacing in patients with AF is discussed in detail elsewhere. (See 'Atrioventricular node ablation with pacing' below and "Cardiac resynchronization therapy in atrial fibrillation", section on 'Cardiac resynchronization therapy outcomes in patients with atrial fibrillation'.) Rate control in heart failure with reduced ejection fraction Indications We pursue a rate control strategy for patients in whom rhythm control is not tolerated or has been unsuccessful. A rate control strategy is sometimes the preferred initial strategy in a subset of patients as outlined above. (See 'Exceptions' above.) Among patients with HF, rate control to prevent rapid AF usually leads to an improvement in symptoms. Slowing of the ventricular rate often leads to a moderate or even marked improvement in LV function [9,25,26]. (See 'mechanisms of cardiac dysfunction' above.) Rate control goal The broad goal of rate control is to minimize symptoms with exercise and rest. Thus, the adequacy of rate control should be assessed in both circumstances [21]. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) The optimal heart rate in patients with AF and HF has not been well studied and is not certain. Our authors generally start with a heart rate goal of <85 beats per minute at rest and <110 beats per minute during moderate exercise (the strict approach). If this is not possible, the goal becomes <110 beats per minute at rest (the lenient approach). https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 15/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate In a symptomatic patient in whom the ventricular rate varies markedly with minimal changes in activity, a rhythm control strategy may be necessary. Medications Although we prefer to use just one rate-slowing medication, sometimes more than one medication is required to achieve adequate heart rate control. When titrating therapy, we measure the patient's ventricular rates at rest and with moderate exertion. (See 'Rate control goal' above.) Beta blocker We usually select a beta blocker as first therapy due to their superior safety profile in both AF and HF. We would avoid starting a beta blocker if the patient had decompensated HF. Most patients with preexisting HFrEF are already on a beta blocker for treatment of HF, and if possible, we increase the dosage of their medication. The alternatives of digoxin (lesser efficacy) and amiodarone (more side effects) have significant limitations. We start with carvedilol, extended-release metoprolol succinate, or bisoprolol. The doses should be optimized before considering a second agent. These drugs are discussed in detail separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence' and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Elective and long-term management' and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Carvedilol is started at an oral dose of 3.125 mg twice daily. The usual dosage range is 3.125 to 25 mg twice daily but may be titrated higher for the purpose of treating HFrEF (up to 25 to 50 mg, depending on the patient's weight). A possible adverse effect of carvedilol is hypotension since this beta blocker also has alpha-adrenergic-receptor- blocking action [51]. Metoprolol succinate is started at an oral dose of 25 mg daily. This can be titrated up to a target dose of 200 mg daily in patients with HFrEF. Even if AF rate control is achieved at lower doses, the target for metoprolol succinate is higher for HFrEF. Bisoprolol is started at an oral dose of 2.5 mg once daily; the dose is increased gradually as tolerated to achieve ventricular rate control, and in patients with HFrEF, the target dose is 10 mg daily. Beta blockers have been shown to improve symptoms but not survival in AF and HF. In a meta-analysis of AF patients in 11 randomized trials of over 3000 patients, beta blockers reduced the ventricular rate (by 12 beats per minute) but did not decrease mortality when https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 16/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate compared with placebo (overall death rate 20 percent; HR 0.96, 95% CI 0.81-1.12) [52]. This finding was consistent with a prior study [53]. Digoxin In patients who cannot receive a beta blocker or are not adequately rate controlled despite their maximal-tolerated dose, and in whom rhythm control will not be attempted, digoxin may be considered. This may be relevant for patients with decompensated HF, in whom initiation or increase of beta blockers is contraindicated. If such a patient also has rapid AF requiring rate control, use of digoxin is suggested. However, digoxin is often ineffective when used alone. If two drugs are needed to control for long-term rate, we suggest adding digoxin to a beta blocker. Dosing and administration of digoxin are described separately. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification" and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Amiodarone In the event of inadequate rate control with beta blockers and/or digoxin, amiodarone can be used either alone or in combination with other rate control medications. We do not generally use amiodarone as a long-term rate control medication, but in the acute setting, it can assist with rate control as it is being loaded or can be used as a temporary rate control agent in patients who are unable to tolerate other therapies [43]. We exercise care when using amiodarone, especially in those without adequate anticoagulation since there is the possibility of pharmacologically restoring sinus rhythm. The usual maintenance dose of amiodarone from AF is 100 to 200 mg daily after a loading dose. Therapies that should be avoided for AF rate control and HFrEF include dronedarone, class IC drugs, and nondihydropyridine calcium channel blockers (verapamil and diltiazem). (See "Calcium channel blockers in heart failure with reduced ejection fraction" and "Drugs that should be avoided or used with caution in patients with heart failure".) Atrioventricular node ablation with pacing Rate control can also be achieved with radiofrequency ablation of the atrioventricular node and permanent pacemaker placement. This strategy may be useful in patients in whom rate control with antiarrhythmic drug or CA has failed or is contraindicated. Atrioventricular node ablation with pacing can be particularly helpful for patients with permanent AF. (See "Atrial fibrillation: Atrioventricular node ablation".) https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 17/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate If the LVEF is 45 percent or less and there is an expectation that ventricular pacing will occur more than 25 percent of the time, a biventricular, His bundle, or left bundle pacing system (also called cardiac resynchronization therapy) should be considered instead of a standard right ventricular pacing system. (See "Atrial fibrillation: Atrioventricular node ablation", section on 'Cardiac resynchronization therapy'.) In addition, atrioventricular node ablation may be necessary for some patients with HF and AF who are referred for cardiac resynchronization therapy for treatment of HF. This is because intact atrioventricular conduction may "override" pace and thus reduce efficacy of the cardiac resynchronization therapy device. In particular, atrioventricular node ablation may be beneficial for patients who are not pacing at least 90 percent with cardiac resynchronization therapy [54]. (See "Cardiac resynchronization therapy in atrial fibrillation", section on 'Role of atrioventricular node ablation in patients with heart failure and atrial fibrillation'.) Left bundle or His bundle pacing have also become options, although randomized controlled clinical trials have yet to definitively demonstrate an advantage of this approach versus a cardiac resynchronization therapy approach. Heart failure with preserved ejection fraction Our long-term management approach to patients with AF and HFpEF is similar to that of patients with AF and HFrEF. The main differences are with respect to the choice of specific rhythm and rate control medications. Rhythm control Rhythm control is the preferred long-term strategy for most patients. (See 'Evidence for cardiovascular benefit' above.) Antiarrhythmic therapy and CA approaches are similar in HFpEF and HFrEF. Some medication such as dofetilide and sotalol tend to have fewer complications in patients with preserved LVEF (See 'Rhythm control' above.) The efficacy and safety of CA have been evaluated in patients with diastolic HF. A meta-analysis of 12 retrospective cohort studies confirmed the safety of CA for patients with HFpEF; over a one- to three-year follow up, complications occurred in <1 percent of patients [55]. Fifty-eight percent of patients maintained sinus rhythm without using an antiarrhythmic medication. Admission for HF and all-cause mortality each occurred in 6 percent of patients. Rate control in heart failure with preserved ejection fraction For patients with AF and HFpEF, we attempt to maintain a resting heart rate of 80 bpm or less ("strict rate control"). Whereas some data indicate that faster rates may be acceptable (lenient rate control), this is not generally recommended. Exceptions include: https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 18/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate A patient with paroxysmal AF with frequent episodes of fast AF and slow, symptomatic rates when in sinus rhythm. A patient with permanent AF who is asymptomatic with resting rates as fast as 110 beats per minute. However, this group of patients has not been well studied. We typically start with a beta blocker. (See 'Medications' above.) In patients with HFpEF (but not HFrEF), we use a nondihydropyridine calcium channel blocker if a beta blocker is not tolerated. We use digoxin cautiously in HFpEF, but it can be helpful in combination with a beta blocker to control ventricular response rate, especially in older patients. Other strategies are similar to rate control strategies in patients with AF and HFrEF. (See 'Rate control in heart failure with reduced ejection fraction' above.) PROGNOSIS Observational studies present conflicting data as to whether AF is an independent predictor of mortality in patients with HF [6-8,56-59]. Most were performed several years ago and may not be as generalizable to current patients. However, two more recent studies suggest AF may be associated with increased mortality among patients with HF. A meta-analysis of 16 studies with nearly 54,000 patients showed that among patients with HF, AF was associated with modestly increased mortality (odds ratio of 1.4 among seven randomized trials of HF therapy; 1.15 among nine observational studies) [60]. A registry study of nearly one million patients with HF suggested that new-onset AF was associated with worse mortality than long-standing AF, over a follow-up period of over 13 years [61]. In this analysis, patients who developed new-onset AF had greater mortality than patients with long-standing AF (59 versus 49 percent). Among persons with HF and AF compared with persons with neither condition, the adjusted odds of death was 8.76 (95% CI 8.31 9.23). A post-hoc analysis of a beta blocker trial of nearly 2400 participants with HF showed that new- onset AF (in 190 patients) predicted worse HF-related outcomes [62]. In this study, participants with new-onset AF were at a higher risk of HF mortality (28 versus 23 percent, HR 2.0, 95% CI 1.50-2.67) and had more HF hospitalization days (average of 15 versus 7 days per patient) than those who did not develop AF. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 19/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Heart failure in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Heart failure and atrial fibrillation (The Basics)") SUMMARY AND RECOMMENDATIONS Background and epidemiology Comorbid atrial fibrillation (AF) and heart failure (HF) is common. The prevalence of AF in patients with HF increases from 4 to 50 percent as HF functional class declines. (See 'Introduction' above and 'Epidemiology' above.) AF can impair myocardial atrial and ventricular function, which can both cause and worsen HF. (See 'mechanisms of cardiac dysfunction' above.) Acute management In all patients, we anticoagulate (irrespective of ejection fraction [EF] or whether a long-term rate or rhythm control management strategy is employed), treat acute HF decompensation with diuretics and vasodilators, and correct potential reversible causes of AF and HF. (See 'Acute decompensation' above.) In patients with AF and acute HF, we target rate control to <120 beats per minute; digoxin, amiodarone, and diltiazem are appropriate agents in this setting. (See 'Acute rate control' above.) https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 20/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Cardioversion is rarely employed in the setting of AF with acute HF decompensation. (See 'Role of cardioversion' above.) Long-term management For most patients with AF and compensated HF, we suggest rhythm rather than rate control as an initial treatment strategy (Grade 2B). (See 'Long-term management' above.) A rate control strategy may be preferred in patients with long-standing AF or severe left atrial enlargement, as cardioversion is less likely to be successful or durable in these patients. A rate control strategy may also be reasonable for those unwilling to undergo the burdens of a rhythm control strategy, particularly if they tolerate AF well. (See 'Preference for rhythm over rate control' above and 'Rhythm control' above.) We employ a stepwise approach, including the following: Long-term anticoagulation Patients require anticoagulation prior to, during, and after electrical or pharmacologic cardioversion and catheter ablation (CA). (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Cardioversion After acute stabilization, for nearly all patients with AF and HF, we suggest electrical cardioversion as initial treatment (Grade 2C). This can be done without an antiarrhythmic medication if this is the first episode of AF, AF is well tolerated, HF is not difficult to manage, and there is no hemodynamically significant mitral regurgitation or left atrial enlargement. (See 'Electrical cardioversion' above.) Antiarrhythmics For patients who return to persistent AF after electrical cardioversion or fail cardioversion, we suggest dofetilide (Grade 2C). Contraindications to dofetilide include QT prolongation, potassium fluctuations, and renal dysfunction. Amiodarone is a reasonable alternative for older individuals and sotalol for patients with mild renal dysfunction. (See 'Rhythm control' above.) Catheter ablation For patients with symptomatic AF who have HF without acute decompensation, and failure of antiarrhythmic drug therapy, we suggest CA of AF (Grade 2B). This recommendation assumes that the patient is a reasonable candidate. (See 'Catheter ablation' above.) Rate control If a rate control strategy is chosen in patients with HF with reduced EF (HFrEF), we recommend beta blockers rather than calcium channel blockers or digoxin as initial therapy (Grade 1B). (See 'Rate control in heart failure with reduced ejection fraction' above.) https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 21/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate We also suggest beta blocker therapy for rate control in patients with HF with preserved EF (HFpEF) (Grade 2C). Nondihydropyridine calcium channel blocker therapy is an alternative in patients with HFpEF who cannot tolerate or do not respond to beta blocker therapy. We use a heart rate goal of <85 beats per minute at rest and <110 beats per minute during moderate exercise (the strict approach). If this is not possible, the goal becomes <110 beats per minute at rest (the lenient approach). Lenient rate control goal is used more in patients with HFpEF. (See 'Rate control goal' above.) Atrioventricular node ablation with pacing For patients who fail a rate control strategy using medication and are either not candidates for or have failed a rhythm control strategy, atrioventricular node ablation with pacing is an effective therapeutic option. (See 'Atrioventricular node ablation with pacing' above and "Atrial fibrillation: Atrioventricular node ablation".) Prognosis AF is associated with an increased mortality and increased risk of HF progression. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff thank Dr. Alan Cheng for his contributions as an author to prior versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lip GY, Heinzel FR, Gaita F, et al. European Heart Rhythm Association/Heart Failure Association joint consensus document on arrhythmias in heart failure, endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society. Europace 2016; 18:12. 2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 3. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 22/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate 4. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 5. Gopinathannair R, Chen LY, Chung MK, et al. Managing Atrial Fibrillation in Patients With Heart Failure and Reduced Ejection Fraction: A Scientific Statement From the American Heart Association. Circ Arrhythm Electrophysiol 2021; 14:HAE0000000000000078. 6. Carson PE, Johnson GR, Dunkman WB, et al. The influence of atrial fibrillation on prognosis in mild to moderate heart failure. The V-HeFT Studies. The V-HeFT VA Cooperative Studies Group. Circulation 1993; 87:VI102. 7. Stevenson WG, Stevenson LW, Middlekauff HR, et al. Improving survival for patients with atrial fibrillation and advanced heart failure. J Am Coll Cardiol 1996; 28:1458. 8. Dries DL, Exner DV, Gersh BJ, et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1998; 32:695. 9. Joglar JA, Acusta AP, Shusterman NH, et al. Effect of carvedilol on survival and hemodynamics in patients with atrial fibrillation and left ventricular dysfunction: retrospective analysis of the US Carvedilol Heart Failure Trials Program. Am Heart J 2001; 142:498. 10. Mahoney P, Kimmel S, DeNofrio D, et al. Prognostic significance of atrial fibrillation in patients at a tertiary medical center referred for heart transplantation because of severe heart failure. Am J Cardiol 1999; 83:1544. 11. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003; 91:2D. 12. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325:303. 13. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 314:1547. 14. Doval HC, Nul DR, Grancelli HO, et al. Randomised trial of low-dose amiodarone in severe congestive heart failure. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Lancet 1994; 344:493. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 23/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate 15. Johnstone D, Limacher M, Rousseau M, et al. Clinical characteristics of patients in studies of left ventricular dysfunction (SOLVD). Am J Cardiol 1992; 70:894. 16. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999; 100:2312. 17. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995; 333:77. 18. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316:1429. 19. Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992; 340:1173. 20. Nicoli CD, O'Neal WT, Levitan EB, et al. Atrial fibrillation and risk of incident heart failure with reduced versus preserved ejection fraction. Heart 2022; 108:353. 21. Cha YM, Redfield MM, Shen WK, Gersh BJ. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation 2004; 109:2839. 22. Santhanakrishnan R, Wang N, Larson MG, et al. Atrial Fibrillation Begets Heart Failure and Vice Versa: Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction. Circulation 2016; 133:484. 23. Pozzoli M, Cioffi G, Traversi E, et al. Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm. J Am Coll Cardiol 1998; 32:197. 24. Grogan M, Smith HC, Gersh BJ, Wood DL. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol 1992; 69:1570. 25. Kieny JR, Sacrez A, Facello A, et al. Increase in radionuclide left ventricular ejection fraction after cardioversion of chronic atrial fibrillation in idiopathic dilated cardiomyopathy. Eur Heart J 1992; 13:1290. 26. Redfield MM, Kay GN, Jenkins LS, et al. Tachycardia-related cardiomyopathy: a common cause of ventricular dysfunction in patients with atrial fibrillation referred for atrioventricular ablation. Mayo Clin Proc 2000; 75:790. 27. Sobue Y, Watanabe E, Lip GYH, et al. Thromboembolisms in atrial fibrillation and heart failure patients with a preserved ejection fraction (HFpEF) compared to those with a reduced https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 24/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate ejection fraction (HFrEF). Heart Vessels 2018; 33:403. 28. Li A, Li MK, Crowther M, Vazquez SR. Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review. Thromb Res 2020; 194:240. 29. Mar PL, Gopinathannair R, Gengler BE, et al. Drug Interactions Affecting Oral Anticoagulant Use. Circ Arrhythm Electrophysiol 2022; 15:e007956. 30. Chang SH, Chou IJ, Yeh YH, et al. Association Between Use of Non-Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation. JAMA 2017; 318:1250. 31. Hill K, Sucha E, Rhodes E, et al. Amiodarone, Verapamil, or Diltiazem Use With Direct Oral Anticoagulants and the Risk of Hemorrhage in Older Adults. CJC Open 2022; 4:315. 32. Rillig A, Magnussen C, Ozga AK, et al. Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure. Circulation 2021; 144:845. 33. Parkash R, Wells GA, Rouleau J, et al. Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients With Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial. Circulation 2022; 145:1693. 34. Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol 2013; 61:1894. 35. Khan MN, Ja s P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359:1778. 36. Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol 2014; 7:31. 37. Prabhu S, Taylor AJ, Costello BT, et al. Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study. J Am Coll Cardiol 2017; 70:1949. 38. Joy PS, Gopinathannair R, Olshansky B. Effect of Ablation for Atrial Fibrillation on Heart Failure Readmission Rates. Am J Cardiol 2017; 120:1572. 39. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008; 358:2667. 40. Suman-Horduna I, Roy D, Frasure-Smith N, et al. Quality of life and functional capacity in patients with atrial fibrillation and congestive heart failure. J Am Coll Cardiol 2013; 61:455. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 25/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate 41. Torp-Pedersen C, M ller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999; 341:857. 42. Pedersen OD, Bagger H, Keller N, et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation 2001; 104:292. 43. Deedwania PC, Singh BN, Ellenbogen K, et al. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHF-STAT). The Department of Veterans Affairs CHF-STAT Investigators. Circulation 1998; 98:2574. 44. Weinfeld MS, Drazner MH, Stevenson WG, Stevenson LW. Early outcome of initiating amiodarone for atrial fibrillation in advanced heart failure. J Heart Lung Transplant 2000; 19:638. 45. Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996; 94:2535. 46. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 47. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089. 48. Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med 2018; 378:417. 49. Turagam MK, Garg J, Whang W, et al. Catheter Ablation of Atrial Fibrillation in Patients With Heart Failure: A Meta-analysis of Randomized Controlled Trials. Ann Intern Med 2019; 170:41. 50. Anselmino M, Matta M, D'Ascenzo F, et al. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2014; 7:1011. 51. Taniguchi T, Ohtani T, Mizote I, et al. Switching from carvedilol to bisoprolol ameliorates adverse effects in heart failure patients with dizziness or hypotension. J Cardiol 2013; 61:417. 52. Kotecha D, Flather MD, Altman DG, et al. Heart Rate and Rhythm and the Benefit of Beta- Blockers in Patients With Heart Failure. J Am Coll Cardiol 2017; 69:2885. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 26/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate 53. Rienstra M, Damman K, Mulder BA, et al. Beta-blockers and outcome in heart failure and atrial fibrillation: a meta-analysis. JACC Heart Fail 2013; 1:21. 54. Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace 2009; 11 Suppl 5:v82. 55. Androulakis E, Sohrabi C, Briasoulis A, et al. Catheter Ablation for Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta- Analysis. J Clin Med 2022; 11. 56. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003; 107:2920.

reduced versus preserved ejection fraction. Heart 2022; 108:353. 21. Cha YM, Redfield MM, Shen WK, Gersh BJ. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation 2004; 109:2839. 22. Santhanakrishnan R, Wang N, Larson MG, et al. Atrial Fibrillation Begets Heart Failure and Vice Versa: Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction. Circulation 2016; 133:484. 23. Pozzoli M, Cioffi G, Traversi E, et al. Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm. J Am Coll Cardiol 1998; 32:197. 24. Grogan M, Smith HC, Gersh BJ, Wood DL. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol 1992; 69:1570. 25. Kieny JR, Sacrez A, Facello A, et al. Increase in radionuclide left ventricular ejection fraction after cardioversion of chronic atrial fibrillation in idiopathic dilated cardiomyopathy. Eur Heart J 1992; 13:1290. 26. Redfield MM, Kay GN, Jenkins LS, et al. Tachycardia-related cardiomyopathy: a common cause of ventricular dysfunction in patients with atrial fibrillation referred for atrioventricular ablation. Mayo Clin Proc 2000; 75:790. 27. Sobue Y, Watanabe E, Lip GYH, et al. Thromboembolisms in atrial fibrillation and heart failure patients with a preserved ejection fraction (HFpEF) compared to those with a reduced https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 24/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate ejection fraction (HFrEF). Heart Vessels 2018; 33:403. 28. Li A, Li MK, Crowther M, Vazquez SR. Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review. Thromb Res 2020; 194:240. 29. Mar PL, Gopinathannair R, Gengler BE, et al. Drug Interactions Affecting Oral Anticoagulant Use. Circ Arrhythm Electrophysiol 2022; 15:e007956. 30. Chang SH, Chou IJ, Yeh YH, et al. Association Between Use of Non-Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation. JAMA 2017; 318:1250. 31. Hill K, Sucha E, Rhodes E, et al. Amiodarone, Verapamil, or Diltiazem Use With Direct Oral Anticoagulants and the Risk of Hemorrhage in Older Adults. CJC Open 2022; 4:315. 32. Rillig A, Magnussen C, Ozga AK, et al. Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure. Circulation 2021; 144:845. 33. Parkash R, Wells GA, Rouleau J, et al. Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients With Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial. Circulation 2022; 145:1693. 34. Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol 2013; 61:1894. 35. Khan MN, Ja s P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359:1778. 36. Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol 2014; 7:31. 37. Prabhu S, Taylor AJ, Costello BT, et al. Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study. J Am Coll Cardiol 2017; 70:1949. 38. Joy PS, Gopinathannair R, Olshansky B. Effect of Ablation for Atrial Fibrillation on Heart Failure Readmission Rates. Am J Cardiol 2017; 120:1572. 39. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008; 358:2667. 40. Suman-Horduna I, Roy D, Frasure-Smith N, et al. Quality of life and functional capacity in patients with atrial fibrillation and congestive heart failure. J Am Coll Cardiol 2013; 61:455. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 25/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate 41. Torp-Pedersen C, M ller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999; 341:857. 42. Pedersen OD, Bagger H, Keller N, et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation 2001; 104:292. 43. Deedwania PC, Singh BN, Ellenbogen K, et al. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHF-STAT). The Department of Veterans Affairs CHF-STAT Investigators. Circulation 1998; 98:2574. 44. Weinfeld MS, Drazner MH, Stevenson WG, Stevenson LW. Early outcome of initiating amiodarone for atrial fibrillation in advanced heart failure. J Heart Lung Transplant 2000; 19:638. 45. Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996; 94:2535. 46. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 47. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089. 48. Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med 2018; 378:417. 49. Turagam MK, Garg J, Whang W, et al. Catheter Ablation of Atrial Fibrillation in Patients With Heart Failure: A Meta-analysis of Randomized Controlled Trials. Ann Intern Med 2019; 170:41. 50. Anselmino M, Matta M, D'Ascenzo F, et al. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2014; 7:1011. 51. Taniguchi T, Ohtani T, Mizote I, et al. Switching from carvedilol to bisoprolol ameliorates adverse effects in heart failure patients with dizziness or hypotension. J Cardiol 2013; 61:417. 52. Kotecha D, Flather MD, Altman DG, et al. Heart Rate and Rhythm and the Benefit of Beta- Blockers in Patients With Heart Failure. J Am Coll Cardiol 2017; 69:2885. https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 26/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate 53. Rienstra M, Damman K, Mulder BA, et al. Beta-blockers and outcome in heart failure and atrial fibrillation: a meta-analysis. JACC Heart Fail 2013; 1:21. 54. Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace 2009; 11 Suppl 5:v82. 55. Androulakis E, Sohrabi C, Briasoulis A, et al. Catheter Ablation for Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta- Analysis. J Clin Med 2022; 11. 56. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003; 107:2920. 57. Crijns HJ, Tjeerdsma G, de Kam PJ, et al. Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure. Eur Heart J 2000; 21:1238. 58. Olsson LG, Swedberg K, Ducharme A, et al. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol 2006; 47:1997. 59. Wasywich CA, Whalley GA, Gamble GD, et al. Does rhythm matter? The prognostic importance of atrial fibrillation in heart failure. Heart Lung Circ 2006; 15:353. 60. Mamas MA, Caldwell JC, Chacko S, et al. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur J Heart Fail 2009; 11:676. 61. Ziff OJ, Carter PR, McGowan J, et al. The interplay between atrial fibrillation and heart failure on long-term mortality and length of stay: Insights from the, United Kingdom ACALM registry. Int J Cardiol 2018; 252:117. 62. Aleong RG, Sauer WH, Davis G, Bristow MR. New-onset atrial fibrillation predicts heart failure progression. Am J Med 2014; 127:963. Topic 977 Version 71.0 https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 27/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 28/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 29/30 7/6/23, 3:10 PM The management of atrial fibrillation in patients with heart failure - UpToDate Contributor Disclosures Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Wilson S Colucci, MD Grant/Research/Clinical Trial Support: Merck [Heart failure]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/the-management-of-atrial-fibrillation-in-patients-with-heart-failure/print 30/30

7/6/23, 3:09 PM Therapeutic use of ibutilide - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Therapeutic use of ibutilide : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 19, 2022. INTRODUCTION Ibutilide is a class III antiarrhythmic drug available only for intravenous use for the termination of atrial arrhythmias. An oral form is not available because of extensive first-pass metabolism [1]. The physiology and pharmacology of ibutilide use and the side effects that can occur will be reviewed here. The pharmacokinetics of ibutilide, drug interactions, and the various clinical settings in which ibutilide might be used are discussed in detail separately. MECHANISMS OF ACTION Cellular mechanisms Like other class III antiarrhythmic agents ( table 1), ibutilide prolongs repolarization in atrial and ventricular myocardium [1,2]. The class III drugs block IKr, the rapid component of the cardiac delayed rectifier potassium current. This results in prolonged repolarization, increased action potential duration, and lengthening of the refractory period [1]. Ibutilide increases the refractoriness of atrial and ventricular myocardium, the atrioventricular node, His-Purkinje system, and accessory pathway [3]. In addition, ibutilide activates a slow, delayed inward sodium current that occurs early during repolarization [1,4]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs" and 'Major side effects' below.) Effects on the ECG Ibutilide has two major effects on the electrocardiogram (ECG): it produces mild slowing of the sinus rate and, as with other class III antiarrhythmic drugs, https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 1/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate prolongation of the QT interval. There is no effect on the PR interval or QRS duration. The degree of QT prolongation associated with ibutilide is related to the dose, the rate of infusion, and the serum concentration [5]. Prolongation of the QT interval provides the substrate for torsades de pointes (TdP), a polymorphic ventricular tachycardia. The QT interval returns to baseline within two to four hours after stopping the infusion. (See 'Proarrhythmia' below and 'Discontinuing ibutilide infusion' below.) Mechanism of proarrhythmic effect Like other drugs that prolong the QT interval and cause torsades de pointes, ibutilide blocks IKr, the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization [6]. IKr results from a heteromeric complex formed by a tetrameric potassium channel encoded by the KCNH2 gene (formerly called HERG gene) in complex with an accessory subunit encoded by the MirP1 gene (KCNE2). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Pathophysiology'.) Ibutilide exhibits "reverse use dependence", which is defined as an inverse correlation between the heart rate and QT interval. As a result, the QT interval decreases as the heart rate increases and lengthens as the heart rate slows. This explains why drug-induced polymorphic ventricular tachycardia (VT) is more commonly seen with bradycardia. The effect of heart rate may be mediated by changes in the local extracellular potassium concentration [7]. Lower heart rates result in less potassium moving out of the cell during repolarization (before subsequent reuptake by the Na-K-ATPase pump), since there are fewer repolarizations. The associated reduction in extracellular potassium concentration enhances the degree of drug-induced inhibition of IKr, increasing the QT interval. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) PHARMACOKINETICS Ibutilide has a half-life of 2 to 12 hours. It is extensively metabolized by the liver to eight metabolites. Only one metabolite exhibits antiarrhythmic activity, but its level is only approximately 10 percent of the parent drug level. As a result, this metabolite plays no role in the efficacy of ibutilide. Although almost 90 percent of the drug or its metabolites are detected in the urine, only 7 percent is excreted as the native, active drug. CLINICAL USES https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 2/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate Ibutilide is approved for the acute termination of atrial fibrillation and atrial flutter of recent onset. Since there is no oral preparation of ibutilide, it has no role in the long-term prevention of these arrhythmias. Ibutilide is not approved for the treatment of ventricular arrhythmias, and its efficacy for these arrhythmias is unknown. Atrial fibrillation Intravenous ibutilide is useful and effective for the pharmacologic cardioversion of recent-onset atrial fibrillation [8]. As with other antiarrhythmic drugs, the efficacy of ibutilide is greatest when the atrial fibrillation is of short duration ( figure 1) [9]. While it is of clear benefit in atrial fibrillation that has been present for seven days or less, the evidence is less robust but also suggests efficacy for atrial fibrillation of more than seven days duration. Most patients studied had arrhythmia for less than 90 days [9-11]. Similar efficacy has not been demonstrated with arrhythmia duration exceeding 90 days [12]. (See "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) The indications for pharmacologic cardioversion of atrial fibrillation and the settings in which ibutilide might be used are discussed separately. (See "Atrial fibrillation: Cardioversion".) In addition to the general use of ibutilide for cardioversion of atrial fibrillation, it has also been used in specific settings: As pretreatment before electrical cardioversion. (See "Atrial fibrillation: Cardioversion", section on 'Preprocedural antiarrhythmic drugs'.) To convert atrial fibrillation to sinus rhythm in patients with Wolff-Parkinson-White syndrome. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Atrial fibrillation with preexcitation'.) To convert atrial fibrillation to sinus rhythm after cardiac surgery or cardiac transplantation [13,14]. (See "Atrial fibrillation and flutter after cardiac surgery".) Ibutilide also appears to be a safe and effective antiarrhythmic agent for cardioversion of recent- onset atrial fibrillation and flutter in elderly patients. In a study of 32 patients (mean age 76 years) with recent-onset atrial fibrillation (19 patients) or atrial flutter (13 patients), the overall rate of successful conversion was 59 percent with a mean conversion time was 33 minutes [15]. Ibutilide-induced lengthening of the QTc interval was 17 21 milliseconds. Atrial flutter Ibutilide is effective for the cardioversion of atrial flutter [9-11,16], including atrial flutter that occurs after cardiac surgery [13]. (See "Restoration of sinus rhythm in atrial flutter" and "Atrial fibrillation and flutter after cardiac surgery".) https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 3/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate Ibutilide in children and in patients with congenital heart disease The safety and efficacy of ibutilide for cardioversion of atrial flutter and atrial fibrillation in children and in patients with congenital heart disease was reviewed in a report of 19 patients, age 6 months to 34 years (median 16 years) [17]. Ibutilide successfully restored sinus rhythm in 71 percent of arrhythmia episodes, with success during the first administration in 12 of 19 (63 percent). Fourteen episodes in six patients required electrical cardioversion after ibutilide failed. There were no episodes of symptomatic bradycardia, and only one episode each of polymorphic and monomorphic ventricular tachycardia. With careful monitoring, ibutilide can be effective for children and young patients with congenital heart disease for cardioversion of atrial arrhythmias. Chemical cardioversion of atrial fibrillation or flutter with ibutilide and other antiarrhythmic drugs Similar to ibutilide, intravenous esmolol has a short half-life, which makes it appealing for use in the acute conversion of atrial fibrillation. A randomized, prospective study comparing the combination of intravenous esmolol plus ibutilide with ibutilide monotherapy for conversion of recent-onset atrial fibrillation with a rapid ventricular rate showed improvement in the rate of conversion to sinus rhythm in the combined ibutilide/esmolol group (67 percent with the combination versus 46 percent for ibutilide monotherapy) [18]. The slower the ventricular rate at the time of ibutilide administration, the greater was the probability of conversion to sinus rhythm. In addition, there was a marked reduction in the incidence of immediate atrial fibrillation recurrence in the group receiving both esmolol and ibutilide. The ibutilide/esmolol combination was also associated with a lower risk of torsade de pointes. Patients receiving amiodarone Combination therapy may be a useful cardioversion method for chronic atrial fibrillation or flutter for patients on amiodarone who are treated with ibutilide. The efficacy and safety of cardioversion with combination amiodarone and ibutilide was evaluated in patients on long-term oral amiodarone and referred for elective cardioversion of atrial fibrillation (81 percent) or atrial flutter (19 percent) [12]. Patients, who were in the arrhythmia for a mean of 196 before cardioversion and were taking amiodarone for a mean of 153 days, were administered 2 mg intravenous ibutilide. Within 30 minutes of infusion, ibutilide converted 54 percent with atrial flutter and 39 percent with atrial fibrillation. One episode of torsade de pointes occurred although QT-interval prolongation after ibutilide was noted. Thirty- five (90 percent) of 39 patients who did not convert with ibutilide underwent successful electrical cardioversion. Patients receiving propafenone In a trial using combination therapy, concurrent administration of propafenone plus ibutilide for pharmacological cardioversion of persistent atrial fibrillations was found safe and more effective than ibutilide alone [19]. Among 100 consecutive patients (66 men, mean age 65 years) with persistent atrial fibrillation (mean https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 4/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate duration 99 days) who were admitted for elective pharmacological cardioversion and were randomly assigned to either intravenous ibutilide (1 mg plus an additional 1 mg, if required) or oral propafenone (600 mg) plus intravenous ibutilide, successful cardioversion occurred in 41 percent with ibutilide alone, compared with 71 percent with propafenone plus ibutilide. A comparable increase in the QTc interval was observed in both groups, but one case of sustained torsade de pointes, requiring electrical cardioversion, was observed in the propafenone plus ibutilide group. Patients undergoing catheter ablation for atrial fibrillation In patients with persistent atrial fibrillation undergoing catheter ablation, ibutilide administration was not shown to increase procedural efficacy and long-term freedom from atrial arrythmias [20]. In patients with persistent atrial fibrillation who are undergoing a catheter-based ablation, incorporation of electroanatomic mapping allows for the detection and targeting of complex fractionated atrial electrograms (CFAEs). Since ibutilide reduces CFAEs, it was hypothesized that ibutilide administration prior to CFAE ablation would identify sites critical for persistent atrial fibrillation maintenance, allowing for improved procedural efficacy and long-term freedom from atrial arrhythmias. In the MAGIC-AF trial, 200 patients undergoing a first-ever persistent atrial fibrillation catheter ablation procedure were randomly assigned to 0.25 mg of intravenous ibutilide or saline placebo upon completion of pulmonary vein isolation. CFAE sites were then targeted with ablation. The study found that despite a reduction in CFAE area and greater atrial fibrillation termination during CFAE ablation, procedure efficacy was not statistically higher when CFAE ablation was guided by ibutilide administration versus placebo (56 versus 49 percent) [20]. (See "Atrial fibrillation: Catheter ablation" and "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists".) ADMINISTRATION Dosing The recommended dose of ibutilide varies with patient size: For patients weighing less than 60 kg, the dose is 0.01 mg/kg infused over 10 minutes. If the arrhythmia does not terminate within 10 minutes after the end of the infusion, a second bolus (same dose over 10 minutes) may be given. For patients weighing more than 60 kg, the dose is 1 mg over 10 minutes. Again, if the arrhythmia does not terminate within 10 minutes after the end of the infusion, a second bolus of 1 mg over 10 minutes may be given. Role of magnesium Intravenous magnesium sulfate enhances the ability of intravenous ibutilide to successfully convert atrial fibrillation or flutter, and it can attenuate the QT interval https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 5/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate prolongation associated with ibutilide therapy. Two cohort studies have shown that the concurrent administration of magnesium (doses of four to five grams administered intravenously) with ibutilide is associated with a greater chance of successful chemical conversion [21,22]. One of the two studies also reported a significantly lower rate of polymorphic ventricular tachycardia in patients who received the magnesium/ibutilide combination compared with patients who received only ibutilide [22]. MAJOR SIDE EFFECTS Side effects with the use of ibutilide are infrequent and typically transient. In one report, the only noncardiac side effects that occurred more frequently than with placebo were nausea (1.9 percent), headache (3.6 percent), and renal failure (0.3 percent) [9]. The most serious side effects are those involving the cardiovascular system. As a result, ibutilide should not be used in patients with severe structural cardiac disease, prolonged QT interval, or underlying sinus node disease. Additional information about potential drug interactions can be found using the Lexicomp drug interactions tool. Proarrhythmia Proarrhythmia, particularly nonsustained or sustained polymorphic (torsades de pointes) or monomorphic ventricular tachycardia (VT), is the most important toxic reaction. Because of the risk of ventricular tachycardia, particularly torsades de pointes, patients treated with ibutilide should be observed with continuous ECG monitoring for at least four hours after the infusion is finished and longer if needed until the QTc interval has returned to baseline. In several large series, polymorphic VT was seen in between four and eight percent of patients [10,11,16,23]. Sustained episodes requiring cardioversion were seen in approximately two percent of patients. In addition to polymorphic VT, nonsustained monomorphic VT occurred in three to four percent of patients [10,11]. The majority of episodes of sustained polymorphic VT occurred within ten minutes of the first dose (before the second dose would be given, if necessary). Torsades de pointes may be more common in women, occurring in six percent of women in one series (versus three percent of men) [23]. In addition, the risk was increased in patients with heart failure (eleven percent versus four percent in those without heart failure) [16]. Class IC antiarrhythmic drugs, which slow conduction by blocking sodium channels, also have the potential for proarrhythmia. However, since class IC drugs do not cause QT prolongation, it has also been suggested these drugs can be used safely with ibutilide. In two reports including a total of 175 patients with atrial fibrillation or atrial flutter, 150 were treated with propafenone and 25 were treated with flecainide [24,25]. All were treated with ibutilide up to 2 mg, which was https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 6/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate successful in restoring sinus rhythm in 62 percent. Only two patients developed nonsustained polymorphic VT with one developing sustained polymorphic VT (two percent of patients), a rate consistent with that seen in patients not taking a class IC antiarrhythmic drug. The potential for polymorphic VT is increased in patients who are being treated with another drug that prolongs the QT interval. However, the risk of proarrhythmia does not appear to be increased when ibutilide is given with amiodarone [12]. Other cardiac toxicities Ibutilide has been associated with a number of cardiac side effects other than proarrhythmia [26]: Hypotension 2 percent. Usually the degree of hypotension is mild and responds to fluid resuscitation. Sinus tachycardia or supraventricular tachycardia 2.7 percent. Sinus bradycardia 1.2 percent. Atrioventricular block 1.5 percent. Bundle branch block 1.9 percent. All of the above arrhythmias and conduction changes have been reported transient with minimal or no associated symptoms. Hemodynamic effects Ibutilide produces no clinically significant changes in left ventricular function or hemodynamics, including mean pulmonary artery pressure or pulmonary capillary wedge pressure, even in patients with reduced left ventricular ejection fraction [27]. Discontinuing ibutilide infusion In most patients who respond to ibutilide, arrhythmia termination is seen within 40 to 60 minutes after beginning the infusion (mean 27 to 33 minutes in two studies) [11,16]. The infusion should be stopped for the following reasons: The presenting arrhythmia is terminated. The patient develops ventricular tachycardia (sustained or nonsustained). The patient develops marked prolongation of the QT interval (to a corrected QT interval >500 msec with narrow QRS, or corrected QT >550 msec in patients with bundle branch block). SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 7/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Mechanism and pharmacokinetics Ibutilide, a class III antiarrhythmic drug, blocks IKr, the rapid component of the cardiac delayed rectifier potassium current. This results in prolonged repolarization, increased action potential duration, and lengthening of the refractory period. (See 'Mechanisms of action' above.) Effects on electrocardiogram Ibutilide has two major effects on the electrocardiogram (ECG): it produces mild slowing of the sinus rate and, as with other class III antiarrhythmic drugs, prolongation of the QT interval. There is no effect on the PR interval or QRS duration. Prolongation of the QT interval provides the substrate for torsades de pointes (TdP), a polymorphic ventricular tachycardia. (See 'Mechanisms of action' above.) Clinical uses Ibutilide is approved for the acute termination of atrial fibrillation and atrial flutter and is most useful and effective for the pharmacologic cardioversion of atrial fibrillation less than or equal to seven days duration. (See 'Atrial fibrillation' above and 'Atrial flutter' above and "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) Side effects Proarrhythmia, particularly nonsustained or sustained polymorphic ventricular tachycardia (VT) (torsades de pointes) or monomorphic VT, is the most important toxicity associated with ibutilide. Because of the risk of VT, particularly torsades de pointes, patients treated with ibutilide should be observed with continuous ECG monitoring for at least four hours after the infusion is finished, or until the QTc interval has returned to baseline. (See 'Proarrhythmia' above.) The ibutilide infusion should be stopped for the following reasons (see 'Discontinuing ibutilide infusion' above): The presenting arrhythmia is terminated. The patient develops VT (sustained or nonsustained). The patient develops marked prolongation of the QT interval. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 8/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate 1. Murray KT. Ibutilide. Circulation 1998; 97:493. 2. Cimini MG, Brunden MN, Gibson JK. Effects of ibutilide fumarate, a novel antiarrhythmic agent, and its enantiomers on isolated rabbit myocardium. Eur J Pharmacol 1992; 222:93. 3. Glatter KA, Dorostkar PC, Yang Y, et al. Electrophysiological effects of ibutilide in patients with accessory pathways. Circulation 2001; 104:1933. 4. Lee KS. Ibutilide, a new compound with potent class III antiarrhythmic activity, activates a slow inward Na+ current in guinea pig ventricular cells. J Pharmacol Exp Ther 1992; 262:99. 5. Buchanan LV, Kabell G, Brunden MN, Gibson JK. Comparative assessment of ibutilide, D- sotalol, clofilium, E-4031, and UK-68,798 in a rabbit model of proarrhythmia. J Cardiovasc Pharmacol 1993; 22:540. 6. Yang T, Snyders DJ, Roden DM. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects. Circulation 1995; 91:1799. 7. Yang T, Roden DM. Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 1996; 93:407. 8. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 9. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL- sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568. 10. Ellenbogen KA, Stambler BS, Wood MA, et al. Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study. J Am Coll Cardiol 1996; 28:130. 11. Abi-Mansour P, Carberry PA, McCowan RJ, et al. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Study Investigators. Am Heart J 1998; 136:632. 12. Glatter K, Yang Y, Chatterjee K, et al. Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients receiving amiodarone therapy. Circulation 2001; 103:253. 13. VanderLugt JT, Mattioni T, Denker S, et al. Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery. Circulation 1999; 100:369. 14. Tallaj JA, Franco V, Rayburn BK, et al. Safety and efficacy of ibutilide in heart transplant recipients. J Heart Lung Transplant 2009; 28:505. https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 9/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate 15. Gowda RM, Khan IA, Punukollu G, et al. Use of ibutilide for cardioversion of recent-onset atrial fibrillation and flutter in elderly. Am J Ther 2004; 11:95. 16. Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation 1996; 94:1613. 17. Hoyer AW, Balaji S. The safety and efficacy of ibutilide in children and in patients with congenital heart disease. Pacing Clin Electrophysiol 2007; 30:1003. 18. Fragakis N, Bikias A, Delithanasis I, et al. Acute beta-adrenoceptor blockade improves efficacy of ibutilide in conversion of atrial fibrillation with a rapid ventricular rate. Europace 2009; 11:70. 19. Korantzopoulos P, Kolettis TM, Papathanasiou A, et al. Propafenone added to ibutilide increases conversion rates of persistent atrial fibrillation. Heart 2006; 92:631. 20. Singh SM, d'Avila A, Kim YH, et al. The modified stepwise ablation guided by low-dose ibutilide in chronic atrial fibrillation trial (The MAGIC-AF Study). Eur Heart J 2016; 37:1614. 21. Tercius AJ, Kluger J, Coleman CI, White CM. Intravenous magnesium sulfate enhances the ability of intravenous ibutilide to successfully convert atrial fibrillation or flutter. Pacing Clin Electrophysiol 2007; 30:1331. 22. Patsilinakos S, Christou A, Kafkas N, et al. Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. Am J Cardiol 2010; 106:673. 23. Gowda RM, Khan IA, Punukollu G, et al. Female preponderance in ibutilide-induced torsade de pointes. Int J Cardiol 2004; 95:219. 24. Chiladakis JA, Kalogeropoulos A, Patsouras N, Manolis AS. Ibutilide added to propafenone for the conversion of atrial fibrillation and atrial flutter. J Am Coll Cardiol 2004; 44:859. 25. Hongo RH, Themistoclakis S, Raviele A, et al. Use of ibutilide in cardioversion of patients with atrial fibrillation or atrial flutter treated with class IC agents. J Am Coll Cardiol 2004; 44:864. 26. http://www.bionichepharmausa.com/pdf/Ibutilide_Fumarate_PI.pdf. 27. Stambler BS, Beckman KJ, Kadish AH, et al. Acute hemodynamic effects of intravenous ibutilide in patients with or without reduced left ventricular function. Am J Cardiol 1997; 80:458. Topic 924 Version 31.0 https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 10/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 11/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 12/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate Reversion of AF with antiarrhythmic drugs is related to arrhythmia duration In a study comparing two doses of intravenous ibutilide with intravenous sotalol for acute reversion of atrial fibrillation, the rate of successful reversion was inversely related to the duration of the arrhythmia prior to therapy. Data from: Vos MA, Golitsyn SR, Stangl K, et al for the Ibutilide/Sotalol Comparator Study Group, Heart 1998; 79:568. Graphic 62459 Version 2.0 https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 13/14 7/6/23, 3:10 PM Therapeutic use of ibutilide - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 14/14

7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment of arrhythmias associated with the Wolff- Parkinson-White syndrome : Luigi Di Biase, MD, PhD, FHRS, FACC, Edward P Walsh, MD : Samuel L vy, MD, Bradley P Knight, MD, FACC : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 30, 2023. INTRODUCTION Conduction from the atria to the ventricles normally occurs via the atrioventricular node (AV)- His-Purkinje system. Patients with a preexcitation syndrome have an additional pathway, known as an accessory pathway, which directly connects the atria and ventricles, bypassing the AV node. Normal conduction through the AV node is slower than conduction over the accessory pathway. Thus, when there is conduction over an accessory pathway, the ventricles are activated earlier than if the impulse had traveled through the AV node. This early activation, referred to as preexcitation, is responsible for the classic electrocardiographic (ECG) findings of a shortened PR interval and, in most patients, a delta wave ( waveform 1). Symptoms, ranging from mild palpitations to syncope and, rarely, even sudden cardiac death, are the result of tachycardia, usually due to a macroreentrant circuit involving the AV node, the ventricles, the accessory pathway, and the atria. This classic supraventricular tachycardia associated with WPW syndrome is called AV reentrant or reciprocating tachycardia (AVRT). However, preexcited atrial fibrillation (AF) or atrial flutter with a rapid ventricular response may also result in symptoms. Fortunately, the incidence of sudden death in patients with the WPW syndrome is quite low, ranging from 0 to 0.39 percent annually in several large case series, with the lowest risk seen in asymptomatic patients. Patients with the WPW syndrome are usually treated because of symptomatic arrhythmias. Treatment may sometimes be extended to asymptomatic patients with a WPW pattern if certain https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 1/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate "high-risk" features are present. However, most asymptomatic patients with the WPW electrocardiographic pattern are not treated. Treatment options for persons with arrhythmias and the WPW syndrome include nonpharmacologic therapies (ie, catheter ablation of the accessory pathway) as well as pharmacologic therapy (to slow ventricular heart rates or to prevent arrhythmias). The choice of the optimal therapy depends on the acuity of the arrhythmia(s) and the risk of sudden cardiac death, with pharmacologic agents being the treatment of choice for most acute arrhythmias, while catheter ablation is nearly always preferred for the long-term prevention of recurrent arrhythmias involving the accessory pathway. This topic will review the available therapeutic options for the treatment of arrhythmias in the WPW syndrome. The clinical manifestations, approach to diagnosis, and the types of arrhythmias which can occur in persons with an accessory pathway and the WPW pattern are discussed separately. (See "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis" and "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) ACUTE TREATMENT OF SYMPTOMATIC ARRHYTHMIAS While the preferred long-term treatment approach for patients with an accessory pathway, preexcitation, and symptomatic arrhythmias is catheter-based radiofrequency ablation, patients who present with an acute arrhythmia often require initial pharmacologic therapy for ventricular rate control or restoration of sinus rhythm. However, because of the electrophysiologic differences between AV nodal tissue and tissue comprising an accessory pathway, standard therapy for heart rate control may actually worsen symptoms and lead to clinical deterioration in patients with a tachycardia involving an accessory pathway. Knowledge of the presence of an accessory pathway is critical in choosing the correct initial pharmacologic therapy. (See 'Treatment to prevent recurrent arrhythmias' below and "Overview of the acute management of tachyarrhythmias".) Initial assessment of hemodynamic stability As with any patient presenting with a symptomatic tachyarrhythmia, patients with a tachycardia suspected to involve an accessory pathway should undergo an initial assessment of hemodynamic status. Patients who are hemodynamically stable can be evaluated and treated according to the type of suspected arrhythmia. However, patients with hemodynamic instability or compromise related to an ongoing tachycardia should undergo urgent electrical cardioversion [1,2]. The technique for urgent https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 2/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate electrical cardioversion is discussed elsewhere. (See "Cardioversion for specific arrhythmias".) Orthodromic AVRT In patients with orthodromic atrioventricular reciprocating tachycardia (AVRT), antegrade conduction occurs via the AV node with retrograde conduction via an accessory pathway. In such patients, antegrade conduction across the AV node is typically the "weak link" of the reentrant circuit. Thus, the approach to patients with orthodromic AVRT is similar to patients with other types of paroxysmal supraventricular tachycardia, where relatively specific therapies that lengthen AV nodal refractoriness and depress its conduction can block the impulse within the AV node and terminate and prevent the tachycardia. (See "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway", section on 'Narrow complex AVRT' and "Overview of the acute management of tachyarrhythmias", section on 'Regular narrow QRS complex tachyarrhythmias'.) We employ a step-wise approach to termination of orthodromic AVRT ( table 1). We recommend initial treatment of acute symptomatic orthodromic AVRT with one or more vagal maneuvers (such as the Valsalva maneuver and carotid sinus massage) [1,2]. These may be sufficient to cause AV node block and tachycardia termination in many patients [3]. (See "Vagal maneuvers".) If vagal maneuvers are ineffective, pharmacologic therapy with an AV nodal blocking agent (ie, adenosine, verapamil, beta blockers) should be instituted: We suggest intravenous adenosine rather than intravenous verapamil as the initial choice based on its efficacy and short half-life. Intravenous adenosine is effective for acute termination of orthodromic AVRT in 80 to 90 percent of patients [4-6]. Its ultrashort duration of action makes it a preferred agent before resorting to emergent DC cardioversion in the patient whose hemodynamic state is more tenuous. The protocol for intravenous adenosine administration is described in the algorithm ( algorithm 1). Prior to adenosine administration, the patient should be advised of the possibility of feeling lightheaded, dizzy, or near syncopal during the injection. On rare occasions, adenosine has been reported to transiently increase atrial vulnerability to AF, a potentially serious proarrhythmic effect, and cause atrial ectopy that can reinitiate orthodromic AVRT after acute tachycardia termination [4,7-9]. If adenosine is ineffective, we proceed with intravenous verapamil as the second line agent. Intravenous verapamil, given as 5 mg boluses in a full-grown patient (0.1 mg/kg in children to a maximum dose of 5 mg; contraindicated in children less than 12 months of age) every https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 3/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate two to three minutes (up to a cumulative initial dose of up to 15 mg), is as effective as adenosine for acutely terminating orthodromic AVRT, provided that the patient is not profoundly hypotensive or suffering from heart failure associated with severely depressed ventricular systolic function rather than the rapid heart rate ( table 1) [10,11]. (See "Calcium channel blockers in the treatment of cardiac arrhythmias".) If vagal maneuvers, adenosine, and verapamil are all ineffective in terminating orthodromic AVRT, second line therapy choices include intravenous procainamide and beta blockers approved for intravenous administration (propranolol, metoprolol, and esmolol) ( table 1) [12-14]. Procainamide (20 to 50 mg/minute given intravenously while monitoring the blood pressure closely every 5 to 10 minutes until the arrhythmia terminates, hypotension ensues, the QRS is prolonged by more than 50 percent, or a total of 17 mg/kg [1.2 g for a 70 kg patient] has been given) slows conduction and prolongs refractoriness in atrial and ventricular myocardium, accessory pathways, and the His-Purkinje system, while having no effect or causing slight shortening of AV nodal refractory period [15,16]. For young children, the dose for procainamide is a bolus given over 15 to 30 minutes (7 to 10 mg/kg bolus for infants <12 months of age compared with 10 to 15 mg/kg bolus for children older than 12 months), followed by an infusion of 20 to 50 micrograms/kg/minute. Procainamide is the preferred drug if the orthodromic AVRT presents as a wide QRS complex tachycardia due to functional or preexisting chronic bundle branch block or if the diagnosis of orthodromic AVRT is in doubt. (See "Wide QRS complex tachycardias: Approach to management".) Metoprolol 2.5 to 5 mg IV bolus over two to five minutes; if no response, an additional 2.5 to 5 mg IV bolus may be administered every 10 minutes to a total dose of 15 mg. Permanent junctional reciprocating tachycardia Permanent junctional reciprocating tachycardia (PJRT) is a persistent tachycardia (with a long RP interval on the surface electrocardiogram) that most often occurs in early childhood and is usually caused by a rare type of orthodromic AVRT involving a slowly conducting concealed accessory pathway, which is usually posteroseptal in location. As implied by the name, PJRT is incessant. (See "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway", section on 'Permanent junctional reciprocating tachycardia'.) Ablation of the accessory pathway is the preferred treatment for PJRT caused by a slowly conducting accessory pathway since this arrhythmia is often refractory to medical therapy. In a cohort of 194 patients (median age at diagnosis 3.2 months, 57 percent less than one year of age) from 11 institutions treated for PJRT between 2000 and 2010, initial medical management https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 4/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate (attempted in 76 percent of patients) led to complete control of the arrhythmia in only 23 percent of patients [17]. An additional 47 percent of patients had clinical improvement with slower and/or less sustained tachycardia, but perfect pharmacologic control is less common. However, in patients presenting with acute symptomatic PJRT, the choice of initial medical therapy is similar to conventional orthodromic AVRT [18]. Adenosine and verapamil can be tried but usually only interrupt PJRT for a few beats. Intravenous procainamide will occasionally result in a longer-lasting interruption of PJRT, but it rarely results in perfect control. As a temporizing measure prior to ablation, effective medical control of PJRT can often be achieved with oral flecainide. (See 'Orthodromic AVRT' above and 'Catheter ablation' below.) Antidromic AVRT In patients with antidromic atrioventricular reciprocating tachycardia (AVRT), antegrade conduction occurs via the accessory pathway with retrograde conduction usually via the AV node (or sometimes via a second accessory pathway if multiple pathways are present). Even though retrograde AV node conduction may be a "weak link" during antidromic AVRT, in the acute setting it is difficult to exclude the possibility of a second accessory pathway as the retrograde limb without formal electrophysiologic testing, and treatment must be done cautiously. Assuming the tachycardia is strictly regular and monomorphic, a trial of a short- acting AV node-specific blocking drug such as adenosine ( algorithm 1) can still be attempted, but failure to convert the tachycardia should make one suspicious of a second accessory pathway participating in the circuit, at which point an alternate agent such as procainamide should be considered. Practically speaking, verification of an antidromic AVRT is difficult outside the electrophysiology laboratory, so the intravenous drug of choice for acute treatment to terminate known or suspected antidromic AVRT is procainamide [2]. Procainamide is typically infused intravenously at 20 to 50 mg/minute given while monitoring the blood pressure closely every 5 to 10 minutes until the arrhythmia terminates, hypotension ensues, the QRS is prolonged by more than 50 percent, or a total of 17 mg/kg (1.2 g for a 70 kg patient) has been given. Even if it does not result in tachycardia termination, intravenous procainamide will usually slow the tachycardia rate and improve the hemodynamic state ( table 1). If the diagnosis is not certain, the patient should be considered to have an undiagnosed wide QRS tachycardia; of particular concern is ventricular tachycardia, which can become hemodynamically unstable or even degenerate into ventricular fibrillation following administration of one of these drugs. If uncertainty ever exists about the exact tachycardia mechanism, a presumptive diagnosis of ventricular tachycardia should be made, and the patient https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 5/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate treated accordingly. (See "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway", section on 'Wide complex AVRT' and "Wide QRS complex tachycardias: Approach to the diagnosis" and "Wide QRS complex tachycardias: Approach to management".) Atrial fibrillation with preexcitation In patients with an accessory pathway capable of antegrade conduction who develop AF, conduction to the ventricle often occurs through a combination of the normal conduction pathway (via the AV node) and the accessory pathway. However, because most accessory pathways have a shorter refractory period than the AV node, the ventricular rate can be more rapid if AV conduction occurs preferentially via the accessory pathway. As such, AV nodal blocking drugs (adenosine, verapamil, beta blockers, and digoxin) should be avoided in patients with preexcited AF since blocking the AV node will promote conduction down the accessory pathway and may sometimes directly enhance the rate of conduction over the accessory pathway. (See 'When to avoid AV nodal blockers' below.) The goals of acute drug therapy for preexcited AF are prompt control of the ventricular response and, ideally, termination of AF. If the patient is unstable because of a rapid ventricular response, electrical cardioversion should be performed. For more stable patients, trials of intravenous medications can be performed cautiously. Treatment of preexcited AF requires a parenteral drug with rapid onset of action that lengthens antegrade refractoriness and slows conduction in both the AV node/His-Purkinje system and the accessory pathway. The following is our approach to the acute treatment of patients with preexcited AF, which is consistent with published professional society guidelines [1,2,19]: For patients who are hemodynamically unstable, we recommend urgent electrical cardioversion [1,2,19]. (See "Cardioversion for specific arrhythmias", section on 'External cardioversion/defibrillation'.) For patients who are hemodynamically stable, we suggest initial medical therapy for rhythm control versus rate control. This is based on the greater ease of controlling the ventricular rate in sinus rhythm. While there is no clear first-line medication for rhythm control, options include procainamide and ibutilide [1,2]. Intravenous procainamide is effective for acute therapy of preexcited AF because of its effects on atrial and ventricular myocardium without any AV nodal blocking effect. Because of its effect on atrial myocardium, procainamide may terminate AF; however, if AF persists, the ventricular rate usually slows due to effects on refractoriness and conduction in the accessory pathway. The pediatric experience with ibutilide is very limited, so procainamide is usually the preferred intravenous drug option for preexcited AF in the younger population. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 6/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Procainamide is typically infused intravenously at 20 to 50 mg/minute given while monitoring the blood pressure closely every 5 to 10 minutes until the arrhythmia terminates, hypotension ensues, the QRS is prolonged by more than 50 percent, or a total of 17 mg/kg (1.2 g for a 70 kg patient) has been given. Even if it does not result in tachycardia termination, intravenous procainamide will usually slow the tachycardia rate and improve the hemodynamic state ( table 1). This is often followed by an infusion of 1 to 4 mg/minute. For young children, the dose for procainamide is a bolus given over 15 to 30 minutes (7 to 10 mg/kg bolus for infants <12 months of age compared with 10 to 15 mg/kg bolus for children older than 12 months), followed by an infusion of 20 to 50 micrograms/kg/minute. Ibutilide, a class III antiarrhythmic drug that prolongs the refractoriness of the AV node, His-Purkinje system, and accessory pathway, is useful for acute termination of AF and atrial flutter. In one series of 22 patients with WPW and AF during an electrophysiologic study, ibutilide prolonged the shortest preexcited RR interval and terminated the arrhythmia in 95 percent [20]. (See "Therapeutic use of ibutilide".) For all patients with preexcited AF, we recommend not using standard AV nodal blocking medications (ie, beta blockers, non-dihydropyridine calcium channel blockers [verapamil and diltiazem], digoxin, adenosine, and amiodarone). Blocking the AV node may result in increased conduction of atrial impulses to the ventricle by way of the accessory pathway, increasing the ventricular rate and potentially resulting in hemodynamic instability. (See 'When to avoid AV nodal blockers' below.) The class IC antiarrhythmic drugs flecainide and propafenone and the class III agent dofetilide are effective when used in this setting, but the parenteral formulations of these drugs are not approved for use in some countries, including the United States [21-24]. When to avoid AV nodal blockers AV node-specific antiarrhythmic drugs that are normally used to control the ventricular rate during AF are contraindicated ( table 1) for patients with preexcited AF: Verapamil is perhaps the most dangerous AV nodal blocker to administer to patients with preexcited AF [25-27]. Intravenous verapamil lengthens AV node refractoriness, decreases concealed conduction into the accessory pathway, and has no direct effect on the accessory pathway. Myocardial contractility and systemic vascular resistance are also reduced; these effects may cause a reflex increase in already elevated sympathetic tone that further shortens accessory pathway refractoriness. Precipitation of cardiac arrest by https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 7/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate degeneration of preexcited AF to ventricular fibrillation has been reported after intravenous verapamil administration [27]. Adenosine causes an effect similar to verapamil and also can precipitate ventricular fibrillation. Adenosine will not convert AF and has only a transient effect on the AV node. Its use is contraindicated in AF. Beta blockers, when used alone, do not increase accessory pathway refractoriness. Additionally, inhibition of AV node conduction may enhance the preexcited ventricular rate response by decreasing the degree of concealed retrograde conduction into the accessory pathway. An accessory pathway with a short intrinsic antegrade refractory period that was initially competing with the AV node could then become the dominant route for rapid, antegrade conduction. Amiodarone, which may slow conduction in an accessory pathway during chronic oral administration, is not known to slow accessory pathway conduction with acute IV administration [28,29]. Because amiodarone also has beta blocking properties, it may increase conduction via the accessory pathway, leading to a faster ventricular rate and the potential for ventricular fibrillation [19]. Amiodarone should generally not be used in patients with AF and accessory pathway. Digoxin is also contraindicated because of blockade of AV nodal conduction and its unpredictable effect on accessory pathway refractoriness [30]. The vagomimetic action of digoxin lengthens AV node refractoriness and reduces concealed retrograde conduction into the accessory pathway. TREATMENT TO PREVENT RECURRENT ARRHYTHMIAS Once patients with the Wolff-Parkinson-White syndrome have been stabilized following an acute episode of symptomatic tachyarrhythmia, patients should be evaluated for additional therapy aimed at preventing recurrent symptomatic arrhythmias. The preferred long-term treatment approach for nearly all patients with an accessory pathway, preexcitation, and a symptomatic arrhythmia is catheter ablation of the accessory pathway. However, for patients who are not candidates for ablation procedures, or for very select patients with rare, well-tolerated arrhythmias, antiarrhythmic therapy is an alternative. When antiarrhythmic drugs are used, the choice of agent is determined by the etiology of the arrhythmia and its electrophysiologic properties ( table 1). https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 8/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Catheter ablation For patients with an accessory pathway and symptomatic arrhythmias including orthodromic AVRT, antidromic AVRT, and preexcited AF or atrial flutter, we recommend catheter ablation rather than pharmacologic therapy [1]. Initial case-series demonstrated both the safety and efficacy of this approach, data which have been replicated in numerous studies [31-37]. The standard energy source used to ablate accessory pathways is radiofrequency current, although cryoenergy can be used as an alternative to radiofrequency energy to ablate accessory pathways that are in close proximity to the AV node or bundle of His [38]. (See "Overview of catheter ablation of cardiac arrhythmias".) Indications for ablation Patients with an accessory pathway are candidates for ablation in the following settings: Symptomatic tachyarrhythmias. Occupations in which the development of symptoms would put themselves or others at risk (eg, truck drivers or airline pilots, some athletes). Selected asymptomatic patients. (See 'Asymptomatic patients' below.) Symptomatic patients Symptom control is the most common indication for ablation. The 2015 ACC/AHA/HRS guidelines on the management of supraventricular arrhythmias recommended catheter ablation as a first-line therapy for patients who have had symptomatic AVRT or preexcited AF [1]. Asymptomatic patients The optimal approach is controversial in asymptomatic patients who are coincidentally found to have evidence of an accessory pathway on an ECG (ie, WPW pattern) [39-41]. The risk of sudden cardiac death (SCD) is low, and the risk of developing symptoms also appears to be low, although a wide range of incidences have been reported [42,43]. Among those with a WPW ECG pattern, the likelihood of developing symptoms varies with age. Children are at the highest risk, while those who remain asymptomatic over age 35 years are unlikely to develop symptoms [40]. In a prospective study of 550 asymptomatic patients with WPW ECG pattern who were followed for a median of 22 months, 13 patients (2.4 percent) developed ventricular fibrillation (VF) [44], most of whom (11 of 13) were children. Fortunately, all of the patients developed warning symptoms (usually presyncope or dizziness) and sought medical attention, and none died from the VF episode. The 2015 ACC/AHA/HRS guidelines state that observation of patients with WPW pattern alone is reasonable; however, the guidelines also state that catheter ablation is reasonable in asymptomatic patients [1]. Additionally, in a 2012 consensus statement on the management of asymptomatic young patients with the WPW pattern, ablation is recommended for patients felt https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 9/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate to be at higher risk of SCD based on the results of electrophysiologic testing [45]. (See "Wolff- Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis", section on 'Electrophysiology studies (EPS)'.) For most asymptomatic patients with preexcitation, particularly those over age 35 to 40 years, we suggest observation. However, in some asymptomatic patients, particularly children, who are felt to be at higher risk of an arrhythmia or SCD, we suggest risk stratification to identify individuals who may benefit from treatment ( algorithm 2). Localizing the accessory pathway The location of most accessory pathways can be estimated using the preexcitation pattern on the surface electrocardiogram. However, more precise localization of the accessory pathway during catheter-based mapping prior to catheter ablation utilizes several parameters [34]. To determine the atrial insertion site, the earliest site of retrograde atrial activation during orthodromic atrioventricular (AV) reciprocating tachycardia (AVRT) or ventricular pacing must be identified [46,47]. The assumption is that the local retrograde ventriculoatrial (VA) interval on the recording electrode will be shortest at the atrial insertion site. Compared with pacing at sites more remote from the accessory pathway, atrial pacing near the atrial insertion of the accessory pathway will create a greater degree of preexcitation with a shorter delay between the stimulus and the onset of the delta wave [48]. More precise localization of the ventricular insertion site is obtained by mapping along the AV groove in sinus rhythm to determine the site of earliest ventricular activation during preexcited beats. Local ventricular activation at the ventricular insertion site frequently precedes the onset of the delta wave on the surface ECG by 10 to 40 milliseconds ( waveform 2) [49,50]. If preexcitation is minimal in sinus rhythm, then atrial pacing can be performed to facilitate ventricular preexcitation by delaying AV nodal conduction. Efficacy The acute success rate with catheter-based ablation is approximately 85 to 95 percent but can approach 100 percent depending upon the location of the accessory pathway and the precision of pathway localization [34-37,44]. Success rates are lower (84 to 89 percent) for septal accessory pathways ( waveform 3 and waveform 4) [31,32,35,36,51-55]. Additionally, long-term success rates may be closer to 80 percent at five years post-ablation [56]. As examples of the efficacy of ablation: In a meta-analysis that included data from 64 studies, including 3495 patients undergoing radiofrequency catheter ablation (RFA) and 749 patients undergoing cryoablation of septal accessory pathways, acute procedural success was similar with either approach (89 versus https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 10/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate 86 percent with RFA versus cryoablation, respectively) [55]. Long-term success rates were higher with RFA (88 versus 76 percent with cryoablation), although cryoablation resulted in lower risk of persistent AV block (0 versus 3 percent with RFA). In a study of 519 patients from a single, large volume center who underwent EP study and radiofrequency ablation of accessory pathways in the late 1990s and were followed for an average of 22 months, accessory pathway conduction was abolished in 92 percent of patients, although one or two additional ablation procedures were required in 6 percent [54]. In a single-center, prospective observational study of 1168 patients who underwent RFA between May 2005 and May 2010 and were followed for a median of eight years, there were no episodes of ventricular fibrillation or sudden cardiac death [44]. In addition to location (ie, septal, lateral, etc) of the accessory pathway, the efficacy of catheter ablation can be affected by the presence of multiple accessory pathways and the depth of the accessory pathway within the myocardial (ie, epicardial versus endocardial). Multiple accessory pathways Multiple accessory pathways are found in as many as 13 percent of patients with WPW syndrome. Ablation of multiple accessory pathways is possible, but it requires a longer procedure time and is associated with a higher rate of recurrence [35,57,58]. As an example, in one study of 858 patients undergoing EP study and ablation for WPW syndrome in which multiple accessory pathways were identified in 8.5 percent of patients, procedural success was similar for single and multiple pathways, but the rate of recurrent arrhythmias over a mean follow-up of 43 months was significantly higher in persons with multiple accessory pathways (9.5 versus 2.5 percent) [58]. Epicardial accessory pathway location One reason that catheter ablation may fail is with an accessory pathway that is located closer to the epicardial surface. In such patients, the usual ablation procedure via transvenous catheters at the endocardial surface may not affect the critical tissue. Although not widely done, percutaneous epicardial ablation is possible via subxiphoid access of the pericardial space. The feasibility of this approach was demonstrated in a report of 48 patients with a variety of arrhythmias (10 with WPW syndrome) who had failed endocardial ablation [59]. Via subxiphoid instrumentation, 5 of the 10 patients had accessory pathways localized to the epicardial surface, and three were successfully ablated. Catheter ablation is also effective in the treatment of PJRT. From a cohort of 194 patients (median age at diagnosis 3.2 months, 57 percent less than one year of age) from 11 institutions treated for PJRT between 2000 and 2010, 140 patients underwent a total of 175 catheter ablation https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 11/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate procedures [17]. PJRT was successfully eliminated in 90 percent of patients, with minor complications reported in only 9 percent of patients, and no major complications. Arrhythmia recurrence Recurrent arrhythmias involving an accessory pathway, manifested by return of delta waves on the electrocardiogram or spontaneous paroxysmal supraventricular tachycardia, have been reported in 5 to 12 percent of patients [36,51,52,58,60]. The recurrence rate is higher with ablation of multiple pathways or right free wall or septal accessory pathways [53,58,60]. Approximately one-half of recurrences occur in the first 12 hours after the procedure [60]. Repeat ablation usually leads to permanent cure in patients who experience a recurrence [60]. To unmask any residual conduction via an accessory pathway prior to ending the ablation procedure, intravenous adenosine can be administered to transiently block the AV node. We primarily use adenosine when there is difficulty determining if the pathway has been successfully ablated. AF can recur following accessory pathway ablation; however, the ability for AF to be preexcited with conduction via an accessory pathway should be reduced or eliminated following ablation. In a series of 91 patients with documented paroxysmal AF prior to successful ablation of an accessory pathways, 18 (20 percent) had recurrent episodes of AF at two-year follow-up, although advancing age was the only independent predictor of recurrent AF on multivariate analysis [61]. Complications Data on complication rates come from both case series and a voluntary national registry. The reported incidence of nonfatal complications is on the order of 2 to 4 percent, which is similar to rates seen with ablation procedures for other arrhythmias [35,36,45]. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) The incidence and nature of complications in general clinical practice was illustrated in a report from a voluntary national registry in the United States of 3357 patients undergoing EP study and ablation for a variety of indications [36]. Among the 654 patients treated for WPW syndrome, major procedural complications occurred in 2 percent, most commonly cardiac tamponade. Specific complications may occur that are related to the anatomic site of ablation, including complete AV block resulting from ablation of a septal accessory pathway near the AV node, acute interatrial shunting related to transseptal catheterization for ablation of left-sided accessory pathways (although there are usually no adverse long-term sequelae), and inappropriate sinus tachycardia may be present following ablation of a posteroseptal accessory pathway, suggesting disruption of the parasympathetic and/or sympathetic innervation of the sinus and AV nodes [62-68]. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 12/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Surgical ablation Prior to the advent of catheter-mediated radiofrequency ablation, surgical ablation of accessory pathways was the standard technique in patients with drug-refractory WPW syndrome. The long-term success rate for WPW surgery is now almost 100 percent with an operative mortality rate of less than 1 percent [69-71]. Despite these excellent outcomes, catheter-mediated radiofrequency ablation has emerged as the preferred therapy for treatment of accessory pathways. However, surgical ablation remains an effective treatment strategy in patients suffering from highly symptomatic and hemodynamically unstable, drug-refractory arrhythmias in whom radiofrequency energy catheter ablation has failed, when performed at centers with a proven track record of success in performing the procedure [72]. Medical therapy for arrhythmia prevention For patients with an accessory pathway and symptomatic arrhythmias (including orthodromic AVRT, antidromic AVRT, and preexcited AF or atrial flutter) who are not candidates for or who refuse ablation of the accessory pathway, we suggest pharmacologic therapy aimed at preventing further arrhythmias and/or slowing the ventricular response rate [1]. Chronic therapy with verapamil or digoxin should be avoided in all patients with WPW syndrome. For recurrent orthodromic AVRT The efficacy of an antiarrhythmic drug in preventing orthodromic atrioventricular reciprocating tachycardia (AVRT) is related to its ability to alter the electrophysiologic properties of the circuit, rendering it incapable of sustaining reentry. Antiectopic activity to decrease the number of arrhythmia triggers (eg, premature atrial complex [PACs; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat] and ventricular premature beats) is another desirable effect. The class IC antiarrhythmic drugs flecainide and propafenone ( table 2) possess the most favorable benefit/risk ratio and are the drugs of choice for prevention of recurrent orthodromic AVRT [73-76]. An important exception is the presence of known coronary disease, a setting in which class IC drugs can increase mortality due to proarrhythmia [77]. Both flecainide and propafenone have been approved for prevention of paroxysmal supraventricular tachyarrhythmias, including orthodromic AVRT. Propafenone has a potential advantage since it also has mild beta blocking activity [75,76]. Beta blockers are still occasionally used as second-line therapy for chronic suppression of orthodromic AVRT in patients with "low-risk" WPW accessory pathways (eg, only intermittently manifest or know to have a long effective refractory period), but they are not advised for patients who have developed or may develop preexcited AF. Chronic therapy with verapamil or digoxin should be avoided in all patients with WPW syndrome. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 13/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate The class IA antiarrhythmic drugs ( table 2) lengthen antegrade and retrograde refractoriness and slow conduction in the accessory pathway. However, these drugs are less potent than the class IC drugs, they only minimally lengthen AV node refractoriness, and they have a substantial risk of intolerable noncardiac adverse effects. Amiodarone has multiple electrophysiologic effects that make it effective in suppressing orthodromic AVRT, including beta blocking activity, class III effects to prolong action potential repolarization, blockade of the fast sodium and slow calcium inward currents, and suppression of ectopic beats [78-80] (see "Amiodarone: Clinical uses"). These effects result in slowing of impulse conduction and lengthening of refractoriness in both the bypass tract and the AV node/His-Purkinje system. However, it has a number of common adverse effects, including pulmonary, thyroid, and hepatic toxicity, which is a concern for patients with WPW who are often young and may require many years of therapy. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) For recurrent antidromic AVRT Ablation of the accessory pathway is the preferred therapy

successfully ablated. Catheter ablation is also effective in the treatment of PJRT. From a cohort of 194 patients (median age at diagnosis 3.2 months, 57 percent less than one year of age) from 11 institutions treated for PJRT between 2000 and 2010, 140 patients underwent a total of 175 catheter ablation https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 11/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate procedures [17]. PJRT was successfully eliminated in 90 percent of patients, with minor complications reported in only 9 percent of patients, and no major complications. Arrhythmia recurrence Recurrent arrhythmias involving an accessory pathway, manifested by return of delta waves on the electrocardiogram or spontaneous paroxysmal supraventricular tachycardia, have been reported in 5 to 12 percent of patients [36,51,52,58,60]. The recurrence rate is higher with ablation of multiple pathways or right free wall or septal accessory pathways [53,58,60]. Approximately one-half of recurrences occur in the first 12 hours after the procedure [60]. Repeat ablation usually leads to permanent cure in patients who experience a recurrence [60]. To unmask any residual conduction via an accessory pathway prior to ending the ablation procedure, intravenous adenosine can be administered to transiently block the AV node. We primarily use adenosine when there is difficulty determining if the pathway has been successfully ablated. AF can recur following accessory pathway ablation; however, the ability for AF to be preexcited with conduction via an accessory pathway should be reduced or eliminated following ablation. In a series of 91 patients with documented paroxysmal AF prior to successful ablation of an accessory pathways, 18 (20 percent) had recurrent episodes of AF at two-year follow-up, although advancing age was the only independent predictor of recurrent AF on multivariate analysis [61]. Complications Data on complication rates come from both case series and a voluntary national registry. The reported incidence of nonfatal complications is on the order of 2 to 4 percent, which is similar to rates seen with ablation procedures for other arrhythmias [35,36,45]. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) The incidence and nature of complications in general clinical practice was illustrated in a report from a voluntary national registry in the United States of 3357 patients undergoing EP study and ablation for a variety of indications [36]. Among the 654 patients treated for WPW syndrome, major procedural complications occurred in 2 percent, most commonly cardiac tamponade. Specific complications may occur that are related to the anatomic site of ablation, including complete AV block resulting from ablation of a septal accessory pathway near the AV node, acute interatrial shunting related to transseptal catheterization for ablation of left-sided accessory pathways (although there are usually no adverse long-term sequelae), and inappropriate sinus tachycardia may be present following ablation of a posteroseptal accessory pathway, suggesting disruption of the parasympathetic and/or sympathetic innervation of the sinus and AV nodes [62-68]. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 12/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Surgical ablation Prior to the advent of catheter-mediated radiofrequency ablation, surgical ablation of accessory pathways was the standard technique in patients with drug-refractory WPW syndrome. The long-term success rate for WPW surgery is now almost 100 percent with an operative mortality rate of less than 1 percent [69-71]. Despite these excellent outcomes, catheter-mediated radiofrequency ablation has emerged as the preferred therapy for treatment of accessory pathways. However, surgical ablation remains an effective treatment strategy in patients suffering from highly symptomatic and hemodynamically unstable, drug-refractory arrhythmias in whom radiofrequency energy catheter ablation has failed, when performed at centers with a proven track record of success in performing the procedure [72]. Medical therapy for arrhythmia prevention For patients with an accessory pathway and symptomatic arrhythmias (including orthodromic AVRT, antidromic AVRT, and preexcited AF or atrial flutter) who are not candidates for or who refuse ablation of the accessory pathway, we suggest pharmacologic therapy aimed at preventing further arrhythmias and/or slowing the ventricular response rate [1]. Chronic therapy with verapamil or digoxin should be avoided in all patients with WPW syndrome. For recurrent orthodromic AVRT The efficacy of an antiarrhythmic drug in preventing orthodromic atrioventricular reciprocating tachycardia (AVRT) is related to its ability to alter the electrophysiologic properties of the circuit, rendering it incapable of sustaining reentry. Antiectopic activity to decrease the number of arrhythmia triggers (eg, premature atrial complex [PACs; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat] and ventricular premature beats) is another desirable effect. The class IC antiarrhythmic drugs flecainide and propafenone ( table 2) possess the most favorable benefit/risk ratio and are the drugs of choice for prevention of recurrent orthodromic AVRT [73-76]. An important exception is the presence of known coronary disease, a setting in which class IC drugs can increase mortality due to proarrhythmia [77]. Both flecainide and propafenone have been approved for prevention of paroxysmal supraventricular tachyarrhythmias, including orthodromic AVRT. Propafenone has a potential advantage since it also has mild beta blocking activity [75,76]. Beta blockers are still occasionally used as second-line therapy for chronic suppression of orthodromic AVRT in patients with "low-risk" WPW accessory pathways (eg, only intermittently manifest or know to have a long effective refractory period), but they are not advised for patients who have developed or may develop preexcited AF. Chronic therapy with verapamil or digoxin should be avoided in all patients with WPW syndrome. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 13/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate The class IA antiarrhythmic drugs ( table 2) lengthen antegrade and retrograde refractoriness and slow conduction in the accessory pathway. However, these drugs are less potent than the class IC drugs, they only minimally lengthen AV node refractoriness, and they have a substantial risk of intolerable noncardiac adverse effects. Amiodarone has multiple electrophysiologic effects that make it effective in suppressing orthodromic AVRT, including beta blocking activity, class III effects to prolong action potential repolarization, blockade of the fast sodium and slow calcium inward currents, and suppression of ectopic beats [78-80] (see "Amiodarone: Clinical uses"). These effects result in slowing of impulse conduction and lengthening of refractoriness in both the bypass tract and the AV node/His-Purkinje system. However, it has a number of common adverse effects, including pulmonary, thyroid, and hepatic toxicity, which is a concern for patients with WPW who are often young and may require many years of therapy. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) For recurrent antidromic AVRT Ablation of the accessory pathway is the preferred therapy for chronic prevention of antidromic AVRT. An important concern about long-term medical therapy of this arrhythmia is the potential for very rapid ventricular rates should AF develop, given that the accessory pathway is capable of antegrade preexcited conduction during AF. We suggest drug therapy for the prevention of recurrent antidromic AVRT only in patients who are not candidates for or who refuse ablation of the accessory pathway. (See 'Catheter ablation' above.) The selection of an effective antiarrhythmic drug should be based upon the effect of the drug on the electrophysiologic properties of the various parts of the reentrant circuit and on the ability to suppress the arrhythmia. The AV nodal blocking agents (beta blockers, calcium channel blockers, and digoxin) are contraindicated because of the possible occurrence of AF with accelerated conduction down the accessory pathway. (See 'When to avoid AV nodal blockers' above.) The class IC drugs flecainide and propafenone ( table 2) are the agents of choice in the absence of other contraindications such as underlying structural heart disease or myocardial ischemia ( table 1). These drugs may increase mortality in patients with known coronary disease due to proarrhythmia [77]. Class IA drugs and amiodarone are also effective but are less desirable because of side effects. For recurrent preexcited atrial fibrillation Ablation of the accessory pathway is the preferred therapy for the prevention of recurrent preexcited AF. While ablation of the accessory pathway will not directly impact the development of AF, it should prevent the possibility of very rapid ventricular rates due to antegrade conduction via the accessory pathway. We suggest https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 14/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate medical therapy for the prevention of recurrent preexcited AF only in patients who are not candidates for, or refuse, ablation of the accessory pathway. (See 'Catheter ablation' above.) The drug selected for prevention of intermittent AF in the WPW syndrome should possess antifibrillatory activity on the atrial myocardium, antiectopic activity to suppress both PACs and ventricular premature beats that can induce AF, and should prevent AVRT since the latter can subsequently degenerate into AF. The drug must also lengthen refractoriness in both the accessory pathway and the AV node and His-Purkinje system to provide adequate background protection against a rapid ventricular response should AF intermittently occur. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Atrial fibrillation in adults: Use of oral anticoagulants".) The class IC drugs flecainide and propafenone ( table 2) possess the best electrophysiologic profile for achieving these goals if no cardiac contraindications exist [81,82]. Class IA drugs are less potent and have more noncardiac adverse effects as previously noted. Amiodarone may be useful for the prevention of recurrent AF when class IC and IA drugs are ineffective and/or not tolerated and when ablation therapy is inappropriate or has failed [83,84]. Amiodarone should not be used in the acute management of AF. (See 'When to avoid AV nodal blockers' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Catheter ablation of arrhythmias" and "Society guideline links: Supraventricular arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 15/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Wolff-Parkinson-White syndrome (The Basics)") Beyond the Basics topic (see "Patient education: Wolff-Parkinson-White syndrome (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Patients requiring treatment Symptomatic patients Patients with the Wolff-Parkinson-White (WPW) syndrome with symptomatic arrhythmia are generally treated to manage the symptoms caused by the arrhythmia and reduce the risk of a life-threatening arrhythmia. (See 'Acute treatment of symptomatic arrhythmias' above and 'Treatment to prevent recurrent arrhythmias' above.) Asymptomatic patients For most asymptomatic patients with preexcitation, particularly those over age 35 to 40, we suggest observation rather than ablation or pharmacotherapy (Grade 2C). However, risk stratification is performed in certain asymptomatic patients who are felt to be at higher risk of an arrhythmia or sudden cardiac death (SCD; particularly children, individuals with congenital heart disease, and those with cardiomyopathy) to identify those who may benefit from treatment ( algorithm 2). (See 'Asymptomatic patients' above.) Treatment options These include nonpharmacologic therapies (ie, catheter ablation of the accessory pathway) as well as pharmacologic therapy (to slow ventricular heart rates or to prevent arrhythmias). The choice of the optimal therapy depends on the acuity of the arrhythmia(s) and the risk of sudden cardiac death. (See 'Acute treatment of symptomatic arrhythmias' above and 'Treatment to prevent recurrent arrhythmias' above.) Hemodynamic instability All patients with any arrhythmia (ie, orthodromic atrioventricular reciprocating tachycardia [AVRT], antidromic AVRT, atrial fibrillation/flutter) involving an accessory pathway should undergo prompt initial assessment of hemodynamic status. Patients who are felt to be hemodynamically unstable related to their arrhythmia should undergo urgent electrical cardioversion. (See 'Initial assessment of hemodynamic stability' above and "Cardioversion for specific arrhythmias".) https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 16/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Acute orthodromic AVRT For patients with acute symptomatic orthodromic AVRT who are hemodynamically stable, our approach is as follows ( table 1) (see 'Orthodromic AVRT' above): Initial therapy We recommend initial treatment with one or more vagal maneuvers rather than pharmacologic therapy (Grade 1B). Pharmacologic therapy If vagal maneuvers are ineffective, pharmacologic therapy with an AV nodal blocking agent (ie, adenosine, verapamil, beta blockers) should be instituted. We suggest intravenous adenosine rather than intravenous verapamil as the initial choice based on its efficacy and short half-life (Grade 2B). If adenosine is ineffective, we proceed with intravenous verapamil as the second line agent. If orthodromic AVRT persists, intravenous procainamide and beta blockers approved for intravenous administration (eg, propranolol, metoprolol, and esmolol) are additional therapeutic options. Acute antidromic AVRT For patients with acute symptomatic antidromic AVRT who are hemodynamically stable, we treat with intravenous procainamide in an effort to terminate the tachycardia or, if the tachycardia persists, slow the ventricular response. (See 'Antidromic AVRT' above.) Acute atrial fibrillation For patients with acute symptomatic preexcited atrial fibrillation (AF) who are hemodynamically stable, our approach is as follows (see 'Atrial fibrillation with preexcitation' above): Recommended therapy We suggest initial medical therapy for rhythm control versus rate control (Grade 2C). This is based on the greater ease of controlling the ventricular rate in sinus rhythm. While there is no clear first-line medication for rhythm control, options include procainamide and ibutilide. Drugs to avoid For all patients with preexcited AF, we recommend against using standard AV nodal blocking medications (ie, beta blockers, non-dihydropyridine calcium channel blockers [verapamil and diltiazem], digoxin, adenosine, and amiodarone) (Grade 1A). Blocking the AV node may result in increased conduction of atrial impulses to the ventricle by way of the accessory pathway, increasing the ventricular rate and potentially resulting in hemodynamic instability. (See 'When to avoid AV nodal blockers' above.) Prevention of recurrent arrhythmias https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 17/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate First-line therapy For patients with an accessory pathway and symptomatic arrhythmias including orthodromic AVRT, antidromic AVRT, and preexcited AF or atrial flutter, we recommend catheter ablation (Grade 1A). (See 'Catheter ablation' above.) Alternate therapy For patients with an accessory pathway and symptomatic arrhythmias (including orthodromic AVRT, antidromic AVRT, and preexcited AF or atrial flutter) who are not candidates for, or refuse, ablation of the accessory pathway, we suggest pharmacologic therapy (Grade 2C). (See 'Medical therapy for arrhythmia prevention' above.) For prevention of recurrent orthodromic AVRT in the absence of underlying structural heart disease, class IC antiarrhythmic drugs (eg, flecainide, propafenone) are the drugs of choice, although beta blockers, class IA antiarrhythmic drugs, and amiodarone may also be considered. For prevention of recurrent antidromic AVRT and preexcited AF in the absence of underlying structural heart disease, class IC antiarrhythmic drugs (eg, flecainide, propafenone) are also the drugs of choice. However, the AV nodal blocking agents (beta blockers, calcium channel blockers, and digoxin) are contraindicated in these patients, so class IA antiarrhythmic drugs and amiodarone should be considered in patients with concurrent structural heart disease. Failed catheter ablation For patients with preexcitation and symptomatic arrhythmias or AF or atrial flutter who have failed catheter ablation of the accessory pathway, we typically perform a repeat attempt at catheter ablation or consider proceeding with surgical ablation. (See 'Catheter ablation' above and 'Surgical ablation' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2016; 133:e506. 2. Brugada J, Katritsis DG, Arbelo E, et al. 2019 ESC Guidelines for the management of patients with supraventricular tachycardiaThe Task Force for the management of patients with https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 18/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate supraventricular tachycardia of the European Society of Cardiology (ESC). Eur Heart J 2020; 41:655. 3. Walker S, Cutting P. Impact of a modified Valsalva manoeuvre in the termination of paroxysmal supraventricular tachycardia. Emerg Med J 2010; 27:287. 4. Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Dis 1989; 32:73. 5. diMarco JP, Sellers TD, Lerman BB, et al. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. J Am Coll Cardiol 1985; 6:417. 6. DiMarco JP, Sellers TD, Berne RM, et al. Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 1983; 68:1254. 7. Exner DV, Muzyka T, Gillis AM. Proarrhythmia in patients with the Wolff-Parkinson-White syndrome after standard doses of intravenous adenosine. Ann Intern Med 1995; 122:351. 8. Dougherty AH, Gilman JK, Wiggins S, et al. Provocation of atrioventricular reentry tachycardia: a paradoxical effect of adenosine. Pacing Clin Electrophysiol 1993; 16:8. 9. DiMarco JP, Miles W, Akhtar M, et al. Adenosine for paroxysmal supraventricular tachycardia: dose ranging and comparison with verapamil. Assessment in placebo-controlled, multicenter trials. The Adenosine for PSVT Study Group. Ann Intern Med 1990; 113:104. 10. Rinkenberger RL, Prystowsky EN, Heger JJ, et al. Effects of intravenous and chronic oral verapamil administration in patients with supraventricular tachyarrhythmias. Circulation 1980; 62:996. 11. Sung RJ, Elser B, McAllister RG Jr. Intravenous verapamil for termination of re-entrant supraventricular tachycardias: intracardiac studies correlated with plasma verapamil concentrations. Ann Intern Med 1980; 93:682. 12. Jackman WM, Friday KJ, Fitzgerald DM, et al. Use of intracardiac recordings to determine the site of drug action in paroxysmal supraventricular tachycardia. Am J Cardiol 1988; 62:8L. 13. Kowey PR, Friehling TD, Marinchak RA. Electrophysiology of beta blockers in supraventricular arrhythmias. Am J Cardiol 1987; 60:32D. 14. Anderson S, Blanski L, Byrd RC, et al. Comparison of the efficacy and safety of esmolol, a short-acting beta blocker, with placebo in the treatment of supraventricular tachyarrhythmias. The Esmolol vs Placebo Multicenter Study Group. Am Heart J 1986; 111:42. 15. Mandel WJ, Laks MM, Obayashi K, et al. The Wolff-Parkinson-White syndrome: pharmacologic effects of procaine amide. Am Heart J 1975; 90:744. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 19/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate 16. Wellens HJ. The wide QRS tachycardia. Ann Intern Med 1986; 104:879. 17. Kang KT, Potts JE, Radbill AE, et al. Permanent junctional reciprocating tachycardia in children: a multicenter experience. Heart Rhythm 2014; 11:1426. 18. Dorostkar PC, Silka MJ, Morady F, Dick M 2nd. Clinical course of persistent junctional reciprocating tachycardia. J Am Coll Cardiol 1999; 33:366. 19. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 20. Glatter KA, Dorostkar PC, Yang Y, et al. Electrophysiological effects of ibutilide in patients with accessory pathways. Circulation 2001; 104:1933. 21. Bianconi L, Boccadamo R, Pappalardo A, et al. Effectiveness of intravenous propafenone for conversion of atrial fibrillation and flutter of recent onset. Am J Cardiol 1989; 64:335. 22. Suttorp MJ, Kingma JH, Jessurun ER, et al. The value of class IC antiarrhythmic drugs for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm. J Am Coll Cardiol 1990; 16:1722. 23. Suttorp MJ, Kingma JH, Lie-A-Huen L, Mast EG. Intravenous flecainide versus verapamil for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm. Am J Cardiol 1989; 63:693. 24. Krahn AD, Klein GJ, Yee R. A randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of intravenously administered dofetilide in patients with Wolff- Parkinson-White syndrome. Pacing Clin Electrophysiol 2001; 24:1258. 25. Garratt C, Antoniou A, Ward D, Camm AJ. Misuse of verapamil in pre-excited atrial fibrillation. Lancet 1989; 1:367. 26. Gulamhusein S, Ko P, Carruthers SG, Klein GJ. Acceleration of the ventricular response during atrial fibrillation in the Wolff-Parkinson-White syndrome after verapamil. Circulation 1982; 65:348. 27. McGovern B, Garan H, Ruskin JN. Precipitation of cardiac arrest by verapamil in patients with Wolff-Parkinson-White syndrome. Ann Intern Med 1986; 104:791. 28. Boriani G, Biffi M, Frabetti L, et al. Ventricular fibrillation after intravenous amiodarone in Wolff-Parkinson-White syndrome with atrial fibrillation. Am Heart J 1996; 131:1214. 29. Simonian SM, Lotfipour S, Wall C, Langdorf MI. Challenging the superiority of amiodarone for rate control in Wolff-Parkinson-White and atrial fibrillation. Intern Emerg Med 2010; 5:421. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 20/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate 30. Sellers TD Jr, Bashore TM, Gallagher JJ. Digitalis in the pre-excitation syndrome. Analysis during atrial fibrillation. Circulation 1977; 56:260. 31. Jackman WM, Wang XZ, Friday KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med 1991; 324:1605. 32. Kuck KH, Schl ter M, Geiger M, et al. Radiofrequency current catheter ablation of accessory atrioventricular pathways. Lancet 1991; 337:1557. 33. Calkins H, Sousa J, el-Atassi R, et al. Diagnosis and cure of the Wolff-Parkinson-White syndrome or paroxysmal supraventricular tachycardias during a single electrophysiologic test. N Engl J Med 1991; 324:1612. 34. Chen SA, Tai CT. Ablation of atrioventricular accessory pathways: current technique-state of the art. Pacing Clin Electrophysiol 2001; 24:1795. 35. Calkins H, Langberg J, Sousa J, et al. Radiofrequency catheter ablation of accessory atrioventricular connections in 250 patients. Abbreviated therapeutic approach to Wolff- Parkinson-White syndrome. Circulation 1992; 85:1337. 36. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 2000; 23:1020. 37. Aguinaga L, Primo J, Anguera I, et al. Long-term follow-up in patients with the permanent form of junctional reciprocating tachycardia treated with radiofrequency ablation. Pacing Clin Electrophysiol 1998; 21:2073. 38. Rodriguez LM, Geller JC, Tse HF, et al. Acute results of transvenous cryoablation of supraventricular tachycardia (atrial fibrillation, atrial flutter, Wolff-Parkinson-White syndrome, atrioventricular nodal reentry tachycardia). J Cardiovasc Electrophysiol 2002; 13:1082. 39. Wellens HJ. Should catheter ablation be performed in asymptomatic patients with Wolff- Parkinson-White syndrome? When to perform catheter ablation in asymptomatic patients with a Wolff-Parkinson-White electrocardiogram. Circulation 2005; 112:2201. 40. Pappone C, Santinelli V. Should catheter ablation be performed in asymptomatic patients with Wolff-Parkinson-White syndrome? Catheter ablation should be performed in asymptomatic patients with Wolff-Parkinson-White syndrome. Circulation 2005; 112:2207. 41. Chevalier P, Cadi F, Scridon A, et al. Prophylactic radiofrequency ablation in asymptomatic patients with Wolff-Parkinson-White is not yet a good strategy: a decision analysis. Circ Arrhythm Electrophysiol 2013; 6:185. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 21/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate 42. Todd DM, Klein GJ, Krahn AD, et al. Asymptomatic Wolff-Parkinson-White syndrome: is it time to revisit guidelines? J Am Coll Cardiol 2003; 41:245. 43. Etheridge SP, Escudero CA, Blaufox AD, et al. Life-threatening event risk in children with Wolff-Parkinson-White syndrome: a multicenter international study. J Am Coll Cardiol EP 2018; 4:433. 44. Pappone C, Vicedomini G, Manguso F, et al. Wolff-Parkinson-White syndrome in the era of catheter ablation: insights from a registry study of 2169 patients. Circulation 2014; 130:811. 45. Pediatric and Congenital Electrophysiology Society (PACES), Heart Rhythm Society (HRS), American College of Cardiology Foundation (ACCF), et al. PACES/HRS expert consensus statement on the management of the asymptomatic young patient with a Wolff-Parkinson- White (WPW, ventricular preexcitation) electrocardiographic pattern: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the American Academy of Pediatrics (AAP), and the Canadian Heart Rhythm Society (CHRS). Heart Rhythm 2012; 9:1006. 46. Crossen KJ, Lindsay BD, Cain ME. Reliability of retrograde atrial activation patterns during ventricular pacing for localizing accessory pathways. J Am Coll Cardiol 1987; 9:1279. 47. Jackman WM, Friday KJ, Yeung-Lai-Wah JA, et al. New catheter technique for recording left free-wall accessory atrioventricular pathway activation. Identification of pathway fiber orientation. Circulation 1988; 78:598. 48. Denes P, Wyndham CR, Amat-y-Leon F, et al. Atrial pacing at multiple sites in the Wolff- Parkinson-White syndrome. Br Heart J 1977; 39:506. 49. Mitchell LB, Mason JW, Scheinman MM, et al. Recordings of basal ventricular preexcitation from electrode catheters in patients with accessory atrioventricular connections. Circulation 1984; 69:233. 50. Chen X, Borggrefe M, Shenasa M, et al. Characteristics of local electrogram predicting successful transcatheter radiofrequency ablation of left-sided accessory pathways. J Am Coll Cardiol 1992; 20:656. 51. Scheinman MM. Catheter ablation for cardiac arrhythmias, personnel, and facilities. North American Society of Pacing and Electrophysiology Ad Hoc Committee on Catheter Ablation. Pacing Clin Electrophysiol 1992; 15:715. 52. Kay GN, Epstein AE, Dailey SM, Plumb VJ. Role of radiofrequency ablation in the management of supraventricular arrhythmias: experience in 760 consecutive patients. J Cardiovasc Electrophysiol 1993; 4:371. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 22/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate 53. Calkins H, Yong P, Miller JM, et al. Catheter ablation of accessory pathways, atrioventricular nodal reentrant tachycardia, and the atrioventricular junction: final results of a prospective, multicenter clinical trial. The Atakr Multicenter Investigators Group. Circulation 1999; 99:262. 54. Dagres N, Clague JR, Kottkamp H, et al. Radiofrequency catheter ablation of accessory pathways. Outcome and use of antiarrhythmic drugs during follow-up. Eur Heart J 1999; 20:1826. 55. Bravo L, Atienza F, Eidelman G, et al. Safety and efficacy of cryoablation vs. radiofrequency ablation of septal accessory pathways: systematic review of the literature and meta- analyses. Europace 2018; 20:1334. 56. Backhoff D, Klehs S, Muller MJ, et al. Long-term follow-up after radiofrequency catheter ablation of accessory atrioventricular pathways in children. J Am Coll Cardiol EP 2018; 4:448. 57. Chen SA, Hsia CP, Chiang CE, et al. Reappraisal of radiofrequency ablation of multiple accessory pathways. Am Heart J 1993; 125:760. 58. Huang JL, Chen SA, Tai CT, et al. Long-term results of radiofrequency catheter ablation in patients with multiple accessory pathways. Am J Cardiol 1996; 78:1375. 59. Schweikert RA, Saliba WI, Tomassoni G, et al. Percutaneous pericardial instrumentation for endo-epicardial mapping of previously failed ablations. Circulation 2003; 108:1329. 60. Langberg JJ, Calkins H, Kim YN, et al. Recurrence of conduction in accessory atrioventricular connections after initially successful radiofrequency catheter ablation. J Am Coll Cardiol 1992; 19:1588. 61. Dagres N, Clague JR, Lottkamp H, et al. Impact of radiofrequency catheter ablation of accessory pathways on the frequency of atrial fibrillation during long-term follow-up; high recurrence rate of atrial fibrillation in patients older than 50 years of age. Eur Heart J 2001; 22:423. 62. Liu J, Dole LR. Late complete atrioventricular block complicating radiofrequency catheter ablation of a left posteroseptal accessory pathway. Pacing Clin Electrophysiol 1998; 21:2136. 63. Seidl K, Hauer B, Zahn R, Senges J. Unexpected complete AV block following transcatheter ablation of a left posteroseptal accessory pathway. Pacing Clin Electrophysiol 1998; 21:2139. 64. Kessler DJ, Pirwitz MJ, Horton RP, et al. Intracardiac shunts resulting from transseptal catheterization for ablation of accessory pathways in otherwise normal hearts. Am J Cardiol 1998; 82:391. 65. Fitchet A, Turkie W, Fitzpatrick AP. Transeptal approach to ablation of left-sided arrhythmias does not lead to persisting interatrial shunt: a transesophageal echocardiographic study. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 23/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Pacing Clin Electrophysiol 1998; 21:2070. 66. Kocovic DZ, Harada T, Shea JB, et al. Alterations of heart rate and of heart rate variability after radiofrequency catheter ablation of supraventricular tachycardia. Delineation of parasympathetic pathways in the human heart. Circulation 1993; 88:1671. 67. Psychari SN, Theodorakis GN, Koutelou M, et al. Cardiac denervation after radiofrequency ablation of supraventricular tachycardias. Am J Cardiol 1998; 81:725. 68. Hamdan MH, Page RL, Wasmund SL, et al. Selective parasympathetic denervation following posteroseptal ablation for either atrioventricular nodal reentrant tachycardia or accessory pathways. Am J Cardiol 2000; 85:875. 69. Cox JL, Gallagher JJ, Cain ME. Experience with 118 consecutive patients undergoing operation for the Wolff-Parkinson-White syndrome. J Thorac Cardiovasc Surg 1985; 90:490. 70. Lawrie GM, Lin HT, Wyndham CR, DeBakey ME. Surgical treatment of supraventricular arrhythmias. Results in 67 patients. Ann Surg 1987; 205:700. 71. Johnson DC, Nunn GR, Richards DA, et al. Surgical therapy for supraventricular tachycardia, a potentially curable disorder. J Thorac Cardiovasc Surg 1987; 93:913. 72. Holman WL, Kay GN, Plumb VJ, Epstein AE. Operative results after unsuccessful radiofrequency ablation for Wolff-Parkinson-White syndrome. Am J Cardiol 1992; 70:1490. 73. Kim SS, Lal R, Ruffy R. Treatment of paroxysmal reentrant supraventricular tachycardia with flecainide acetate. Am J Cardiol 1986; 58:80. 74. Ward DE, Jones S, Shinebourne EA. Use of flecainide acetate for refractory junctional tachycardias in children with the Wolff-Parkinson-White syndrome. Am J Cardiol 1986; 57:787. 75. Ludmer PL, McGowan NE, Antman EM, Friedman PL. Efficacy of propafenone in Wolff- Parkinson-White syndrome: electrophysiologic findings and long-term follow-up. J Am Coll Cardiol 1987; 9:1357. 76. Musto B, D'Onofrio A, Cavallaro C, Musto A. Electrophysiological effects and clinical efficacy of propafenone in children with recurrent paroxysmal supraventricular tachycardia. Circulation 1988; 78:863. 77. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 78. Rosenbaum MB, Chiale PA, Ryba D, Elizari MV. Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 1974; 34:215. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 24/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate 79. Wellens HJ, Lie KI, B r FW, et al. Effect of amiodarone in the Wolff-Parkinson-White syndrome. Am J Cardiol 1976; 38:189. 80. Feld GK, Nademanee K, Weiss J, et al. Electrophysiologic basis for the suppression by amiodarone of orthodromic supraventricular tachycardias complicating pre-excitation syndromes. J Am Coll Cardiol 1984; 3:1298. 81. Chouty F, Coumel P. Oral flecainide for prophylaxis of paroxysmal atrial fibrillation. Am J Cardiol 1988; 62:35D. 82. Antman EM, Beamer AD, Cantillon C, et al. Long-term oral propafenone therapy for suppression of refractory symptomatic atrial fibrillation and atrial flutter. J Am Coll Cardiol 1988; 12:1005. 83. Kappenberger LJ, Fromer MA, Steinbrunn W, Shenasa M. Efficacy of amiodarone in the Wolff-Parkinson-White syndrome with rapid ventricular response via accessory pathway during atrial fibrillation. Am J Cardiol 1984; 54:330. 84. Feld GK, Nademanee K, Stevenson W, et al. Clinical and electrophysiologic effects of amiodarone in patients with atrial fibrillation complicating the Wolff-Parkinson-White syndrome. Am Heart J 1988; 115:102. Topic 996 Version 48.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 25/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate GRAPHICS ECG in Wolff-Parkinson-White The 12-lead ECG shows the typical features of Wolff-Parkinson-White; the PR interval is short (*) and the QRS duration prolonged as a result of a delta wave (arrow), indicating ventricular preexcitation. Courtesy of Martin Burke, DO. Graphic 67181 Version 3.0 Normal ECG https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 26/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Normal electrocardiogram showing normal sinus rhythm at a rate of 75 beats/minute, a PR interval of 0.14 seconds, a QRS interval of 0.10 seconds, and a QRS axis of approximately 75 . Courtesy of Ary Goldberger, MD. Graphic 76183 Version 4.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 27/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Medical therapy of arrhythmias associated with Wolff-Parkinson-White syndrome Arrhythmia Treatment options Contraindicated therapies Orthodromic AV reentrant tachycardia Acute termination* Unstable patients: Synchronized cardioversion Stable patients: First line: Vagal maneuvers Second line: IV adenosine Third line: IV verapamil OR IV diltiazem Other therapies: IV procainamide OR IV beta blocker; synchronized cardioversion if other therapies are ineffective or not feasible

20:1826. 55. Bravo L, Atienza F, Eidelman G, et al. Safety and efficacy of cryoablation vs. radiofrequency ablation of septal accessory pathways: systematic review of the literature and meta- analyses. Europace 2018; 20:1334. 56. Backhoff D, Klehs S, Muller MJ, et al. Long-term follow-up after radiofrequency catheter ablation of accessory atrioventricular pathways in children. J Am Coll Cardiol EP 2018; 4:448. 57. Chen SA, Hsia CP, Chiang CE, et al. Reappraisal of radiofrequency ablation of multiple accessory pathways. Am Heart J 1993; 125:760. 58. Huang JL, Chen SA, Tai CT, et al. Long-term results of radiofrequency catheter ablation in patients with multiple accessory pathways. Am J Cardiol 1996; 78:1375. 59. Schweikert RA, Saliba WI, Tomassoni G, et al. Percutaneous pericardial instrumentation for endo-epicardial mapping of previously failed ablations. Circulation 2003; 108:1329. 60. Langberg JJ, Calkins H, Kim YN, et al. Recurrence of conduction in accessory atrioventricular connections after initially successful radiofrequency catheter ablation. J Am Coll Cardiol 1992; 19:1588. 61. Dagres N, Clague JR, Lottkamp H, et al. Impact of radiofrequency catheter ablation of accessory pathways on the frequency of atrial fibrillation during long-term follow-up; high recurrence rate of atrial fibrillation in patients older than 50 years of age. Eur Heart J 2001; 22:423. 62. Liu J, Dole LR. Late complete atrioventricular block complicating radiofrequency catheter ablation of a left posteroseptal accessory pathway. Pacing Clin Electrophysiol 1998; 21:2136. 63. Seidl K, Hauer B, Zahn R, Senges J. Unexpected complete AV block following transcatheter ablation of a left posteroseptal accessory pathway. Pacing Clin Electrophysiol 1998; 21:2139. 64. Kessler DJ, Pirwitz MJ, Horton RP, et al. Intracardiac shunts resulting from transseptal catheterization for ablation of accessory pathways in otherwise normal hearts. Am J Cardiol 1998; 82:391. 65. Fitchet A, Turkie W, Fitzpatrick AP. Transeptal approach to ablation of left-sided arrhythmias does not lead to persisting interatrial shunt: a transesophageal echocardiographic study. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 23/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Pacing Clin Electrophysiol 1998; 21:2070. 66. Kocovic DZ, Harada T, Shea JB, et al. Alterations of heart rate and of heart rate variability after radiofrequency catheter ablation of supraventricular tachycardia. Delineation of parasympathetic pathways in the human heart. Circulation 1993; 88:1671. 67. Psychari SN, Theodorakis GN, Koutelou M, et al. Cardiac denervation after radiofrequency ablation of supraventricular tachycardias. Am J Cardiol 1998; 81:725. 68. Hamdan MH, Page RL, Wasmund SL, et al. Selective parasympathetic denervation following posteroseptal ablation for either atrioventricular nodal reentrant tachycardia or accessory pathways. Am J Cardiol 2000; 85:875. 69. Cox JL, Gallagher JJ, Cain ME. Experience with 118 consecutive patients undergoing operation for the Wolff-Parkinson-White syndrome. J Thorac Cardiovasc Surg 1985; 90:490. 70. Lawrie GM, Lin HT, Wyndham CR, DeBakey ME. Surgical treatment of supraventricular arrhythmias. Results in 67 patients. Ann Surg 1987; 205:700. 71. Johnson DC, Nunn GR, Richards DA, et al. Surgical therapy for supraventricular tachycardia, a potentially curable disorder. J Thorac Cardiovasc Surg 1987; 93:913. 72. Holman WL, Kay GN, Plumb VJ, Epstein AE. Operative results after unsuccessful radiofrequency ablation for Wolff-Parkinson-White syndrome. Am J Cardiol 1992; 70:1490. 73. Kim SS, Lal R, Ruffy R. Treatment of paroxysmal reentrant supraventricular tachycardia with flecainide acetate. Am J Cardiol 1986; 58:80. 74. Ward DE, Jones S, Shinebourne EA. Use of flecainide acetate for refractory junctional tachycardias in children with the Wolff-Parkinson-White syndrome. Am J Cardiol 1986; 57:787. 75. Ludmer PL, McGowan NE, Antman EM, Friedman PL. Efficacy of propafenone in Wolff- Parkinson-White syndrome: electrophysiologic findings and long-term follow-up. J Am Coll Cardiol 1987; 9:1357. 76. Musto B, D'Onofrio A, Cavallaro C, Musto A. Electrophysiological effects and clinical efficacy of propafenone in children with recurrent paroxysmal supraventricular tachycardia. Circulation 1988; 78:863. 77. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 78. Rosenbaum MB, Chiale PA, Ryba D, Elizari MV. Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 1974; 34:215. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 24/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate 79. Wellens HJ, Lie KI, B r FW, et al. Effect of amiodarone in the Wolff-Parkinson-White syndrome. Am J Cardiol 1976; 38:189. 80. Feld GK, Nademanee K, Weiss J, et al. Electrophysiologic basis for the suppression by amiodarone of orthodromic supraventricular tachycardias complicating pre-excitation syndromes. J Am Coll Cardiol 1984; 3:1298. 81. Chouty F, Coumel P. Oral flecainide for prophylaxis of paroxysmal atrial fibrillation. Am J Cardiol 1988; 62:35D. 82. Antman EM, Beamer AD, Cantillon C, et al. Long-term oral propafenone therapy for suppression of refractory symptomatic atrial fibrillation and atrial flutter. J Am Coll Cardiol 1988; 12:1005. 83. Kappenberger LJ, Fromer MA, Steinbrunn W, Shenasa M. Efficacy of amiodarone in the Wolff-Parkinson-White syndrome with rapid ventricular response via accessory pathway during atrial fibrillation. Am J Cardiol 1984; 54:330. 84. Feld GK, Nademanee K, Stevenson W, et al. Clinical and electrophysiologic effects of amiodarone in patients with atrial fibrillation complicating the Wolff-Parkinson-White syndrome. Am Heart J 1988; 115:102. Topic 996 Version 48.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 25/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate GRAPHICS ECG in Wolff-Parkinson-White The 12-lead ECG shows the typical features of Wolff-Parkinson-White; the PR interval is short (*) and the QRS duration prolonged as a result of a delta wave (arrow), indicating ventricular preexcitation. Courtesy of Martin Burke, DO. Graphic 67181 Version 3.0 Normal ECG https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 26/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Normal electrocardiogram showing normal sinus rhythm at a rate of 75 beats/minute, a PR interval of 0.14 seconds, a QRS interval of 0.10 seconds, and a QRS axis of approximately 75 . Courtesy of Ary Goldberger, MD. Graphic 76183 Version 4.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 27/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Medical therapy of arrhythmias associated with Wolff-Parkinson-White syndrome Arrhythmia Treatment options Contraindicated therapies Orthodromic AV reentrant tachycardia Acute termination* Unstable patients: Synchronized cardioversion Stable patients: First line: Vagal maneuvers Second line: IV adenosine Third line: IV verapamil OR IV diltiazem Other therapies: IV procainamide OR IV beta blocker; synchronized cardioversion if other therapies are ineffective or not feasible Chronic prevention First line: Catheter ablation of the accessory pathway Second line: Oral flecainide or propafenone in the absence of structural or ischemic heart disease Third line: Oral IA antiarrhythmic agent OR oral amiodarone Antidromic AV reentrant tachycardia Acute termination* Unstable patients: Adenosine, verapamil, diltiazem, Synchronized cardioversion beta blockers, digoxin should all be avoided if NOT certain of diagnosis Stable patients (if CERTAIN of the diagnosis): Same progression of therapies as acute termination of orthodromic AVRT Stable patients (if NOT certain of the diagnosis): IV procainamide, synchronized cardioversion if procainamide is ineffective or not available https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 28/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Chronic prevention First line: Catheter ablation of the accessory pathway Digoxin Beta blockers Second line: Oral flecainide or propafenone in the absence of Verapamil, diltiazem structural or ischemic heart disease Other therapies: Oral IA antiarrhythmic agent OR oral amiodarone Pre-excited atrial fibrillation Acute termination* Unstable patients: Amiodarone Synchronized cardioversion Stable patients: Digoxin Beta blockers First line: IV ibutilide or IV procainamide Adenosine Other therapies: IC antiarrhythmic agent or dofetilide; synchronized cardioversion if other therapies are ineffective or not available Verapamil, diltiazem Chronic prevention First line: Catheter ablation or the accessory pathway Oral digoxin Second line: Oral flecainide or propafenone in the absence of structural or ischemic heart disease Third line: Oral IA antiarrhythmic agent OR oral amiodarone AVRT: atrioventricular reciprocating tachycardia; IV: intravenous; class IC: flecainide, propafenone; class IA: quinidine, procainamide, disopyramide. Cardioversion is indicated if hemodynamically unstable or drugs are ineffective. Ablation of the accessory pathway is generally preferred to cure the arrhythmia. Procainamide is the intravenous drug of choice for acute termination of suspected antidromic AVRT. If the tachycardia is definitely known to be antidromic AVRT, and it has been verified that the AV node (rather than a second accessory pathway) is acting as the retrograde limb of the circuit, one could consider treatment with an agent such as adenosine similar to therapy for orthodromic AVRT, https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 29/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate but it is rare to have all of the necessary data in the acute setting to justify use of AV nodal blocking agents. Graphic 62762 Version 7.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 30/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Approach to adenosine dosing in stable adults with suspected supraventricular tachyarrhythmia This figure summarizes the initial dosing, administration, and need for repeat dosing of adenosine in a hemo stable adult with suspected AV node-dependent SVT. Adenosine can be used as a diagnostic aid to identify th rhythm or as a therapy to terminate SVTs that rely on AV node conduction. AV node-dependent SVTs include A reentrant tachycardia (AVNRT) and AV reentrant (or reciprocating) tachycardia (AVRT). The management of su node-dependent SVT in hemodynamically stable adults commonly starts with a trial of 1 or more vagal mane proceeding to adenosine therapy. If the patient has hemodynamically unstable SVT, cardioversion is indicate UpToDate content for details on management of SVTs. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 31/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate AV: atrioventricular; SVT: supraventricular tachycardia; IV: intravenous; ACC: American College of Cardiology; American Heart Association; HRS: Heart Rhythm Society; ECG: electrocardiogram. Lower adenosine doses are indicated in certain clinical settings. If central venous administration is perform adenosine dose is 3 mg; if needed (SVT persists and there is no AV block), the dose may be increased to 6 mg mg for subsequent doses. For heart transplant recipients, the initial adenosine dose is 1 mg; if needed (SVT p there is no AV block), the dose may be increased to 2 mg and then 3 mg for subsequent doses. An 18 mg dose is more likely to be required to produce AV block in patients with a body weight >70 kg, par [1] those weighing >110 kg. When a third dose is indicated, an alternative approach is to administer 12 mg (in mg) as described in the 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients with Supraventr Tachycardia. [2] SVT termination in response to adenosine includes SVT termination closely followed by SVT recurrence. Refer to UpToDate content on treatment of SVT for dosing of second-line AV nodal blockers. If the SVT pers second-line AV nodal blocker therapy, electrical cardioversion is performed, as discussed in UpToDate conten treatment of SVT. SVTs that are not AV node dependent include atrial flutter, atrial fibrillation, and atrial tachycardia. When AV is induced by adenosine, the ECG may reveal atrial activity diagnostic of these rhythms. References: 1. Prabhu S, Mackin V, McLellan AJA, et al. Determining the optimal dose of adenosine for unmasking dormant pulmonary vein co following atrial brillation ablation: Electrophysiological and hemodynamic assessment. DORMANT-AF study. J Cardiovasc Electr 28:13. 2. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS guideline for the management of adult patients with supraventricular report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Hea Society. Circulation 2016; 133:e506. Graphic 141417 Version 3.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 32/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Algorithmic approach to risk stratification of asymptomatic patients with Wolff-Parkinson-White ECG pattern ECG: electrocardiogram; EPS: electrophysiology studies; AVRT: atrioventricular reciprocating tachycardia; AF: atrial fibrillation; WPW: Wolff-Parkinson-White. Preexcitation on the surface ECG is identified by a short PR interval (less than 120 milliseconds) leading into QRS, which is widened with a slurred upstroke (delta wave). Preexcitation is defined as intermittent when an ECG at any point in time shows the loss of preexcitation. In patients who are unable to perform exercise testing (eg, very young patients), ambulatory ECG monitoring or, rarely, sodium channel blocker challenge with procainamide is an alternative to assess for persistent or intermittent preexcitation. All approaches to risk stratification in patients with ventricular preexcitation are imperfect and can be associated with false positives as well as false negatives. https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 33/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Options for invasive EPS include the standard transvenous intracardiac EPS or a transesophageal atrial EPS. Refer to the UpToDate topic on treatment of symptomatic arrhythmias in patients with WPW. For most asymptomatic patients with preexcitation and no high- risk features identified on EPS, particularly those over age 35 to 40 years, we suggest observation. However, in some asymptomatic patients, particularly children, some electrophysiologists discuss and/or proceed with catheter ablation as a therapeutic option even in the absence of high risk features. Refer to UpToDate content on treatment of WPW for additional information. Graphic 119379 Version 3.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 34/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Intracardiac and surface electrocardiogram (ECG) recordings during electrophysiologic (EP) study in Wolff-Parkinson-White syndrome Shown are five surface ECG leads (I, aVF, V1, V3, V6) and intracardiac recordings from the high right atrium (HRA), lateral mitral annulus (HBE1-2 and HBE3-4), coronary sinus (proximal to distal, CS9-10, CS7-8, CS5-6, CS3-4, and CS1-2), and the right ventricular apex (RVA3-4). During the diagnostic electrophysiology study, orthodromic atrioventricular reentrant tachycardia was induced. Recordings from the CS demonstrated that the earliest site of ventricular activation was at CS7-8, indicating a left lateral location of the accessory pathway (arrow). The mapping catheter (HBE1-2,3-4) was advanced through a patent foramen ovale to the lateral mitral annulus. Activation mapping was used to select the ablation site; during sinus rhythm, the ablation catheter was maneuvered to the site along the mitral annulus, which recorded earliest ventricular activity (HBE1-2) (ie, the atrial [A] and ventricular [V] electrograms recorded from the ablation catheter tip were continuous and the local ventricular activity preceded the onset of the delta wave on the surface ECG). Graphic 72398 Version 5.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 35/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Radiofrequency ablation for WPW syndrome Surface ECG and intracardiac electrograms from a patient with Wolff- Parkinson-White syndrome (WPW) and a right lateral accessory pathway are simultaneously recorded. The patient is initially being paced from the high right atrium (HRA) at a cycle length of 500 milliseconds to maximize preexcitation. The accessory pathway is localized to an area of the tricuspid annulus (Ta), and radiofrequency (RF) current is delivered via a deflectable tip ablation catheter. Preexcitation disappears (*) within 1.2 seconds. Graphic 51546 Version 4.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 36/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Intracardiac and surface ECG recordings during electrophysiologic study post-radiofrequency ablation of accessory pathway in Wolff- Parkinson-White Shown are five surface leads (I, AVF, V1, V3, and V6) and intracardiac recording from the high right atrium (HRA), lateral mitral annulus (HBE1-2 and HBE3-4), coronary sinus proximal to distal (CS9-10, 7-8, 5-6, 3-4, 1-2), and right ventricular apex (RVA3-4). The tip of the mapping catheter is positioned at the site along the mitral annulus recording the earliest ventricular activity (HBE1-2) (ie, the location of the accessory pathway). Within a few beats after the application of radiofrequency energy (RF on), the delta wave on the ECG disappeared (arrow) and the PR interval normalized. Prior to ablation, the recordings from the CS catheter show continuous atrial (A) and ventricular (V) electrograms; after ablation, there is a normal interval between A and V. Graphic 78363 Version 5.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 37/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 38/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 39/40 7/6/23, 3:09 PM Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome - UpToDate Contributor Disclosures Luigi Di Biase, MD, PhD, FHRS, FACC Consultant/Advisory Boards: Abbott [Ablation products and cardiac devices, defibrillators, or pacemakers of left atrial appendage closure]; Baylis Medical [Cardiac devices, defibrillators, or pacemakers of left atrial appendage closure]; Biosense Webster [Ablation products]; Biotronik [Cardiac devices, defibrillators, or pacemakers of left atrial appendage closure]; Boston Scientific [Ablation products and cardiac devices, defibrillators, or pacemakers of left atrial appendage closure]; Medtronic [Ablation products and cardiac devices, defibrillators, or pacemakers of left atrial appendage closure]; Stereotaxis [Ablation products]; Zoll Medical [Cardiac devices, defibrillators, or pacemakers of left atrial appendage closure]. All of the relevant financial relationships listed have been mitigated. Edward P Walsh, MD No relevant financial relationship(s) with ineligible companies to disclose. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/treatment-of-arrhythmias-associated-with-the-wolff-parkinson-white-syndrome/print 40/40

7/6/23, 3:09 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy : Philip J Podrid, MD, FACC : Wilson S Colucci, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 03, 2023. INTRODUCTION Ventricular arrhythmias, including premature ventricular complexes or beats, ventricular premature complexes or beats, ventricular tachycardia, and ventricular fibrillation, are common in patients with heart failure (HF) and cardiomyopathy, both ischemic and nonischemic in nature [1-3]. The etiology and types of arrhythmias, clinical presentation, diagnosis, and management of ventricular arrhythmias in patients with HF and/or cardiomyopathy will be reviewed here. The secondary and primary prevention of sudden cardiac death in these patients, including a review of the causes of death in HF, and the importance of ventricular arrhythmias in other causes of cardiomyopathy, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, are discussed separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death" and "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis".) TYPES OF ARRHYTHMIA Premature ventricular complexes (PVCs) PVCs occur in 70 to 95 percent of patients with heart failure (HF), and they may be frequent (including bigeminy or trigeminy) and complex (ie, https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 1/24 7/6/23, 3:09 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate multifocal, couplets, or triplets/nonsustained ventricular tachycardia) [4-7]. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation" and "Premature ventricular complexes: Treatment and prognosis".) Among patients with cardiomyopathy, PVCs may be clinically significant for the following reasons: PVCs (particularly when complex, ie, multifocal, couplets [ie, two PVCs in a row], or triplets [ie, three PVCs in a row, often called nonsustained VT]) may be predictors of more malignant arrhythmias and sudden cardiac death (SCD). In patients with a prior myocardial infarction (MI), PVCs are associated with an increased risk of death. By contrast, PVCs do not appear to be associated with a worse prognosis in patients with nonischemic cardiomyopathy, although data are limited [8]. PVCs can cause symptoms, usually palpitations. Symptoms are generally mild, and most patients require no specific therapy. Beta blockers can help to control symptoms (particularly palpitations related to the post-extrasystolic potentiation of myocardial contractility) although they will not usually suppress the PVCs, but most patients with HF and cardiomyopathy already have an indication for a beta blocker. Because of the proarrhythmic risks of antiarrhythmic drugs (which are particularly increased in patients with HF) other than beta blockers, these medications are not used in the routine treatment of PVCs. In the rare circumstance in which a patient is severely symptomatic despite beta blockers, amiodarone or dofetilide appears to be safe in patients with HF, and radiofrequency catheter ablation may also be an option. In rare cases, very frequent PVCs cause a reduction in left ventricular ejection fraction or even less frequently exacerbate left ventricular (LV) dysfunction. In such cases, radiofrequency catheter ablation is a safe and possibly an effective therapy that can reduce the number of PVCs and often restore LV function toward normal. (See "Arrhythmia- induced cardiomyopathy", section on 'Frequent ventricular ectopy'.) Nonsustained ventricular tachycardia Runs of nonsustained ventricular tachycardia (NSVT) have been observed on ambulatory monitoring in 50 to 80 percent of patients with HF or cardiomyopathy [4,7,9]. We define NSVT as three or more consecutive ventricular beats at a rate of greater than 100 beats/minute with a duration of less than 30 seconds (or self-terminating) and no associated hemodynamic collapse. The clinical significance of NSVT can be considered in a similar manner to that of PVCs: https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 2/24 7/6/23, 3:09 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate NSVT may be predictive of future malignant arrhythmias and mortality. An association between NSVT and mortality has been shown in patients with ischemic and hypertrophic cardiomyopathy but not in most other forms of cardiomyopathy. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) Among 1080 patients with class III and IV HF in the PROMISE study, the frequency of NSVT was a significant independent predictor of both sudden and non-sudden death mortality [4]. NSVT is often asymptomatic, but some patients experience palpitations, lightheadedness, presyncope, or dyspnea. Because many of the symptoms that may be attributed to NSVT are vague and nonspecific, it is important to try to correlate symptoms to episodes of NSVT before initiating therapy. In patients with symptoms due to NSVT, options include beta blockers (for which most patients already have an indication), catheter ablation, and, in rare cases of severe and refractory symptoms, amiodarone or dofetilide. In patients with an ischemic cardiomyopathy, the occurrence of nonsustained polymorphic ventricular tachycardia (VT) may be the result of active ischemia. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management".) In rare cases, very frequent NSVT can contribute to or exacerbate LV dysfunction. (See "Arrhythmia-induced cardiomyopathy", section on 'Ventricular arrhythmias'.) Accelerated idioventricular rhythm An accelerated idioventricular rhythm (AIVR), which has also been called "slow VT," arises below the atrioventricular (AV) node (within the ventricular myocardium) and has, by definition, a rate between 60 and 100 beats/minute. When the AIVR is an accelerated rhythm, there is AV dissociation present, but the rate of the QRS complexes is faster than the atrial rate. AIVR occurs in approximately 8 percent of patients with HF or cardiomyopathy [10]. It also occurs in up to 50 percent of patients during an acute MI, most commonly in patients undergoing revascularization (ie, a reperfusion arrhythmia). Most episodes of AIVR are transient and require no treatment. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Accelerated idioventricular rhythm'.) Sustained VT or VF In contrast to the high prevalence of PVCs and NSVT in patients with HF or cardiomyopathy, sustained VT (monomorphic or polymorphic) is unusual, occurring in 5 percent of patients [4,7,9]. Patients with spontaneous sustained VT or resuscitated ventricular fibrillation (VF) are at high risk for SCD [11,12]. Patients with HF or cardiomyopathy (especially with an LVEF 35 percent) who are survivors of SCD due to unstable VT or VF, with or without recurrent stable sustained VT, are typically treated with an implantable cardioverter-defibrillator https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 3/24 7/6/23, 3:09 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate for secondary prevention. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) PATHOGENESIS There are multiple factors responsible for ventricular arrhythmias in patients with heart failure (HF) and cardiomyopathy. These include: Underlying structural myocardial disease Mechanical factors Neurohormonal factors Electrolyte abnormalities Myocardial ischemia Drugs Underlying structural myocardial disease Extensive myocardial damage and fibrosis (including scar from prior myocardial infarction), myocardial infiltration or inflammation, or the loss of cell-to-cell coupling in patients with dilated cardiomyopathy provides the proper substrate for reentry, the mechanism thought to be responsible for most ventricular arrhythmias. A focal mechanism may also contribute to ventricular arrhythmia in patients with a nonischemic cardiomyopathy, probably from an ectopic focus or triggered activity arising from either early afterdepolarizations or delayed afterdepolarizations, without evidence of reentry. Mechanical factors Mechanical factors that can alter the electrophysiologic properties (electromechanical feedback) of myocardial tissue in HF include an increase in wall stress and left ventricular dilation [13,14]. It has been shown that a stretching of atrial or ventricular myocardium can enhance automaticity and result in arrhythmia. Since regions of the heart differ in mechanical function, electromechanical feedback that can cause PVCs may result in an increase in dispersion of action potential duration and membrane recovery. These effects can increase the incidence of arrhythmias, particularly sustained VT or VF. Among 311 patients in the SOLVD (Studies of Left Ventricular Dysfunction) trial, for example, there was a direct correlation between left ventricular end-diastolic volume and the prevalence of ventricular arrhythmia [15]. Neurohormonal factors HF results in the activation of the sympathetic nervous and renin- angiotensin systems and withdrawal of parasympathetic tone, resulting in increased heart rate, reduced heart rate variability, and depressed baroreceptor sensitivity. https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 4/24 7/6/23, 3:09 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Neurohormonal activation can promote arrhythmia formation via a variety of mechanisms: Catecholamines are arrhythmogenic by virtue of their ability to enhance automaticity, precipitate triggered activity, and alter conduction and refractoriness, which may promote reentry. Angiotensin II can indirectly promote arrhythmia formation via low potassium or magnesium levels, resulting from potassium and magnesium loss in the urine. It can also potentiate the effects of the sympathetic nervous system through central or peripheral actions. Both systems may be arrhythmogenic because the associated vasoconstriction alters loading conditions, affecting wall stress and mechanical factors as described above. Electrolyte abnormalities Patients with HF often have electrolyte abnormalities, particularly diuretic-induced hypokalemia and hypomagnesemia, which may be directly arrhythmogenic [16]. Hyperkalemia, as may occur with the use of ACE inhibitors or ARBs, results in slowing of conduction through the myocardium, which may also be a precondition for arrhythmia. In addition, stimulation of beta-2 receptors by circulating epinephrine can transiently lower the plasma potassium concentration by enhancing potassium entry into cells. In the SOLVD trial, for example, non-potassium-sparing diuretic use at baseline was associated with a lower serum concentration of potassium and a higher incidence of arrhythmic death compared with no diuretic use (3.1 versus 1.7 deaths per 100 patient-years) [17]. (See "Use of diuretics in patients with heart failure".) Myocardial ischemia Myocardial ischemia, through its effects on electrolyte shifts, acidosis, heterogeneity of electrophysiologic properties, and other mediators, may lead to alteration in the electrophysiologic milieu, including regional alterations in conduction and refractoriness and enhanced automaticity. These alterations may be enhanced by hypokalemia, increased catecholamine levels, digitalis, and antiarrhythmic agents. While monomorphic ventricular tachycardia (VT) is not usually due to active ischemia, polymorphic VT or ventricular fibrillation (VF) are often ischemia-induced arrhythmias. Drugs The drugs used to treat HF can directly or indirectly precipitate arrhythmia formation. Diuretic-induced electrolyte disturbances may be directly arrhythmogenic. Drugs may be proarrhythmic by prolonging the QT interval ( table 1) (eg, antiarrhythmic medications, certain antifungal and antibiotic agents, certain psychoactive drugs, etc) and predisposing to acquired long QT syndrome and polymorphic VT (which, associated with https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 5/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate QT prolongation, is termed torsades de pointes). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) Phosphodiesterase inhibitors Phosphodiesterase inhibitors are positive inotropic agents that increase intracellular calcium, which can increase cyclic AMP and precipitate afterdepolarizations, resulting in triggered activity. They can also exacerbate ventricular arrhythmias by inducing ischemia [18]. A number of trials have shown that one such agent, milrinone, increased the frequency of all forms of spontaneous arrhythmia [19-21] and, in a long-term survival trial (PROMISE), was associated with a 20 percent excess in mortality compared with placebo [22]. Sympathomimetic drugs Studies with sympathomimetic agents (eg, dobutamine, albuterol) have shown an increased frequency of ventricular arrhythmias and/or increased mortality [23]. The use of sympathomimetic drugs is also associated with an increased incidence of hospitalization for arrhythmia, especially atrial fibrillation, VT, and VF [24]. Digoxin There have been conflicting data on the effect of digoxin on the frequency and clinical significance of arrhythmias in HF. Two relatively large studies found that digoxin did not significantly affect the frequency of ventricular arrhythmias in patients with congestive HF [21,25]. Conversely, other studies in patients with HF after acute myocardial infarction (MI) reported an excess mortality in patients who had complex ventricular arrhythmias who were treated with digitalis [26,27]; however, other reports did not confirm this increased risk in post-MI patients [28,29]. The largest trial evaluating the efficacy of digoxin in HF, the DIG trial, randomly assigned approximately 6800 patients with HF to digoxin or placebo; all patients were also treated with an angiotensin converting enzyme inhibitor and, if necessary, a diuretic [30]. Digoxin was associated with an increase in non-HF cardiac mortality, which included a trend towards increased mortality from arrhythmia. This trend counterbalanced the fewer deaths from progressive HF in patients treated with digoxin, leading to no effect on overall patient survival. (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Digoxin-induced arrhythmias'.) For patients who take digoxin, periodic monitoring of serum levels should be performed, as higher serum digoxin levels have been associated with worse outcomes. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Monitoring serum digoxin'.) CLINICAL MANIFESTATIONS https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 6/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate The type and intensity of symptoms, if present, will vary depending upon the type and duration of the ventricular arrhythmia along with the patient s overall clinical status and significant comorbid conditions. Patients with ventricular premature beats who notice symptoms typically present with palpitations or dizziness, though the vast majority of patients experience few or no symptoms. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Symptoms'.) Patients with nonsustained ventricular tachycardia (NSVT) who notice symptoms typically present with one or more of palpitations, chest pain, shortness of breath, or syncope/presyncope. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'History and associated symptoms'.) Patients with sustained VT may briefly experience the onset of symptoms prior to the abrupt loss of consciousness and sudden cardiac arrest if VT results in hemodynamic collapse. For patients without immediate sudden cardiac arrest, the type and intensity of symptoms are similar to NSVT and will vary depending upon the rate and duration of sustained monomorphic VT along with the presence and severity of underlying heart disease and the presence or absence of significant comorbid conditions. (See "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'History and associated symptoms'.) Syncope in the setting of severe cardiomyopathy and HF requires special consideration. Although these patients may have syncope due to any of the usual causes, they are more likely than other patients to have an arrhythmic etiology. Thus, syncope in this population requires careful evaluation. This evaluation sometimes includes an electrophysiology study, both to exclude the possibility of a bradyarrhythmic cause and to attempt to induce ventricular arrhythmias. Patients in whom no etiology of syncope is found are said to have unexplained syncope. Extended ambulatory ECG monitoring (with an event recorder, patch monitoring, or implantable loop recorder) is often used to establish the etiology for unexplained syncope. Syncope is associated with an increased risk of sudden cardiac death in patients with HF and cardiomyopathy, even if an arrhythmic cause cannot be identified [31-34]. (See 'Diagnostic evaluation' below.) Sleep disordered breathing (SDB), presenting as either obstructive sleep apnea or central sleep apnea syndrome (including Cheyne-Stokes breathing) occurs commonly in patients with HF and is associated with increased cardiac mortality. In a study of 283 patients with HF (170 with no or mild SDB, and 113 with untreated SDB) who already had an implantable cardioverter- https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 7/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate defibrillator (ICD), time periods to first monitored ventricular arrhythmias (VT or ventricular fibrillation) and to first appropriate ICD therapy were significantly shorter in patients with SDB [35]. (See "Sleep-disordered breathing in heart failure", section on 'Arrhythmias'.) DIAGNOSTIC EVALUATION An electrocardiogram (ECG) should be part of the standard evaluation for any patient with suspected premature ventricular complexes (PVCs), nonsustained ventricular tachycardia (NSVT), or sustained VT. The diagnostic evaluation beyond an ECG will vary depending upon the particular arrhythmia in question and the patient s prior investigations, but additional testing may include one or more of ambulatory ECG monitoring, exercise testing, echocardiography, and invasive electrophysiology (EP) studies. The diagnostic evaluation of PVCs, NSVT, and sustained VT is discussed in detail separately. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Additional testing' and "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'Diagnostic evaluation' and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Additional diagnostic evaluation'.) EP studies can demonstrate the mechanisms of induced or spontaneous arrhythmias and characterize the function of the sinus node, the AV node, and the His-Purkinje system. Thus, EP studies can assist in the diagnosis of unexplained symptoms (eg, palpitations or syncope) and arrhythmias. NSVT can be an indication for EP study and possible implantable cardioverter- defibrillator (ICD) therapy in selected patients with a prior myocardial infarction (MI) and ischemic cardiomyopathy who do not otherwise meet criteria for prophylactic ICD implantation. The ability to induce ventricular arrhythmias is not predictive of sudden cardiac death risk in patients with nonischemic cardiomyopathy. Thus, EP testing does not have a role in risk stratification in these patients. In contemporary patient management, however, EP studies are used only in a small minority of patients, typically in the following situations: Patients with structural heart disease and syncope of uncertain etiology (especially if NSVT is present). Patients with a remote MI and NSVT who do not otherwise meet criteria for prophylactic ICD implantation (eg, left ventricular ejection fraction [LVEF] 35 percent). Patients with nonischemic cardiomyopathy and NSVT who do not otherwise meet criteria for prophylactic ICD implantation (eg, LVEF 35 percent). https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 8/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Patients with cardiomyopathy felt to be at high risk, but who are in a "waiting period" prior to ICD implantation (eg, newly diagnosed nonischemic cardiomyopathy and NSVT). DIAGNOSIS The diagnosis of sustained ventricular tachycardia (VT) should be suspected in a patient who presents with either sudden cardiac arrest, syncope, or sustained palpitations, particularly in a patient with a known history of structural heart disease. The diagnosis of nonsustained VT (NSVT) or premature ventricular complexes (PVCs) is more commonly suspected in a patient with intermittent palpitations, which may or may not be associated with other symptoms. The diagnosis of sustained VT, NSVT, or PVCs is typically confirmed following review of an ECG acquired during the arrhythmia. The ECG in patients with VT (sustained or nonsustained) will show a wide QRS complex tachycardia often with the presence of AV dissociation (manifest as an atrial rate slower than the ventricular rate), while the ECG in patients with PVCs will show one or more isolated PVCs . (See "Wide QRS complex tachycardias: Approach to the diagnosis" and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Diagnosis'.) MANAGEMENT The management of ventricular arrhythmias in patients with heart failure (HF) and cardiomyopathy is multifaceted and includes: HF management Arrhythmia control Consideration of an implantable cardioverter-defibrillator (ICD) for primary or secondary prevention of sudden cardiac death (SCD) Heart failure therapy Patients with HF and ventricular arrhythmias should have their HF treated aggressively. Standard therapy for HF due to systolic dysfunction consists of the following: A beta blocker such as carvedilol, metoprolol succinate, or bisoprolol An angiotensin receptor neprilysin inhibitor (ARNI), angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) An aldosterone antagonist in selected patients Diuretics if there is evidence of fluid overload or to prevent recurrent fluid overload https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 9/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate In addition, digoxin and intravenous inotropic agents (eg, milrinone, dobutamine) are occasionally used for acute symptom control, while diuretics are given for congestive symptoms. Many of these drugs can affect the incidence of arrhythmic death in patients with HF or cardiomyopathy. Some of the key points of various HF therapies will be discussed here, while more extended discussions can be found in the related topics. Beta blockers A substantial part of the survival benefit seen with beta blockers in patients with HF is due to a significant reduction in SCD [36-38]. As examples, there were significantly fewer SCDs in trials using carvedilol. In the MERIT-HF trial, there were significantly fewer SCDs (3.9 versus 6.6 percent) and fewer deaths from worsening of HF (1.5 versus 2.9 percent) with metoprolol compared with placebo, while in CIBIS-II, the survival benefit from beta blocker therapy was primarily due to a reduction in SCD (3.6 versus 6.3 percent), with only a nonsignificant trend toward fewer deaths from HF [36]. ACE inhibitors and ARBs ACE inhibitors improve survival in all stages of HF. However, there are conflicting data as to whether ACE inhibitors reduce SCD. A meta-analysis of trials of 15,104 patients within 14 days of an acute myocardial infarction found that ACE inhibitor therapy modestly but significantly reduced the risk of SCD (odds ratio 0.80, absolute benefit approximately 1.4 percent) [39]. However, as noted above, 45 percent of patients who died suddenly in AIRE had severe or worsening HF prior to their death, and only 39 percent of sudden deaths were thought to be due to arrhythmia [40]. The ARBs appear to be as or perhaps slightly less beneficial than ACE inhibitors in patients with HF [41]. The major ARB trial CHARM noted a clear survival benefit but did not report data on SCD [42]. ELITE II, which directly compared losartan with captopril, found a higher rate of SCD with losartan that was not statistically significant [41]. This might suggest that ARBs alone are unlikely to have a major impact on SCD in HF patients. Conversely, however, the addition of ARB to ACE inhibitor therapy in patients with HF in the CHARM-Added trial was found to reduce the rate of SCD, as well as the rate of death from worsening HF [43]. Angiotensin receptor neprilysin inhibitors (ARNI) For some patients, an ARNI such as sacubitril-valsartan can be substituted in place of ACE inhibitor (or single-agent ARB) therapy for patients who have tolerated an ACE inhibitor or ARB. However, some experts recommend the ARNI sacubitril-valsartan as initial oral therapy (in place of ACE inhibitor or single-agent ARB) in hemodynamically stable patients. Aldosterone antagonists The aldosterone antagonists spironolactone and eplerenone significantly reduce overall mortality and SCD in patients with advanced HF [44,45]. They https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 10/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate also reduce the frequency of VPBs and nonsustained ventricular tachycardia (NSVT) [46]. These benefits may reflect a reduction in aldosterone effect on the heart and/or the maintenance of a higher serum potassium concentration. Cardiac resynchronization therapy Cardiac resynchronization therapy appears to reduce the incidence of ventricular tachyarrhythmias in patients with HF and cardiomyopathy. This is discussed in greater detail separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Arrhythmia control The initial management of a patient with sustained VT depends on the hemodynamic stability of the patient ( algorithm 1). Emergency management is required in unstable patients, typically with electrical cardioversion and occasionally antiarrhythmic medications. Additional time may be spent determining the etiology and treating any underlying precipitating factors in patients who are hemodynamically stable (although treatment for such patients should usually be promptly administered). Subsequent management of the patient will be guided by the initial presentation (ie, hemodynamically stable or unstable) and the initial approach to treatment [47]. A full discussion of the treatment of sustained VT is presented separately. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Treatment'.) Patients with symptomatic NSVT or PVCs should usually be treated with beta blockers as the initial therapy. While beta blockers do not usually reduce the frequency of these arrhythmias, they may be effective for reducing or eliminating symptoms. For patients who have very frequent, symptomatic NSVT or PVCs not controlled by medications, catheter ablation can be effective for reducing or eliminating associated symptoms. Antiarrhythmic medications are generally reserved for patients with severely symptomatic NSVT despite therapy with beta blockers who are not candidates for catheter ablation of the VT. A full discussion of the treatment of NSVT and PVCs is presented separately. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'Treatment'.) Prevention of SCD Patients who have been resuscitated from sudden cardiac arrest (due to either sustained VT or ventricular fibrillation) are candidates for, and generally should receive, an ICD for secondary prevention of SCD. Patients who present with sustained VT in the setting of cardiomyopathy and patients with NSVT and/or syncope and inducible sustained ventricular arrhythmia at electrophysiology testing should also generally receive an ICD for secondary prevention. Additionally, many patients with HF and cardiomyopathy (and left ventricular ejection fraction 35 percent) are candidates for ICD implantation as primary prevention of SCD. Secondary and primary prevention of SCD in HF and cardiomyopathy are discussed separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 11/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Heart failure in adults" and "Society guideline links: Ventricular arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Ventricular tachycardia (The Basics)") SUMMARY AND RECOMMENDATIONS Background Ventricular arrhythmias, including premature ventricular complexes (PVCs), ventricular tachycardia (VT), and ventricular fibrillation (VF), are common in patients with heart failure (HF) and cardiomyopathy, occurring in up to 95 percent of this population. (See 'Types of arrhythmia' above.) Pathogenesis Multiple factors may be responsible for ventricular arrhythmias in patients with HF and cardiomyopathy, including underlying structural heart disease, mechanical factors, neurohormonal factors, electrolyte disturbances, myocardial ischemia, and medications. (See 'Pathogenesis' above.) https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 12/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Clinical manifestations The type and intensity of symptoms, if present, will vary depending upon the type and duration of the ventricular arrhythmia along with the patient s overall clinical status and significant comorbid conditions. Patients may experience few or no symptoms with PVCs or short runs of nonsustained VT, or may present with syncope or sudden cardiac arrest due to sustained VT or VF. (See 'Clinical manifestations' above.) Diagnostic evaluation An ECG should be part of the standard evaluation for any patient with suspected PVCs, VT, or VF. The diagnostic evaluation beyond an ECG will vary depending upon the particular arrhythmia in question and the patient s prior investigations, but additional testing may include one or more of ambulatory ECG monitoring, exercise testing, echocardiography, and invasive electrophysiology studies. (See 'Diagnostic evaluation' above.) Management The management of ventricular arrhythmias in patients with HF and cardiomyopathy is multifaceted and includes HF therapy, arrhythmia control, and consideration of an implantable cardioverter-defibrillator (ICD) for primary or secondary prevention of sudden cardiac death (SCD). Heart failure Standard therapy for HF due to systolic dysfunction consists of a beta blocker; an angiotensin receptor neprilysin inhibitor, angiotensin converting enzyme inhibitor, or an angiotensin II receptor blocker (ARB); and in selected patients, an aldosterone antagonist. Digoxin and other inotropic agents are occasionally used for symptom control, while diuretics are given for congestive symptoms. (See 'Heart failure therapy' above.) Arrhythmia control The initial management of a patient with sustained VT depends on the hemodynamic stability of the patient ( algorithm 1), with emergency management required in unstable patients. Subsequent management of VT will be guided by the initial presentation (ie, hemodynamically stable or unstable) and the initial approach to treatment. Patients with symptomatic NSVT or PVCs should usually be treated with beta blockers as the initial therapy. (See 'Arrhythmia control' above.) Prevention of SCD Patients who have been resuscitated from sudden cardiac arrest (due to either sustained VT or VF) are candidates for, and generally should receive, an ICD for secondary prevention of SCD. Additionally, many patients with HF and cardiomyopathy (and left ventricular ejection fraction 35 percent) are candidates for ICD implantation as primary prevention of SCD. (See "Secondary prevention of sudden https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 13/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Hynes BJ, Luck JC, Wolbrette DL, et al. Arrhythmias in Patients with Heart Failure. Curr Treat Options Cardiovasc Med 2002; 4:467. 2. Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardiol 1986; 57:3B. 3. Holmes J, Kubo SH, Cody RJ, Kligfield P. Arrhythmias in ischemic and nonischemic dilated cardiomyopathy: prediction of mortality by ambulatory electrocardiography. Am J Cardiol 1985; 55:146. 4. Teerlink JR, Jalaluddin M, Anderson S, et al. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. PROMISE (Prospective Randomized Milrinone Survival Evaluation) Investigators. Circulation 2000; 101:40. 5. Podrid PJ, Fogel RI, Fuchs TT. Ventricular arrhythmia in congestive heart failure. Am J Cardiol 1992; 69:82G. 6. von Olshausen K, Sch fer A, Mehmel HC, et al. Ventricular arrhythmias in idiopathic dilated cardiomyopathy. Br Heart J 1984; 51:195. 7. Meinertz T, Hofmann T, Kasper W, et al. Significance of ventricular arrhythmias in idiopathic dilated cardiomyopathy. Am J Cardiol 1984; 53:902. 8. Packer M. Lack of relation between ventricular arrhythmias and sudden death in patients with chronic heart failure. Circulation 1992; 85:I50. 9. Singh SN, Fisher SG, Carson PE, Fletcher RD. Prevalence and significance of nonsustained ventricular tachycardia in patients with premature ventricular contractions and heart failure treated with vasodilator therapy. Department of Veterans Affairs CHF STAT Investigators. J Am Coll Cardiol 1998; 32:942. https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 14/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate 10. Grimm W, Hoffmann J, Menz V, et al. Significance of accelerated idioventricular rhythm in idiopathic dilated cardiomyopathy. Am J Cardiol 2000; 85:899. 11. Poll DS, Marchlinski FE, Buxton AE, et al. Sustained ventricular tachycardia in patients with idiopathic dilated cardiomyopathy: electrophysiologic testing and lack of response to antiarrhythmic drug therapy. Circulation 1984; 70:451. 12. Milner PG, Dimarco JP, Lerman BB. Electrophysiological evaluation of sustained ventricular tachyarrhythmias in idiopathic dilated cardiomyopathy. Pacing Clin Electrophysiol 1988; 11:562. 13. White CW, Mirro MJ, Lund DD, et al. Alterations in ventricular excitability in conscious dogs during development of chronic heart failure. Am J Physiol 1986; 250:H1022. 14. Dean JW, Lab MJ. Arrhythmia in heart failure: role of mechanically induced changes in electrophysiology. Lancet 1989; 1:1309. 15. Koilpillai C, Qui ones MA, Greenberg B, et al. Relation of ventricular size and function to heart failure status and ventricular dysrhythmia in patients with severe left ventricular dysfunction. Am J Cardiol 1996; 77:606. 16. Gottlieb SS, Baruch L, Kukin ML, et al. Prognostic importance of the serum magnesium

condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Ventricular tachycardia (The Basics)") SUMMARY AND RECOMMENDATIONS Background Ventricular arrhythmias, including premature ventricular complexes (PVCs), ventricular tachycardia (VT), and ventricular fibrillation (VF), are common in patients with heart failure (HF) and cardiomyopathy, occurring in up to 95 percent of this population. (See 'Types of arrhythmia' above.) Pathogenesis Multiple factors may be responsible for ventricular arrhythmias in patients with HF and cardiomyopathy, including underlying structural heart disease, mechanical factors, neurohormonal factors, electrolyte disturbances, myocardial ischemia, and medications. (See 'Pathogenesis' above.) https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 12/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Clinical manifestations The type and intensity of symptoms, if present, will vary depending upon the type and duration of the ventricular arrhythmia along with the patient s overall clinical status and significant comorbid conditions. Patients may experience few or no symptoms with PVCs or short runs of nonsustained VT, or may present with syncope or sudden cardiac arrest due to sustained VT or VF. (See 'Clinical manifestations' above.) Diagnostic evaluation An ECG should be part of the standard evaluation for any patient with suspected PVCs, VT, or VF. The diagnostic evaluation beyond an ECG will vary depending upon the particular arrhythmia in question and the patient s prior investigations, but additional testing may include one or more of ambulatory ECG monitoring, exercise testing, echocardiography, and invasive electrophysiology studies. (See 'Diagnostic evaluation' above.) Management The management of ventricular arrhythmias in patients with HF and cardiomyopathy is multifaceted and includes HF therapy, arrhythmia control, and consideration of an implantable cardioverter-defibrillator (ICD) for primary or secondary prevention of sudden cardiac death (SCD). Heart failure Standard therapy for HF due to systolic dysfunction consists of a beta blocker; an angiotensin receptor neprilysin inhibitor, angiotensin converting enzyme inhibitor, or an angiotensin II receptor blocker (ARB); and in selected patients, an aldosterone antagonist. Digoxin and other inotropic agents are occasionally used for symptom control, while diuretics are given for congestive symptoms. (See 'Heart failure therapy' above.) Arrhythmia control The initial management of a patient with sustained VT depends on the hemodynamic stability of the patient ( algorithm 1), with emergency management required in unstable patients. Subsequent management of VT will be guided by the initial presentation (ie, hemodynamically stable or unstable) and the initial approach to treatment. Patients with symptomatic NSVT or PVCs should usually be treated with beta blockers as the initial therapy. (See 'Arrhythmia control' above.) Prevention of SCD Patients who have been resuscitated from sudden cardiac arrest (due to either sustained VT or VF) are candidates for, and generally should receive, an ICD for secondary prevention of SCD. Additionally, many patients with HF and cardiomyopathy (and left ventricular ejection fraction 35 percent) are candidates for ICD implantation as primary prevention of SCD. (See "Secondary prevention of sudden https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 13/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Hynes BJ, Luck JC, Wolbrette DL, et al. Arrhythmias in Patients with Heart Failure. Curr Treat Options Cardiovasc Med 2002; 4:467. 2. Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardiol 1986; 57:3B. 3. Holmes J, Kubo SH, Cody RJ, Kligfield P. Arrhythmias in ischemic and nonischemic dilated cardiomyopathy: prediction of mortality by ambulatory electrocardiography. Am J Cardiol 1985; 55:146. 4. Teerlink JR, Jalaluddin M, Anderson S, et al. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. PROMISE (Prospective Randomized Milrinone Survival Evaluation) Investigators. Circulation 2000; 101:40. 5. Podrid PJ, Fogel RI, Fuchs TT. Ventricular arrhythmia in congestive heart failure. Am J Cardiol 1992; 69:82G. 6. von Olshausen K, Sch fer A, Mehmel HC, et al. Ventricular arrhythmias in idiopathic dilated cardiomyopathy. Br Heart J 1984; 51:195. 7. Meinertz T, Hofmann T, Kasper W, et al. Significance of ventricular arrhythmias in idiopathic dilated cardiomyopathy. Am J Cardiol 1984; 53:902. 8. Packer M. Lack of relation between ventricular arrhythmias and sudden death in patients with chronic heart failure. Circulation 1992; 85:I50. 9. Singh SN, Fisher SG, Carson PE, Fletcher RD. Prevalence and significance of nonsustained ventricular tachycardia in patients with premature ventricular contractions and heart failure treated with vasodilator therapy. Department of Veterans Affairs CHF STAT Investigators. J Am Coll Cardiol 1998; 32:942. https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 14/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate 10. Grimm W, Hoffmann J, Menz V, et al. Significance of accelerated idioventricular rhythm in idiopathic dilated cardiomyopathy. Am J Cardiol 2000; 85:899. 11. Poll DS, Marchlinski FE, Buxton AE, et al. Sustained ventricular tachycardia in patients with idiopathic dilated cardiomyopathy: electrophysiologic testing and lack of response to antiarrhythmic drug therapy. Circulation 1984; 70:451. 12. Milner PG, Dimarco JP, Lerman BB. Electrophysiological evaluation of sustained ventricular tachyarrhythmias in idiopathic dilated cardiomyopathy. Pacing Clin Electrophysiol 1988; 11:562. 13. White CW, Mirro MJ, Lund DD, et al. Alterations in ventricular excitability in conscious dogs during development of chronic heart failure. Am J Physiol 1986; 250:H1022. 14. Dean JW, Lab MJ. Arrhythmia in heart failure: role of mechanically induced changes in electrophysiology. Lancet 1989; 1:1309. 15. Koilpillai C, Qui ones MA, Greenberg B, et al. Relation of ventricular size and function to heart failure status and ventricular dysrhythmia in patients with severe left ventricular dysfunction. Am J Cardiol 1996; 77:606. 16. Gottlieb SS, Baruch L, Kukin ML, et al. Prognostic importance of the serum magnesium concentration in patients with congestive heart failure. J Am Coll Cardiol 1990; 16:827. 17. Cooper HA, Dries DL, Davis CE, et al. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999; 100:1311. 18. Stambler BS, Wood MA, Ellenbogen KA. Sudden death in patients with congestive heart failure: future directions. Pacing Clin Electrophysiol 1992; 15:451. 19. Holmes JR, Kubo SH, Cody RJ, Kligfield P. Milrinone in congestive heart failure: observations on ambulatory ventricular arrhythmias. Am Heart J 1985; 110:800. 20. Anderson JL, Askins JC, Gilbert EM, et al. Occurrence of ventricular arrhythmias in patients receiving acute and chronic infusions of milrinone. Am Heart J 1986; 111:466. 21. DiBianco R, Shabetai R, Kostuk W, et al. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989; 320:677. 22. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991; 325:1468. 23. Dies F, Krell MJ, Whitlow P, et al. Intermittent dobutamine in ambulatory outpatients with chronic cardiac failure. Circulation 1986; 74(Suppl II):II. 24. Bouvy ML, Heerdink ER, De Bruin ML, et al. Use of sympathomimetic drugs leads to increased risk of hospitalization for arrhythmias in patients with congestive heart failure. https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 15/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Arch Intern Med 2000; 160:2477. 25. Gradman A, Deedwania P, Cody R, et al. Predictors of total mortality and sudden death in mild to moderate heart failure. Captopril-Digoxin Study Group. J Am Coll Cardiol 1989; 14:564. 26. Moss AJ, Davis HT, Conard DL, et al. Digitalis-associated cardiac mortality after myocardial infarction. Circulation 1981; 64:1150. 27. Bigger JT Jr, Fleiss JL, Rolnitzky LM, et al. Effect of digitalis treatment on survival after acute myocardial infarction. Am J Cardiol 1985; 55:623. 28. Ryan TJ, Bailey KR, McCabe CH, et al. The effects of digitalis on survival in high-risk patients with coronary artery disease. The Coronary Artery Surgery Study (CASS). Circulation 1983; 67:735. 29. Muller JE, Turi ZG, Stone PH, et al. Digoxin therapy and mortality after myocardial infarction. Experience in the MILIS Study. N Engl J Med 1986; 314:265. 30. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525. 31. Middlekauff HR, Stevenson WG, Stevenson LW, Saxon LA. Syncope in advanced heart failure: high risk of sudden death regardless of origin of syncope. J Am Coll Cardiol 1993; 21:110. 32. Fonarow GC, Feliciano Z, Boyle NG, et al. Improved survival in patients with nonischemic advanced heart failure and syncope treated with an implantable cardioverter-defibrillator. Am J Cardiol 2000; 85:981. 33. Grimm W, Hoffmann J J , M ller HH, Maisch B. Implantable defibrillator event rates in patients with idiopathic dilated cardiomyopathy, nonsustained ventricular tachycardia on Holter and a left ventricular ejection fraction below 30%. J Am Coll Cardiol 2002; 39:780. 34. Knight BP, Goyal R, Pelosi F, et al. Outcome of patients with nonischemic dilated cardiomyopathy and unexplained syncope treated with an implantable defibrillator. J Am Coll Cardiol 1999; 33:1964. 35. Bitter T, Westerheide N, Prinz C, et al. Cheyne-Stokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter-defibrillator therapies in patients with congestive heart failure. Eur Heart J 2011; 32:61. 36. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001. 37. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 16/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate 1996; 334:1349. 38. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353:9. 39. Domanski MJ, Exner DV, Borkowf CB, et al. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol 1999; 33:598. 40. Cleland JG, Erhardt L, Murray G, et al. Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators. Eur Heart J 1997; 18:41. 41. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355:1582. 42. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362:759. 43. Solomon SD, Wang D, Finn P, et al. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation 2004; 110:2180. 44. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709. 45. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309. 46. Ramires FJ, Mansur A, Coelho O, et al. Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol 2000; 85:1207. 47. Santangeli P, Rame JE, Birati EY, Marchlinski FE. Management of Ventricular Arrhythmias in Patients With Advanced Heart Failure. J Am Coll Cardiol 2017; 69:1842. Topic 968 Version 29.0 https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 17/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate GRAPHICS Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or infarction, especially with prominent T-wave inversions GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders particularly hypokalemia and hypomagnesemia Starvation Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga (ibogaine), licorice extract in overuse via Intracranial disease Hypothyroidism electrolyte disturbances Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate insecticides AV block: Second or third degree Medications* High risk Adagrasib Cisaparide (restricted availability) Lenvatinib Selpercatinib Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine (intracoronary) Vandetanib Dofetilide Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 18/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Capecitabine Entrectinib Isoflurane Quetiapine Carbetocin Erythromycin Levofloxacin (systemic) Ribociclib Certinib Escitalopram Risperidone Lofexidine Chloroquine Etelcalcetide Saquinavir Meglumine antimoniate Citalopram Fexinidazole Sevoflurane Clarithromycin Flecainide Sparfloxacin Midostaurin Clofazimine Floxuridine Sunitinib Moxifloxacin Clomipramine Fluconazole Tegafur Nilotinib Clozapine Fluorouracil (systemic) Terbutaline Olanzapine Crizotinib Thioridazine Ondansetrol (IV > oral) Flupentixol Dabrafenib Toremifene Gabobenate dimeglumine Dasatinib Vemurafenib Osimertinib Deslurane Voriconazole Oxytocin Gemifloxacin Domperidone Pazopanib Gilteritinib Doxepin Pentamidine Halofantrine Doxifluridine Pilsicainide Haloperidol (oral) Pimozide Imipramine Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole (systemic) Romidepsin Anagrelide Foscarnet Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- lumefantrine Glasdegib Mizolastine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine (rare reports) Nortriptyline Benperidol Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus (systemic) Olodaterol Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 19/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Degarelix Lefamulin Pasireotide Triclabendazole Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. [1,2] . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 20/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 21/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Algorithm for initial treatment of SMVT in responsive patients with a pulse SMVT: sustained monomorphic ventricular tachycardia; CV: cardioversion. Hemodynamically unstable patients have evidence of hemodynamic compromise, such as hypotension, altered mental status, chest pain, or heart failure. Hemodynamically stable patients should have none of these findings. Initial choice of pharmacologic agents includes: Intravenous lidocaine (1 to 1.5 mg/kg [typically 75 to 100 mg] at a rate of 25 to 50 mg/minute; lower doses of 0.5 to 0.75 mg/kg can be repeated every 5 to 10 minutes as needed), which may be more effective in the setting of acute myocardial ischemia or infarction Intravenous procainamide (20 to 50 mg/minute until arrhythmia terminates or a maximum dose of 17 mg/kg is administered) Intravenous amiodarone (150 mg IV over 10 minutes, followed by 1 mg/minute for the next six hours; bolus can be repeated if VT recurs) Electrical cardioversion should be synchronized if possible, using 100-joule biphasic shock or 200- joule monophasic shock. If first shock is unsuccessful, energy level should be escalated on subsequent shocks. Conditions associated with SMVT include myocardial ischemia, electrolyte disturbances (eg, hypokalemia, hypomagnesemia), drug-related proarrhythmia, and heart failure. https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 22/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Graphic 108831 Version 1.0 https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 23/24 7/6/23, 3:10 PM Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Wilson S Colucci, MD Grant/Research/Clinical Trial Support: Merck [Heart failure]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/ventricular-arrhythmias-overview-in-patients-with-heart-failure-and-cardiomyopathy/print 24/24

7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Wearable cardioverter-defibrillator : Mina K Chung, MD : Richard L Page, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 22, 2023. INTRODUCTION The implantable cardioverter-defibrillator (ICD) has been shown to improve survival from sudden cardiac arrest and to improve overall survival in several populations at high risk for sudden cardiac death (SCD). However, there remain situations in which implantation of an ICD is immediately not feasible (eg, patients with an active infection), may be of uncertain benefit, may not be covered by third-party payers (eg, early post-myocardial infarction, patients with limited life expectancy or new onset systolic heart failure), or when an ICD must be removed (eg, infection). In cases where ICD implantation must be deferred, a wearable cardioverter-defibrillator (WCD) offers an alternative approach for the prevention of SCD. The WCD (LifeVest [Zoll Medical Corporation] or Assure [Kestra Medical Technologies, Inc]) is an external device capable of automatic detection and defibrillation of ventricular tachycardia and ventricular fibrillation ( picture 1 and figure 1). While the WCD can be worn for years, typically the device is used for several months as temporary protection against SCD. The indications, efficacy, and limitations of the wearable cardioverter-defibrillator will be discussed here. Detailed discussions of the roles of the ICD are presented separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 1/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate DESCRIPTION AND FUNCTIONS OF THE WCD The WCD is an external device capable of automatic detection and defibrillation of ventricular tachycardia (VT) or ventricular fibrillation (VF) [1]. The approved devices do not have pacing capabilities and therefore are unable to provide therapy for bradycardic events or antitachycardic pacing. Wearing the WCD The WCD is composed of dry, nonadhesive monitoring electrodes, defibrillation electrodes incorporated into a chest strap or vest assembly, and a defibrillation battery and monitor unit ( picture 1). The Assure WCD garment has two styles designed for female and male body habitus and different sizes. The monitoring electrodes are positioned circumferentially around the chest and provide two to four surface electrocardiogram (ECG) leads. The defibrillation electrodes are positioned in a vest assembly for apex-posterior defibrillation. Proper fitting is required to achieve adequate skin contact to avoid noise and frequent alarms. Detection and delivery of shocks Arrhythmia detection by the WCD is programmed using ECG rate and morphology criteria. The system is programmed to define ventricular arrhythmias when the ventricular heart rate exceeds a preprogrammed rate threshold with an ECG morphology that does not match a baseline electrocardiographic template. Typical programming is reflected in default device settings: VT detection 150 beats per minute (LifeVest) or 170 beats per minute (Assure). Programmable ranges for LifeVest are 120 to 250 beats per minute, not to exceed the VF detection rate; for Assure they are, 130 to the programmed VF threshold minus 10 beats per minute. VF detection 200 beats per minute. Programmable ranges are 120 to 250 beats per minute (LifeVest) or 180 to 220 beats per minute (Assure). Treatment with 150 joules (LifeVest) or 170 joules (Assure) shocks for up to five shocks. For the Zoll LifeVest WCD, the tachycardia detection rate is programmable for VF between 120 and 250 beats per minute, and the VF shock delay can be programmed from 25 to 55 seconds. The VT detection rate is programmable between 120 bpm to the VF setting with a VT shock delay https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 2/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate of 60 to 180 seconds. VT signals can allow synchronized shock delivery on the R wave, but if the R wave cannot be identified, unsynchronized shocks will be delivered. For the Kestra Assure WCD, the tachycardia detection rate is programmable for VF between 180 and 220 beats per minute, and for VT detection programmable from 130 beats per minute up to the programmed VF rate: 10 beats per minute. Detection utilizes a segment-based analysis of 4.8-second segments that continuously overlap by 2.4 seconds. VF confirmation requires two out of two segments (approximately 5 seconds), and VT confirmation requires 15 out of 19 segments (approximately 45 seconds). The first and last segments must be in the programmed treatment zone. If an arrhythmia is detected, vibration and audible alarms are initiated. A flashing red light and shock icon are activated on the Assure monitor. Although shocks may be transmitted to bystanders in physical contact with the patient being shocked by a WCD, a voice cautions the patient and bystanders to the impending shock. Patients are trained to hold a pair of response buttons on the LifeVest device or press the alert button on the Assure device during these alarms to avoid receiving a shock while awake. A patient's response serves as a test of consciousness; if no response occurs and a shock is indicated, the device charges, extrudes gel from the defibrillation electrodes, and delivers up to five biphasic shocks at preprogrammed energy levels (ranging from 75 to 150 joules for the LifeVest device and 170 joules for the Assure device). The LifeVest device includes a default sleep time from 11 PM to 6 AM, programmable in one-hour increments, which allows additional time for deep sleepers, if they awaken, to abort shocks. Efficacy in terminating VT/VF Shock efficacy with the WCD appears to be similar to that reported with implantable cardioverter-defibrillators (ICDs). However, sudden cardiac death may still occur in those not wearing the device, those with improper positioning of the device, due to bystander interference, due to the inability of the WCD to detect the ECG signal, or due to bradyarrhythmias. These results highlight the importance of patient education and promotion of compliance while using the WCD. The efficacy of the WCD has been tested for induced ventricular tachyarrhythmias as well as for spontaneous events during clinical trials and postmarket studies. When worn properly, the WCD appears to be as effective as an ICD for the termination of VT and VF, with successful shocks occurring in up to 100 percent of cases [1-7]. In a study of induced VT/VF in the electrophysiology laboratory, the WCD successfully detected and terminated VT/VF with 100 percent first-shock success [2]. The following large registry studies of patients with WCDs showed high shock success rates: https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 3/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate In a US postmarket study of 8453 patients who wore a WCD after myocardial infarction, 146 VT/VF events occurred in 133 patients, and the overall shock success rate for terminating VT/VF was 82 percent, with 91 percent immediate survival [6]. In this study, shock success resulting in survival was 95 percent in revascularized and 84 percent in non-revascularized patients, suggesting that lower efficacy rates may be related to ischemic events. In the WEARIT-II registry of 2000 patients who wore a WCD for a median of 90 days, 120 episodes of sustained VT/VF were seen in 41 patients [7]. For 90 of the episodes, patients pressed the response buttons to abort shock delivery, with the majority of sustained VT episodes terminating spontaneously following use of the response button. All of the remaining 30 VT/VF episodes in 22 different patients were successfully terminated with a single shock. Among 6043 German patients who wore the device between April 2010 and October 2013, 94 patients were shocked for sustained VT/VF, with the WCD successfully terminating VT/VF in 88 patients (94 percent) [8]. The WCD appears equally efficacious among patients with and without myocardial ischemia immediately prior to VT/VF detection and shock (as defined by 0.1 mV ST-segment changes on ECG), with first shock termination rates of 96 percent in both groups [9]. Avoiding inappropriate shocks When electronic noise occurs, which may potentially be interpreted at VT or VF, the WCD emits a noise alarm. This electronic noise can often be minimized or eliminated by changing body position or tightening of the electrode belt, and shocks can be avoided by pushing the response buttons. While a dual-chamber ICD with an atrial lead would seemingly have greater ability to discriminate between supraventricular tachycardia (SVT) and VT, the incidence of inappropriate shocks due to atrial fibrillation, sinus tachycardia, or other supraventricular arrhythmias in clinical studies of WCDs has been low. The LifeVest WCD uses a two-channel proprietary vectorcardiogram morphology matching algorithm to prevent shocks during SVT if the QRS is unchanged, and inappropriate shocks can also be averted when the patient presses the response buttons. The Assure WCD uses a four-channel ECG with a single noise-free channel required for analysis and an algorithm that excludes noisy and low amplitude channels ( figure 2). (See 'Inappropriate shocks' below.) In a small study of the 60 patients with a permanent pacemaker, in which a variety of pacing modes (AAI, VVI, DDD) and configurations (unipolar, bipolar) were tested, unipolar DDD pacing triggered VT/VF detection in six patients (10 percent), while no other pacing modes or configurations triggered arrhythmia detection [10]. As such, patients whose pacemaker is https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 4/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate programmed to unipolar DDD pacing should be evaluated for pacemaker reprogramming to a bipolar mode prior to WCD usage. In a study of 130 patients with an ICD and fitted with an ASSURE WCD programmed for detection only and followed for 30 days, of 163 WCD-detected episodes, four were VT/VF and 159 were non-VT/VF with three false-positive shock alarm markers recorded, corresponding to a very low rate of inappropriate detection [11]. No ICD-recorded VT/VF episodes meeting WCD programmed criteria were missed. Median daily use was high at 23 hours. Bradycardia/asystole Neither of the approved WCDs deliver antibradycardic pacing, but they do record the ventricular rate when the heart rate decreases or asystole occurs: For the LifeVest device, asystole recordings are triggered when ventricular heart rates drop below 10 beats per minute or 16 seconds of asystole, and the device automatically records the event with 120 seconds preceding the onset. If using the secure website in conjunction with the WCD, alerts can be configured to prompt the healthcare provider that a patient is experiencing bradycardia or an asystole. For the Assure device, asystole is detected when there is no detected heart rate for >20 seconds (five of seven segments with heart rate 0 beats per minute or amplitude <100 uV); prolonged heart rates below 30 beats per minute may be detected as bradycardia. When asystole or bradycardia is detected, a loud alarm is triggered to attract bystanders and instruct them to call 911 and begin CPR if the patient is unconscious. The alert can be silenced by pressing the alert button or it resolves when a heart rate >30 bpm is detected for >30 seconds. Storage of ECGs and compliance data In addition to delivering therapeutic shocks for life- threatening ventricular arrhythmias, the WCD stores data regarding tachyarrhythmias, bradycardia/asystole (see 'Bradycardia/asystole' above), patient compliance with the device, and noise or interference with its proper functioning. Arrhythmia recordings from the WCD are available for clinician review once stored data are transmitted via a modem to the manufacturer's network. Treatments, patient compliance, ECG records, and system performance can be viewed using a secure website. The WCD stores ECGs from arrhythmia detections, usage, and compliance trends: For the LifeVest system: The system is programmed to define ventricular arrhythmias when the ventricular heart rate exceeds a preprogrammed rate threshold with an ECG morphology that does not match a baseline ECG template. The monitoring software captures 30 seconds of ECG https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 5/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate signal prior to the determination of VT or VF and continuously records until 15 seconds after the alarms stop. Patients can perform manual recordings by pressing response buttons for three seconds, which records the prior 30 seconds plus the next 15 seconds. Data on patient compliance, ECG signal quality, alarm history, and noise occurrence are recorded, including time/date stamps for device on/off switching, monitor connection to the electrodes, and electrode-to-skin contact. Compliance may be determined by assessing the time that the user had the device turned on, the belt connected, and at least one monitoring electrode contacting the skin. For the Assure system: Up to 120 seconds of data are recorded prior to arrhythmia onset detection, confirmation, and therapy are detected, and up to 60 seconds are detected after rate recovery or conversion. Patient activity is also stored, utilizing an accelerometer located in the hub component in the middle of the patient's back. Daily usage is recorded in one-minute increments when the sensors are in contact with the patient's skin. INDICATIONS The WCD is indicated as temporary therapy for patients with a high risk for sudden cardiac death (SCD) [1,12-16]. Our recommended approach is consistent with that of the 2016 science advisory from the American Heart Association (also endorsed by the Heart Rhythm Society) and the 2017 AHA/ACC/HRS guideline [16,17]. Examples of persons who may benefit from the temporary use of a WCD include: Patients with a permanent implantable cardioverter-defibrillator (ICD) that must be explanted, or those with a delay in implanting a newly indicated ICD (eg, due to systemic infection). (See 'Bridge to indicated or interrupted ICD therapy' below.) Patients with reduced left ventricular (LV) systolic function (LVEF 35 percent) who have had a myocardial infarction (MI) within the past 40 days. (See 'Early post-MI patients with LV dysfunction' below.) https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 6/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Patients with reduced LV systolic function (LVEF 35 percent) who have undergone coronary revascularization with coronary artery bypass graft (CABG) surgery in the past three months. (See 'Patients with LV dysfunction early after coronary revascularization' below.) Patients with newly diagnosed nonischemic cardiomyopathy with severely reduced LV systolic function (LVEF 35 percent) that is potentially reversible. (See 'Newly diagnosed nonischemic cardiomyopathy' below.) Patients with severe heart failure who are awaiting heart transplantation. (See 'Bridge to heart transplant' below.) A 2019 systematic review and meta-analysis, which included 33,242 WCD users from 28 studies (the randomized VEST trial and 27 nonrandomized studies), assessed the likelihood of WCD therapy in a broad range of patient populations, including both primary/secondary prevention and ischemic/nonischemic cardiomyopathy patients. The incidence of appropriate shocks was 5 per 100 persons over three months (1.67 percent per month) with mortality while wearing the device noted to be 0.7 per 100 persons over three months [18]. Bridge to indicated or interrupted ICD therapy In some patients with an indication for ICD placement, implantation of the device may be delayed due to comorbid conditions, including [16,17]: Infection Recovery from surgery Lack of vascular access In addition, patients with a preexisting ICD who develop device infection or endocarditis usually require system extraction to effectively treat the infection. Unless the patient is pacemaker dependent, reimplantation in many patients is deferred until the infection is completely cleared after an appropriate course of antibiotics. The WCD may provide protection against ventricular tachyarrhythmias during these periods until an ICD can be implanted [4,5,16]. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".) In a review of 8058 patients who were prescribed the WCD after ICD removal because of infection, median time to reimplantation was 50 days, and 334 (4 percent) experienced 406 ventricular tachycardia/ventricular fibrillation (VT/VF) events, with 348 events treated by the WCD and 54 treatments averted by conscious patients [19]. The one-year cumulative event rate was 10 percent. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 7/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Early post-MI patients with LV dysfunction Among patients with LV ejection fraction (LVEF) 35 percent who are less than 40 days post-MI, there are conflicting data on the benefits of a WCD for primary prevention against SCD. Following discussion of the potential benefits and risks, use of the WCD within this 40-day window could be considered among motivated patients who have LVEF 35 percent and in New York Heart Association (NYHA) functional class II or III, or LVEF <30 percent and in NYHA class I, as these patients would be candidates for ICD implantation after 40 days [16,17]. Patients should be reminded of the importance of compliance with the WCD in order to optimize any potential benefits on prevention of arrhythmic death. Reevaluation of LVEF should occur one to three months after the MI. If LVEF remains 35 percent on follow-up assessment, while the patient is taking appropriate medical therapy, ICD implantation is indicated [16]. After ICD implantation, use of the WCD would be discontinued. Despite advances in the treatment of acute coronary syndromes with early revascularization and effective medical therapies that have reduced mortality, some residual risk of SCD remains in the early period following an MI, especially in the setting of severely reduced LVEF (2.3 percent/month for patients with LVEF 30 percent) [4,20]. However, there are conflicting data on the utility of an ICD in the early post-MI period. In an analysis of 712 patients with a history of MI who were enrolled in the SCD-HeFT trial, there was no evidence of differential mortality benefit with ICDs as a function of time after MI, indicating that the potential benefit of ICD therapy is not restricted only to remote MIs [21]. In the DINAMIT (674 patients) and IRIS (898 patients) trials, which randomized patients with LVEF 35 percent to either early ICD implantation 6 to 40 days after acute MI or medical therapy alone, there was no significant improvement in overall mortality [22,23]. Despite a reduction in arrhythmic deaths among patients with an ICD, there was a higher risk of nonarrhythmic deaths during this early period, resulting in similar overall mortality rates. Professional society guidelines do not recommend ICD implantation for primary prevention of SCD within 40 days of acute MI [16]. However, due to the risk of SCD in some patients early post- MI, the WCD has been studied in this patient population. In the VEST trial, 2302 patients with an acute MI and LVEF 35 percent were randomly assigned (within seven days of hospital discharge) in a 2:1 ratio to wear the WCD in addition to usual medical treatment (1524 patients) or to receive standard medical treatment alone (778 patients) [24]. Over an average follow-up of 84 days, patients in the https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 8/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate WCD group had no significant improvement in the primary outcome of arrhythmic death (25 patients [1.6 percent] versus 19 patients [2.4 percent] with medical therapy alone; relative risk [RR] 0.67; 95% CI 0.37-1.21). Compliance with medical therapy was excellent in both groups, likely contributing to fewer than expected events and the trial possibly being underpowered. However, compliance with WCD usage was markedly lower than expected (median and mean daily wear times of 18 and 14 hours, respectively), with over half of patients assigned to the WCD not wearing it by the end of the 90-day study. Among 48 total deaths in the WCD group, only 12 patients (25 percent) were wearing the WCD at the time of death. Asystolic events not treated by the WCD likely also contributed to the nonsignificant primary outcome results of the trial. A subsequent as-treated and per- protocol analysis of VEST (censoring participants at the time they stopped wearing the WCD) reported a significant reduction in total and arrhythmic mortality among participants wearing the WCD compared with control participants (total mortality hazard ratio 0.25; CI 0.13-0.43; arrhythmic death hazard ratio 0.09; CI 0.02-0.39) [25]. The VEST study also demonstrates the challenges in trying to improve mortality in the post- MI population. Not all patients will survive despite initial appropriate and successful shocks for VT or VF. Of nine patients wearing the WCD with arrhythmic death in the VEST trial, four had been initially successfully treated but subsequently died. Of six patients who had an appropriate shock from the WCD but died during the study, two developed post-VT/VF asystole. Similar WCD shock rates (between 1.5 and 2 percent within 90 days post-MI) have been reported in observational studies [3,5,6]. In registry data from two large registries (involving 3569 and 8453 patients, respectively), similar rates of WCD shocks have been seen (1.7 and 1.6 percent of patients, respectively) [5,6]. Patients with LV dysfunction early after coronary revascularization Among patients with LVEF 35 percent who have undergone coronary revascularization with coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) in the past three months, we offer a WCD to highly motivated patients for primary prevention against SCD [16]. LVEF should be reassessed three months following CABG or PCI. If a sustained ventricular tachyarrhythmia has occurred, or if the LVEF remains 35 percent three months after CABG or PCI, implantation of an ICD is usually indicated [16]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) While professional society guidelines do not specifically exclude ICD implantation for patients with LV dysfunction within three months of revascularization, reimbursement in some countries https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 9/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate may be denied. As an example, in the United States the national coverage decision for the Centers for Medicare & Medicaid Service (CMS) excludes coverage for primary prevention ICDs if patients have had CABG surgery or PCI within the past three months. This is based upon the clinical profile of subjects included in the major ICD trials for primary prevention of SCD in ischemic cardiomyopathy [12,13,26,27]. Despite this exclusion period, patients with LV dysfunction (eg, LVEF 30 percent) have been shown to have significantly higher rates of mortality early after PCI or CABG based on large National Cardiovascular Data Registry (NCDR) and Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database studies, respectively [28,29]. Patients with significant LV dysfunction have higher 30-day mortality rates after coronary artery bypass graft (CABG) surgery than patients with normal LV function. While these persons have an increased risk of SCD due to ventricular arrhythmias, they are also at risk for nonarrhythmic causes of death. There are limited data on the utility of an ICD in the early post-CABG period, as several ICD studies of primary prevention have excluded patients within one to three months after coronary revascularization [12-14]. However, the CABG Patch trial did not report a survival benefit from epicardial ICD implantation at the time of CABG in patients with LVEF 35 percent [27]. (See "Early cardiac complications of coronary artery bypass graft surgery" and "Early noncardiac complications of coronary artery bypass graft surgery".) Professional society guidelines do not recommend ICD implantation for primary prevention of SCD within three months of CABG [16]. However, due to the risk of SCD in some patients early post-CABG, the WCD has been studied in this patient population, in whom wearing the WCD may provide protection from SCD during healing and potential recovery of LV function [3,16,17]. The potential utility for a WCD in this setting is illustrated by the following studies: In a nonrandomized comparison of nearly 5000 patients with LVEF 35 percent from two separate cohorts who underwent revascularization with CABG or percutaneous coronary intervention (PCI) (809 patients discharged with a WCD from a national registry and 4149 patients discharged without WCD from Cleveland Clinic CABG and PCI registries), patients discharged with the WCD had significantly lower 90-day mortality rates (3 versus 7 percent) [30]. While patients using a WCD appear to have improved outcomes, only 1.3 percent of the WCD group received an appropriate therapy while wearing the device, thereby indicating that the majority of the mortality benefit was not attributable to life-saving therapies from the WCD. In a German cohort of 354 patients who wore the WCD, including approximately 90 patients in the early post-CABG period, 7 percent received a shock for a ventricular tachyarrhythmia during the three months of WCD use [4]. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 10/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate In a study of 3569 patients in the United States using the WCD, among which 9 percent of WCD use was early post-CABG, appropriate shocks for a ventricular tachyarrhythmia occurred in 0.8 percent of these patients over a mean follow-up of 47 days [5,31]. Newly diagnosed nonischemic cardiomyopathy In selected patients with newly diagnosed nonischemic cardiomyopathy with severely reduced LV systolic function that is potentially reversible, such as tachycardia- or myocarditis-associated cardiomyopathy, the WCD may be useful for the prevention of SCD due to ventricular arrhythmias while awaiting improvement in LV function [16,17]. While a benefit from ICD implantation has long been recognized in patients with significant LV systolic dysfunction related to underlying ischemic heart disease, an increase in SCD risk and potential benefit from an ICD has also been demonstrated in patients with a nonischemic cardiomyopathy in several studies [14,32]: In SCD-HeFT, which compared ICD implantation with amiodarone treatment alone or placebo for primary prevention of SCD in patients with ischemic or nonischemic heart failure and LVEF 35 percent, patients who received an ICD had significantly improved survival [14]. However, patients within three months of their initial heart failure diagnosis were excluded from this study. In DEFINITE, which compared ICD implantation with standard medical therapy to standard medical therapy alone for primary prevention of SCD in patients with a nonischemic cardiomyopathy, nonsustained VT, and LVEF 35 percent, there was a trend toward improved mortality in patients who received an ICD, regardless of duration since diagnosis [32]. Following DEFINITE, another study reported similar occurrences of lethal arrhythmias irrespective of diagnosis duration in patients with a nonischemic cardiomyopathy and LVEF 35 percent [33]. Major society guidelines recommend implantation of an ICD for nonischemic cardiomyopathy with LVEF 35 percent, provided that a reversible cause of transient LV dysfunction has been excluded and that response to optimal medical therapy has been assessed [16]. The guidelines do not specify a waiting period prior to reassessing LVEF. In the United States, however, the Center for Medicare Services (CMS) requires a three-month period of optimal medical therapy prior to reimbursement for ICD placement for primary prevention (if repeat LVEF assessment continues to show LVEF 35 percent). (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Nonischemic dilated cardiomyopathy'.) https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 11/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate In patients felt to be at high risk of SCD while undergoing a trial of optimal medical therapy, the WCD may provide protection against SCD while awaiting improvement in LV function, although the event rates in this population appear to be lower than patients with ischemic cardiomyopathy [16]. In a post-approval study of the WCD, 0.7 percent of patients prescribed a WCD for recently diagnosed nonischemic cardiomyopathy required shocks for a ventricular tachyarrhythmia over a mean follow-up period of 57 days [5,31]. Among a single-center cohort of 254 patients with newly diagnosed nonischemic cardiomyopathy treated with the WCD between 2004 and 2015 (median duration of treatment 61 days, total follow-up 56.7 patient-years) who were highly compliant with using the WCD (median wear time 22 hours per day), no patients received an appropriate shock, and only three patients (1.2 percent) received an inappropriate shock [34]. This was compared with 6 of 271 patients (2.2 percent) with newly diagnosed ischemic cardiomyopathy who received an appropriate shock; in this group, two (0.7 percent) received inappropriate shocks. Of interest, 39 percent of nonischemic and 32 percent of ischemic cardiomyopathy patients experienced improvement in LVEF to >35 percent, obviating the need for an ICD. In a prospective study of the WCD in advanced heart failure patients (SWIFT), 75 patients hospitalized with heart failure (66 percent nonischemic cardiomyopathy) were prescribed a WCD for three months. Among the nonischemic cardiomyopathy patients, one had recurrent supraventricular tachycardia and another had multiple ventricular premature beats detected, but no WCD therapies were delivered [35]. In the WEARIT II registry, which included 927 patients with nonischemic cardiomyopathy, over a median wear time of 90 days, the treated event rate was 1 percent, compared with 3 percent for the 805 patients with ischemic cardiomyopathy [7]. Special populations include those with alcoholic cardiomyopathy, postpartum cardiomyopathy, or myocarditis, all of which may or may not be associated with improvement in ventricular function with optimal medical therapy and reversal or treatment of causative factors. In a study of 127 patients with alcoholic cardiomyopathy wearing the WCD a median of 51 days, 5.5 percent had appropriate shocks for VT/VF [36]. Improved LVEF occurred in 33 percent, and 23.6 percent received an ICD. In the PROLONG study of 156 patients (111 with nonischemic cardiomyopathy) with newly diagnosed LVEF 35 percent wearing a WCD for an average of 101 days, WCD shocks for VT/VF were experienced by 7.2 percent, compared with 6.7 percent in the 45 patients with https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 12/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate ischemic cardiomyopathy [37]. The event rates were 21.1 percent in the 19 patients with postpartum cardiomyopathy, 0 percent in the six patients with myocarditis, and 4.7 percent in patients with other forms of nonischemic cardiomyopathy. In a separate study of 107 women with peripartum cardiomyopathy, who were matched to 159 nonpregnant women with nonischemic dilated cardiomyopathy, the event rate was 0 in the peripartum cardiomyopathy over an average WCD use of 124 days, compared with two shocks in one patient with nonperipartum nonischemic cardiomyopathy [38]. With such low event rates, the utility of the WCD for newly-diagnosed nonischemic cardiomyopathy has been debated. However, from the WEARIT II registry, the number of VT/VF events per 100 patient-years was 1.5 for treated events versus 12 for untreated events [7]. Presumably, some of the untreated events led to earlier ICD implantation and may represent a nontreatment yield from the WCD monitoring functions. As data remain limited for such patients, the decision on whether to use a WCD remains based on clinical judgment for patients assessed to have high-risk severe newly diagnosed nonischemic cardiomyopathy while undergoing optimization of medical therapy, awaiting improvement in LV function, ICD implantation, or if needed, cardiac transplantation. (See "Treatment and prognosis of myocarditis in adults", section on 'Therapy for arrhythmias'.) Bridge to heart transplant Patients with severe heart failure awaiting heart transplantation represent a group at particularly high risk for SCD [17]. ICD implantation is often recommended for such patients, particularly those discharged to home while awaiting transplantation. The WCD may be a reasonable noninvasive alternative approach, though data on its use in patients awaiting heart transplantation are limited: In one study of 91 cardiac transplant candidates discharged to home (UNOS Status 1B patients receiving home inotrope infusion), among whom 25 had an ICD and 13 used a WCD, two patients died suddenly at home, one who was not wearing his WCD and another who declined use of a WCD [39]. In the 13 patients wearing the WCD, three asymptomatic events occurred with one shock delivered for rapid atrial fibrillation. In a German study of 354 WCD patients, 6 percent wore the WCD while awaiting heart transplantation, with an incidence of ventricular arrhythmias of 11 percent [4]. In the WEARIT study of WCD use in 177 patients with NYHA functional class III or IV heart failure (not listed for heart transplant but with similar functional status to patients who might be listed for heart transplant), one patient received two successful defibrillations [3]. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 13/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate In a registry of 121 patients prescribed a WCD as a bridge to heart transplantation, seven patients (6 percent) received appropriate shocks over an average use of 127 days (median 39 days) [40]. The International Society for Heart and Lung Transplantation Guidelines state as a class I recommendation that an ICD or WCD should be provided for status 1B patients who are discharged home given that the wait for transplantation remains significant [41]. The WCD may also be appropriate in patients whose anticipated waiting time to transplant is short (ie, blood types A and B) if an ICD is not already present [41]. WCD in patients with VADs The role for ICD and WCD therapy remains unclear in patients with ventricular assist devices (VADs). With VADs, circulatory support is often adequate even in the event of a ventricular tachyarrhythmia. However, one study reported the presence of an ICD was associated with improved survival in patients undergoing VAD support [42]. Whether the WCD could impart similar survival benefits in patients awaiting transplantation with VAD support has yet to be studied. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device".) WCD use in hemodialysis patients Patients with end-stage kidney disease on hemodialysis are at high risk for SCD, but they are also at higher risk for infection, bleeding, and other complications of implantable device therapies, which may lead to underutilization of ICDs. Although the arrhythmia event rates for patients on hemodialysis wearing a WCD are not published, a study of 75 hemodialysis patients who experienced sudden cardiac arrest events while wearing a WCD reported that 78.6 percent of events were due to VT/VF and 21.4 percent were due to asystole [43]. Survival was 71, 51, and 31 percent at 24 hours, 30 days, and one year, respectively, which was reported to be improved compared with historical controls. LIMITATIONS AND PRECAUTIONS In spite of its overall efficacy for terminating life-threatening ventricular arrhythmias, the WCD does have some limitations. The device must be fitted to each patient, and some patients may not have a good fit due to body habitus. Its external nature does not allow for pacemaker functionality and introduces a component of patient interaction and compliance as well as the potential for external noise leading to inappropriate shocks. The device must be removed for bathing, but no protection is afforded while the device is off. Therefore, it is advisable that caregivers or other persons be nearby during these periods when the WCD is not worn. Comfort may also be an issue for some patients due to the size and weight of the device. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 14/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Patient size The WCD can only be fitted on patients with a chest circumference less than 57 inches (144 cm); therefore, it may not be an option for morbidly obese patients. However, among 574 patients from the WCD registry, which included normal weight (body mass index [BMI] between 18 and 24.9; n = 157), overweight (BMI between 25 and 29.9; n = 186), and obese (BMI 30; n = 231, including 55 with BMI 40) patients who experienced 623 ventricular tachycardia/ventricular fibrillation (VT/VF) events while wearing the WCD, the median daily wear time (21 hours), first shock success rate (93 to 94 percent), and 24-hour post-shock survival (92 to 94 percent) were similar across all BMI groups [44]. There are also limited data on WCD use in children, in whom the device may not fit properly if the child is small. (See 'Use of the WCD in children' below.) Lack of pacemaker functionality Because of its external nature, the WCD is not able to function as a pacemaker, which limits the possible therapies it can deliver in two ways: The WCD cannot deliver pacing therapies to treat bradycardia or asystole. In the German study, two patients developed asystole while wearing the WCD, and both patients died [4].

percent for the 805 patients with ischemic cardiomyopathy [7]. Special populations include those with alcoholic cardiomyopathy, postpartum cardiomyopathy, or myocarditis, all of which may or may not be associated with improvement in ventricular function with optimal medical therapy and reversal or treatment of causative factors. In a study of 127 patients with alcoholic cardiomyopathy wearing the WCD a median of 51 days, 5.5 percent had appropriate shocks for VT/VF [36]. Improved LVEF occurred in 33 percent, and 23.6 percent received an ICD. In the PROLONG study of 156 patients (111 with nonischemic cardiomyopathy) with newly diagnosed LVEF 35 percent wearing a WCD for an average of 101 days, WCD shocks for VT/VF were experienced by 7.2 percent, compared with 6.7 percent in the 45 patients with https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 12/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate ischemic cardiomyopathy [37]. The event rates were 21.1 percent in the 19 patients with postpartum cardiomyopathy, 0 percent in the six patients with myocarditis, and 4.7 percent in patients with other forms of nonischemic cardiomyopathy. In a separate study of 107 women with peripartum cardiomyopathy, who were matched to 159 nonpregnant women with nonischemic dilated cardiomyopathy, the event rate was 0 in the peripartum cardiomyopathy over an average WCD use of 124 days, compared with two shocks in one patient with nonperipartum nonischemic cardiomyopathy [38]. With such low event rates, the utility of the WCD for newly-diagnosed nonischemic cardiomyopathy has been debated. However, from the WEARIT II registry, the number of VT/VF events per 100 patient-years was 1.5 for treated events versus 12 for untreated events [7]. Presumably, some of the untreated events led to earlier ICD implantation and may represent a nontreatment yield from the WCD monitoring functions. As data remain limited for such patients, the decision on whether to use a WCD remains based on clinical judgment for patients assessed to have high-risk severe newly diagnosed nonischemic cardiomyopathy while undergoing optimization of medical therapy, awaiting improvement in LV function, ICD implantation, or if needed, cardiac transplantation. (See "Treatment and prognosis of myocarditis in adults", section on 'Therapy for arrhythmias'.) Bridge to heart transplant Patients with severe heart failure awaiting heart transplantation represent a group at particularly high risk for SCD [17]. ICD implantation is often recommended for such patients, particularly those discharged to home while awaiting transplantation. The WCD may be a reasonable noninvasive alternative approach, though data on its use in patients awaiting heart transplantation are limited: In one study of 91 cardiac transplant candidates discharged to home (UNOS Status 1B patients receiving home inotrope infusion), among whom 25 had an ICD and 13 used a WCD, two patients died suddenly at home, one who was not wearing his WCD and another who declined use of a WCD [39]. In the 13 patients wearing the WCD, three asymptomatic events occurred with one shock delivered for rapid atrial fibrillation. In a German study of 354 WCD patients, 6 percent wore the WCD while awaiting heart transplantation, with an incidence of ventricular arrhythmias of 11 percent [4]. In the WEARIT study of WCD use in 177 patients with NYHA functional class III or IV heart failure (not listed for heart transplant but with similar functional status to patients who might be listed for heart transplant), one patient received two successful defibrillations [3]. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 13/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate In a registry of 121 patients prescribed a WCD as a bridge to heart transplantation, seven patients (6 percent) received appropriate shocks over an average use of 127 days (median 39 days) [40]. The International Society for Heart and Lung Transplantation Guidelines state as a class I recommendation that an ICD or WCD should be provided for status 1B patients who are discharged home given that the wait for transplantation remains significant [41]. The WCD may also be appropriate in patients whose anticipated waiting time to transplant is short (ie, blood types A and B) if an ICD is not already present [41]. WCD in patients with VADs The role for ICD and WCD therapy remains unclear in patients with ventricular assist devices (VADs). With VADs, circulatory support is often adequate even in the event of a ventricular tachyarrhythmia. However, one study reported the presence of an ICD was associated with improved survival in patients undergoing VAD support [42]. Whether the WCD could impart similar survival benefits in patients awaiting transplantation with VAD support has yet to be studied. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device".) WCD use in hemodialysis patients Patients with end-stage kidney disease on hemodialysis are at high risk for SCD, but they are also at higher risk for infection, bleeding, and other complications of implantable device therapies, which may lead to underutilization of ICDs. Although the arrhythmia event rates for patients on hemodialysis wearing a WCD are not published, a study of 75 hemodialysis patients who experienced sudden cardiac arrest events while wearing a WCD reported that 78.6 percent of events were due to VT/VF and 21.4 percent were due to asystole [43]. Survival was 71, 51, and 31 percent at 24 hours, 30 days, and one year, respectively, which was reported to be improved compared with historical controls. LIMITATIONS AND PRECAUTIONS In spite of its overall efficacy for terminating life-threatening ventricular arrhythmias, the WCD does have some limitations. The device must be fitted to each patient, and some patients may not have a good fit due to body habitus. Its external nature does not allow for pacemaker functionality and introduces a component of patient interaction and compliance as well as the potential for external noise leading to inappropriate shocks. The device must be removed for bathing, but no protection is afforded while the device is off. Therefore, it is advisable that caregivers or other persons be nearby during these periods when the WCD is not worn. Comfort may also be an issue for some patients due to the size and weight of the device. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 14/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Patient size The WCD can only be fitted on patients with a chest circumference less than 57 inches (144 cm); therefore, it may not be an option for morbidly obese patients. However, among 574 patients from the WCD registry, which included normal weight (body mass index [BMI] between 18 and 24.9; n = 157), overweight (BMI between 25 and 29.9; n = 186), and obese (BMI 30; n = 231, including 55 with BMI 40) patients who experienced 623 ventricular tachycardia/ventricular fibrillation (VT/VF) events while wearing the WCD, the median daily wear time (21 hours), first shock success rate (93 to 94 percent), and 24-hour post-shock survival (92 to 94 percent) were similar across all BMI groups [44]. There are also limited data on WCD use in children, in whom the device may not fit properly if the child is small. (See 'Use of the WCD in children' below.) Lack of pacemaker functionality Because of its external nature, the WCD is not able to function as a pacemaker, which limits the possible therapies it can deliver in two ways: The WCD cannot deliver pacing therapies to treat bradycardia or asystole. In the German study, two patients developed asystole while wearing the WCD, and both patients died [4]. In the US post-approval registry study, 23 of 3569 patients (0.6 percent) experienced asystole, with an associated mortality of 74 percent [5]. In the post-myocardial infarction (MI) registry of 8453 patients, 34 died (0.4 percent) with bradycardia-asystole events [6]. In the WEARIT-II registry, 6 of 2000 patients (0.3 percent) had asystole, and all three of the deaths that occurred while wearing the WCD during the study (0.2 percent) occurred following an asystole event [7]. The WCD cannot provide antitachycardia pacing for VT, which can reduce patient shocks, when effective. When considering these limitations, an implantable cardioverter-defibrillator (ICD) would be preferred, if indicated, in a patient who is pacemaker-dependent or in whom antitachycardia pacing is desired as the initial therapy for VT. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) Use in patients with a preexisting permanent pacemaker With certain precautions, the WCD can be used in patients with a preexisting permanent pacemaker. The manufacturer recommends that the device not be worn if the pacemaker stimulus artifact exceeds 0.5 millivolts, as this may mask underlying ventricular fibrillation and prevent appropriate device therapy. Conversely, the VT threshold of the WCD should be set higher than the maximal pacing rate to avoid an inappropriate WCD shock due to oversensing paced beats. Following any WCD shock, the patient's pacemaker should be interrogated to ensure that there has been no damage to the pacemaker or any changes in the pacemaker setting. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 15/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Inappropriate shocks Both the WCD and the ICD may inappropriately deliver shocks due to electronic noise, device malfunction, or detection of supraventricular tachycardia above the preprogrammed rate criteria. Studies of ICDs have reported an incidence of inappropriate shock of 0.2 to 2.3 percent of patients per month [32,45-51]. Comparable rates of inappropriate shocks have been reported among users of the WCD, with rates ranging from 0.5 to 1.4 percent per month [3-7]. In a systematic review and meta-analysis which included 33,242 patients from 28 studies (the randomized VEST trial and 27 nonrandomized studies), inappropriate shocks occurred at a rate of 2 per 100 persons over three months (0.67 percent per month) [18]. Inappropriate shocks with a WCD can be potentially reduced due to the ability to abort shocks while awake by pressing response buttons. (See 'Avoiding inappropriate shocks' above.) Patient compliance and complaints Patients may not comply with wearing the WCD for a variety of reasons, chief among them device size and weight, skin rash, itching, and problems sleeping. However, efficacy of the WCD in the prevention of sudden cardiac death is highly dependent on patient compliance and appropriate use of the device [3-5,7]. In the WEARIT/BIROAD study, 23 percent of the 289 subjects withdrew before reaching a study endpoint, with size and weight of the monitor being the most frequent reason for withdrawal [3]. Skin rash and/or itching were also reported by 6 percent of patients. In the US postmarket study, median and mean daily use were 21.7 hours and 19.9 hours, respectively [5]. Daily use was >90 percent (>21.6 hours) in 52 percent of patients and >80 percent (>19.2 hours) in 71 percent of patients. Longer duration of monitoring correlated with higher compliance rates. WCD use was stopped prematurely in 14 percent, primarily because of comfort issues related to the size and weight of the WCD. In the WEARIT-II registry, median daily use was 22.5 hours [7]. Similar to the US postmarket study, longer duration of monitoring (15 or more days) was associated with higher rates of compliance. In the nationwide German cohort, median daily use among 6043 patients was 23.1 hours for a median of 59 days [8]. Lower rates of compliance were reported in a study of 147 patients from two academic medical centers in Boston, in which median daily use was 21 hours for a median of 50 days [52]. In an international registry of 708 patients, appropriate WCD shock was documented in 2.2 percent, inappropriate shock in 0.5 percent, and mean wear time was 21.2 4.3 hours/day (and was lower in younger patients) [53]. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 16/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate In the WEARIT-France cohort study of 1157 patients, median daily wear time was 23.4 hours, with younger age associated with lower compliance [54]. In the VEST randomized trial after MI, median and mean daily wear times were only 18 and 14 hours, respectively, with over half of patients assigned to the WCD not wearing it by the end of the 90-day study [24]. Among 48 total deaths in the WCD group, only 12 patients (25 percent) were wearing the WCD at the time of death. In the as-treated and per-protocol analysis of VEST [25], better WCD compliance was predicted by cardiac arrest during index MI, higher creatinine, diabetes, prior heart failure, ejection fraction 25 percent, Polish enrolling center, and number of WCD alarms. Worse compliance was associated with being divorced, Asian race, higher body mass index, prior PCI, or any WCD shock. In a study of 130 patients with an ICD and fitted with an ASSURE WCD programmed for detection only and followed for 30 days, median daily use was high at 23 hours [11]. Rates of WCD discontinuation appear similar to reported rates of compliance with other prescribed therapies. One study reported that 15 percent of patients stop using aspirin, ACE inhibitors and beta-blockers within 30 days of a MI [55]. Improved compliance and acceptance of the WCD may be seen with newer devices, which are 40 percent smaller in size and weight or which offer multiple sizes and gender-specific fitting. USE OF THE WCD IN CHILDREN In December 2015, the US Food and Drug Administration (FDA) approved the WCD for use in children, although the WCD was used off-label prior to FDA approval [56]. As such, there are relatively few peer-reviewed publications documenting experience with the WCD in children [57- 59]. In a retrospective review of all patients <18 years of age who were prescribed the WCD between 2009 and 2016 (n = 455 patients), median duration of use was 33 days and wear time 20.6 hours [59]. Eight patients received at least one shock (seven episodes of ventricular tachycardia/ventricular fibrillation [VT/VF] in six patients, two inappropriate shocks due to oversensing), with four of the seven episodes of VT/VF terminated with a single shock and all seven episodes successfully terminated by the WCD. There were seven deaths (1.5 percent); none were wearing the WCD at the time of death. Children require special attention to assure compliance and correct fitting for optimal use. A variety of device harness sizes are available, but the smallest option may still be too large for https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 17/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate smaller children. Additional data on clinical efficacy, compliance, and complications should be collected in children as WCD use increases. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) SUMMARY AND RECOMMENDATIONS Introduction The wearable cardioverter-defibrillator (WCD) is an external device capable of automatic detection and defibrillation of ventricular tachycardia (VT) or ventricular fibrillation (VF) ( picture 1). In cases where the need for an implantable cardioverter- defibrillator (ICD) is felt to be temporary or implantation of the ICD must be deferred, a WCD may be an acceptable alternative approach for the prevention of sudden cardiac death (SCD). (See 'Description and functions of the WCD' above.) Device functions In addition to delivering therapeutic shocks for life-threatening ventricular arrhythmias, the WCD stores data regarding arrhythmias, patient compliance with the device, and noise or interference with its proper functioning. Arrhythmia recordings from the WCD are available for clinician review once stored data are transmitted to the manufacturer's network. (See 'Storage of ECGs and compliance data' above.) Efficacy When worn properly, the WCD appears to be as effective as an ICD for the termination of VT and VF, with successful shocks occurring in nearly 100 percent of cases. In addition, inappropriate shock rates from the WCD appear to be comparable to and in some studies lower than those reported for ICDs. (See 'Efficacy in terminating VT/VF' above and 'Inappropriate shocks' above.) Indications The WCD is an option as temporary therapy for select patients with a high risk for SCD: Among patients with left ventricular ejection fraction (LVEF) 35 percent who are less than 40 days post-myocardial infarction (MI), we discuss the potential benefits and risks of WCD use and offer it to highly motivated patients with NYHA functional class II or III, or LVEF <30 percent and in NYHA class I, as these patients would be candidates for ICD https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 18/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate implantation after 40 days. Reevaluation of LVEF should occur one to three months after the MI. If LVEF remains 35 percent on follow-up assessment, despite appropriate medical therapy, ICD implantation is indicated and should be considered. (See 'Early post-MI patients with LV dysfunction' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Among patients with LVEF 35 percent who have undergone coronary revascularization with coronary artery bypass graft (CABG) surgery in the past three months, we offer a WCD to highly motivated patients for primary prevention against SCD. LVEF should be reassessed three months following CABG. If a sustained ventricular tachyarrhythmia has occurred, or if the LVEF remains 35 percent three months after CABG, implantation of an ICD is usually indicated. (See 'Patients with LV dysfunction early after coronary revascularization' above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) In selected patients with severe but potentially reversible cardiomyopathy, such as tachycardia- or myocarditis-associated cardiomyopathy, the WCD may be useful for the prevention of SCD due to ventricular arrhythmias while awaiting improvement in LV function, ICD implantation, or if needed, cardiac transplantation. (See 'Newly diagnosed nonischemic cardiomyopathy' above.) Patients with severe heart failure awaiting heart transplantation represent a group at particularly high risk for SCD in whom ICD implantation is often recommended. The WCD may be a reasonable noninvasive alternative approach, particularly for patients whose anticipated waiting time to transplant is short if an ICD is not already present. (See 'Bridge to heart transplant' above.) Some patients with an indication for an ICD may require a delay in ICD implantation due to comorbid conditions (ie, infection, recovery from surgery, lack of vascular access). Additionally, some patients who have an ICD need it removed due to infection. In such patients, the WCD may provide protection against ventricular tachyarrhythmias until an ICD can be implanted or reimplanted. (See 'Bridge to indicated or interrupted ICD therapy' above.) Device limitations Limitations of the WCD (compared with a traditional ICD) include the lack of pacemaker functionality, the requirement for patient interaction and compliance, and potential discomfort due to the size and weight of the device. (See 'Limitations and precautions' above.) https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 19/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Sharma PS, Bordachar P, Ellenbogen KA. Indications and use of the wearable cardiac defibrillator. Eur Heart J 2016. 2. Reek S, Geller JC, Meltendorf U, et al. Clinical efficacy of a wearable defibrillator in acutely terminating episodes of ventricular fibrillation using biphasic shocks. Pacing Clin Electrophysiol 2003; 26:2016. 3. Feldman AM, Klein H, Tchou P, et al. Use of a wearable defibrillator in terminating tachyarrhythmias in patients at high risk for sudden death: results of the WEARIT/BIROAD. Pacing Clin Electrophysiol 2004; 27:4. 4. Klein HU, Meltendorf U, Reek S, et al. Bridging a temporary high risk of sudden arrhythmic death. Experience with the wearable cardioverter defibrillator (WCD). Pacing Clin Electrophysiol 2010; 33:353. 5. Chung MK, Szymkiewicz SJ, Shao M, et al. Aggregate national experience with the wearable cardioverter-defibrillator: event rates, compliance, and survival. J Am Coll Cardiol 2010; 56:194. 6. Epstein AE, Abraham WT, Bianco NR, et al. Wearable cardioverter-defibrillator use in patients perceived to be at high risk early post-myocardial infarction. J Am Coll Cardiol 2013; 62:2000. 7. Kutyifa V, Moss AJ, Klein H, et al. Use of the wearable cardioverter defibrillator in high-risk cardiac patients: data from the Prospective Registry of Patients Using the Wearable Cardioverter Defibrillator (WEARIT-II Registry). Circulation 2015; 132:1613. 8. W nig NK, G nther M, Quick S, et al. Experience With the Wearable Cardioverter- Defibrillator in Patients at High Risk for Sudden Cardiac Death. Circulation 2016; 134:635. 9. Kandzari DE, Perumal R, Bhatt DL. Frequency and Implications of Ischemia Prior to Ventricular Tachyarrhythmia in Patients Treated With a Wearable Cardioverter Defibrillator Following Myocardial Infarction. Clin Cardiol 2016; 39:399. 10. Schmitt J, Abaci G, Johnson V, et al. Safety of the Wearable Cardioverter Defibrillator (WCD) in Patients with Implanted Pacemakers. Pacing Clin Electrophysiol 2017; 40:271. 11. Poole JE, Gleva MJ, Birgersdotter-Green U, et al. A wearable cardioverter defibrillator with a low false alarm rate. J Cardiovasc Electrophysiol 2022; 33:831. 12. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 20/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996; 335:1933. 13. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346:877. 14. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225. 15. Al-Khatib SM, Friedman P, Ellenbogen KA. Defibrillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 16. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 17. Piccini JP Sr, Allen LA, Kudenchuk PJ, et al. Wearable Cardioverter-Defibrillator Therapy for the Prevention of Sudden Cardiac Death: A Science Advisory From the American Heart Association. Circulation 2016; 133:1715. 18. Masri A, Altibi AM, Erqou S, et al. Wearable Cardioverter-Defibrillator Therapy for the Prevention of Sudden Cardiac Death: A Systematic Review and Meta-Analysis. JACC Clin Electrophysiol 2019; 5:152. 19. Ellenbogen KA, Koneru JN, Sharma PS, et al. Benefit of the Wearable Cardioverter- Defibrillator in Protecting Patients After Implantable-Cardioverter Defibrillator Explant: Results From the National Registry. JACC Clin Electrophysiol 2017; 3:243. 20. Solomon SD, Zelenkofske S, McMurray JJ, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med 2005; 352:2581. 21. Piccini JP, Al-Khatib SM, Hellkamp AS, et al. Mortality benefits from implantable cardioverter- defibrillator therapy are not restricted to patients with remote myocardial infarction: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Heart Rhythm 2011; 8:393. 22. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter- defibrillator after acute myocardial infarction. N Engl J Med 2004; 351:2481. 23. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med 2009; 361:1427. 24. Olgin JE, Pletcher MJ, Vittinghoff E, et al. Wearable Cardioverter-Defibrillator after Myocardial Infarction. N Engl J Med 2018; 379:1205. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 21/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate 25. Olgin JE, Lee BK, Vittinghoff E, et al. Impact of wearable cardioverter-defibrillator compliance on outcomes in the VEST trial: As-treated and per-protocol analyses. J Cardiovasc Electrophysiol 2020; 31:1009. 26. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999; 341:1882. 27. Bigger JT Jr. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med 1997; 337:1569. 28. Weintraub WS, Grau-Sepulveda MV, Weiss JM, et al. Prediction of long-term mortality after percutaneous coronary intervention in older adults: results from the National Cardiovascular Data Registry. Circulation 2012; 125:1501. 29. Shahian DM, O'Brien SM, Sheng S, et al. Predictors of long-term survival after coronary artery bypass grafting surgery: results from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (the ASCERT study). Circulation 2012; 125:1491. 30. Zishiri ET, Williams S, Cronin EM, et al. Early risk of mortality after coronary artery revascularization in patients with left ventricular dysfunction and potential role of the wearable cardioverter defibrillator. Circ Arrhythm Electrophysiol 2013; 6:117. 31. Verdino RJ. The wearable cardioverter-defibrillator: lifesaving attire or "fashion faux pas?". J Am Coll Cardiol 2010; 56:204. 32. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004; 350:2151. 33. Makati KJ, Fish AE, England HH, et al. Equivalent arrhythmic risk in patients recently diagnosed with dilated cardiomyopathy compared with patients diagnosed for 9 months or more. Heart Rhythm 2006; 3:397. 34. Singh M, Wang NC, Jain S, et al. Utility of the Wearable Cardioverter-Defibrillator in Patients With Newly Diagnosed Cardiomyopathy: A Decade-Long Single-Center Experience. J Am Coll Cardiol 2015; 66:2607. 35. Barsheshet A, Kutyifa V, Vamvouris T, et al. Study of the wearable cardioverter defibrillator in advanced heart-failure patients (SWIFT). J Cardiovasc Electrophysiol 2017; 28:778. 36. Salehi N, Nasiri M, Bianco NR, et al. The Wearable Cardioverter Defibrillator in Nonischemic Cardiomyopathy: A US National Database Analysis. Can J Cardiol 2016; 32:1247.e1. 37. Duncker D, K nig T, Hohmann S, et al. Avoiding Untimely Implantable Cardioverter/Defibrillator Implantation by Intensified Heart Failure Therapy Optimization https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 22/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Supported by the Wearable Cardioverter/Defibrillator-The PROLONG Study. J Am Heart Assoc 2017; 6. 38. Saltzberg MT, Szymkiewicz S, Bianco NR. Characteristics and outcomes of peripartum versus nonperipartum cardiomyopathy in women using a wearable cardiac defibrillator. J Card Fail 2012; 18:21. 39. Lang CC, Hankins S, Hauff H, et al. Morbidity and mortality of UNOS status 1B cardiac transplant candidates at home. J Heart Lung Transplant 2003; 22:419. 40. Opreanu M, Wan C, Singh V, et al. Wearable cardioverter-defibrillator as a bridge to cardiac transplantation: A national database analysis. J Heart Lung Transplant 2015; 34:1305. 41. Gronda E, Bourge RC, Costanzo MR, et al. Heart rhythm considerations in heart transplant candidates and considerations for ventricular assist devices: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates 2006. J Heart Lung Transplant 2006; 25:1043. 42. Cantillon DJ, Tarakji KG, Kumbhani DJ, et al. Improved survival among ventricular assist device recipients with a concomitant implantable cardioverter-defibrillator. Heart Rhythm 2010; 7:466. 43. Wan C, Herzog CA, Zareba W, Szymkiewicz SJ. Sudden cardiac arrest in hemodialysis patients with wearable cardioverter defibrillator. Ann Noninvasive Electrocardiol 2014; 19:247. 44. Wan C, Szymkiewicz SJ, Klein HU. The impact of body mass index on the wearable cardioverter defibrillator shock efficacy and patient wear time. Am Heart J 2017; 186:111. 45. Sweeney MO, Wathen MS, Volosin K, et al. Appropriate and inappropriate ventricular therapies, quality of life, and mortality among primary and secondary prevention implantable cardioverter defibrillator patients: results from the Pacing Fast VT REduces Shock ThErapies (PainFREE Rx II) trial. Circulation 2005; 111:2898. 46. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 47. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008; 51:1357. 48. Klein RC, Raitt MH, Wilkoff BL, et al. Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Cardiovasc Electrophysiol 2003; 14:940. 49. Wilkoff BL, Ousdigian KT, Sterns LD, et al. A comparison of empiric to physician-tailored programming of implantable cardioverter-defibrillators: results from the prospective https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 23/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate randomized multicenter EMPIRIC trial. J Am Coll Cardiol 2006; 48:330. 50. Wilkoff BL, Williamson BD, Stern RS, et al. Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol 2008; 52:541. 51. Wilkoff BL, Hess M, Young J, Abraham WT. Differences in tachyarrhythmia detection and implantable cardioverter defibrillator therapy by primary or secondary prevention indication in cardiac resynchronization therapy patients. J Cardiovasc Electrophysiol 2004; 15:1002. 52. Leyton-Mange JS, Hucker WJ, Mihatov N, et al. Experience With Wearable Cardioverter- Defibrillators at 2 Academic Medical Centers. JACC Clin Electrophysiol 2018; 4:231. 53. El-Battrawy I, Kovacs B, Dreher TC, et al. Real life experience with the wearable cardioverter- defibrillator in an international multicenter Registry. Sci Rep 2022; 12:3203. 54. Garcia R, Combes N, Defaye P, et al. Wearable cardioverter-defibrillator in patients with a transient risk of sudden cardiac death: the WEARIT-France cohort study. Europace 2021; 23:73. 55. Ho PM, Spertus JA, Masoudi FA, et al. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med 2006; 166:1842. 56. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm466852.htm (Access ed on December 21, 2015). 57. Everitt MD, Saarel EV. Use of the wearable external cardiac defibrillator in children. Pacing Clin Electrophysiol 2010; 33:742. 58. Collins KK, Silva JN, Rhee EK, Schaffer MS. Use of a wearable automated defibrillator in children compared to young adults. Pacing Clin Electrophysiol 2010; 33:1119. 59. Spar DS, Bianco NR, Knilans TK, et al. The US Experience of the Wearable Cardioverter- Defibrillator in Pediatric Patients. Circ Arrhythm Electrophysiol 2018; 11:e006163. Topic 15824 Version 35.0 https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 24/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate GRAPHICS Wearable cardioverter-defibrillator The wearable cardioverter-defibrillator consists of a vest incorporating two defibrillation electrodes and four sensing electrocardiographic electrodes connected to a waist unit containing the monitoring and defibrillation electronics. Reproduced with permission from: ZOLL Medical Corporation. Copyright 2012. All rights reserved. Graphic 60103 Version 3.0 https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 25/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Electrocardiogram sensing (A) Five ECG electrodes are positioned circumferentially around the torso at the level of the subxiphoid process, labelled left front (LF), right front (RF), left back (LB), right back (RB), and right leg drive (RLD). Red dashed arrows represent the four differential ECG vectors derived using RLD as a ground reference. (B) Garment interior depicting five embedded, cushioned ECG electrodes and defibrillation pads (two posterior and one anterior). ECG: electrocardiogram. From: Poole JE, Gleva MJ, Birgersdotter-Green U, et al. A wearable cardioverter de brillator with a low false alarm rate. J Cardiovasc Electrophysiol 2022; 33:831. https://onlinelibrary.wiley.com/doi/10.1111/jce.15417. Copyright 2022 Wiley Periodicals, LLC. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). Graphic 140856 Version 1.0 https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 26/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate ASSURE WCD System noise management The A WCD employs three levels of protection to achieve a low false alarm rate due to noise. Level 1 (blue) minimize noise. Level 2 (red) detect and remove noise that does occur. Level 3 (yellow) allow time for remaining noise to subside before alarming. A-WCD: ASSURE WCD System; VT: ventricular tachycardia; VF: ventricular fibrillation; ECG: electrocardiogram. From: Poole JE, Gleva MJ, Birgersdotter-Green U, et al. A wearable cardioverter de brillator with a low false alarm rate. J Cardiovasc Electrophysiol 2022; 33:831. https://onlinelibrary.wiley.com/doi/10.1111/jce.15417. Copyright 2022 Wiley Periodicals, LLC. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). Graphic 140843 Version 1.0 https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 27/28 7/6/23, 3:09 PM Wearable cardioverter-defibrillator - UpToDate Contributor Disclosures Mina K Chung, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard L Page, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 28/28

7/6/23, 3:25 PM Early repolarization - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Early repolarization : Andrew Krahn, MD, Manoj Obeyesekere, MBBS, MD : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2022. INTRODUCTION The term early repolarization (ER), also known as "J waves" or "J-point elevation," has long been used to characterize a QRS-T variant on the electrocardiogram (ECG). Most literature defines ER as being present on the ECG when there is J-point elevation of 0.1 mV in two adjacent leads with either a slurred or notched morphology. Historically, ER has been considered a marker of good health because it is more prevalent in athletes, younger persons, and at slower heart rates. However, contemporary reports, largely based on data from resuscitated sudden cardiac arrest (SCA) patients, suggest an association between ER and an increased risk for arrhythmic death and idiopathic ventricular fibrillation (VF). While some level of increased risk of sudden cardiac death (SCD) has been reported in persons with ER, the relatively high prevalence of the ER pattern in the general population (5 to 13 percent) in comparison with the incidence of idiopathic VF (approximately 10 cases per 100,000 population) means that the ER pattern will nearly always be an incidental ECG finding with no clinical implications. However, a primary arrhythmic disorder such as idiopathic VF due to ER is far more likely when associated with resuscitated SCD in the absence of other etiologies. (See 'ER syndrome' below.) This topic will review the genetics, prevalence, clinical manifestations, and diagnosis of ER and will present an approach to the management of patients with ER and idiopathic VF. DEFINITION https://www.uptodate.com/contents/early-repolarization/print 1/37 7/6/23, 3:25 PM Early repolarization - UpToDate The definition of ER on an ECG is based on well-defined ECG findings ( table 1) [1]. Although the 2013 Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society presented a definition ( table 1), the 2016 American Heart Association (AHA) Scientific Statement [2] highlights the lack of agreement across published studies pertaining to definition. A 2015 consensus document suggested reporting more detailed amplitudes of the J-wave including amplitudes corresponding to J-wave onset (Jo), J-wave peak (Jp), and J-wave termination (Jt), as well as durations D1 (Jo to Jp) and D2 (Jp to Jt), in relation to an end-QRS notch, and of Jp, Jt, and D2, in relation to an end-QRS slur [3]. The majority of publications at the present time merely adopt the amplitude of Jp as the reference point for measuring J-point elevation. The ST segment should be regarded as horizontal or downward sloping if the amplitude of the ST-segment 100 ms after the Jt (interval M) is equal to or less than the amplitude at Jt. The ST segment should be regarded as upward sloping if the amplitude of the ST segment 100 ms after Jt (interval M) is greater than the amplitude at Jt. However, duration measurements K, L, and M, each 100 ms, from Jo, Jp and Jt could be used in the measurement of the ST slope in the presence of a notch or duration measurements L or M, each 100 ms, used in the presence of an end-QRS slur with onset from Jp or Jt to measure slope, respectively ( figure 1). ECG findings On the ECG, ER is defined as either: A sharp well-defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST segment; correspondingly, in negative QRS complexes, J waves may also be negative. The presence of slurring at the terminal part of the QRS complex (since the J-wave or J- point elevation may be hidden in the terminal part of the QRS complex, resulting in the slurring of the terminal QRS complex) ( waveform 1). Most literature defines ER as being present on the ECG when there is J-point elevation of 0.1 mV in two adjacent leads with either a slurred or notched morphology [2,4,5]. The AHA scientific statement proposed the use of ER qualified with descriptive terms such as with ST-segment elevation, the magnitude, ER with terminal slur/notch and also noting the distribution on the ECG and any concomitant ECG findings (eg, J-wave augmentation or short coupled ventricular ectopy). ECG classification Based on data associating arrhythmic risk with spatial distribution of ER, a classification scheme has been proposed [6,7] (see 'Prognosis of ER pattern' below): Type 1 is associated with ER in the lateral precordial leads. This form is common among healthy male athletes and is thought to be largely benign. https://www.uptodate.com/contents/early-repolarization/print 2/37 7/6/23, 3:25 PM Early repolarization - UpToDate Type 2 is associated with ER in the inferior or inferolateral leads and is associated with a moderate level of risk. Type 3 is associated with ER globally in the inferior, lateral, and right precordial leads, and appears to be associated with the highest relative risk, though the absolute risk of sudden death remains small [8]. Type 4, or Brugada syndrome, is marked by J-wave/point elevation in the right precordial leads. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) While this classification system would seem to simplify categorization of the ECG patterns, it has been criticized due to the controversial presumed common pathophysiological substrate across the four types [9,10]. Concealed ER The ER pattern is not always identified on routine ECG due to the intermittent nature of ER [11]. As an example, among 542 persons with baseline ER who underwent repeat ECG examination five years later, ER ( 0.1 mV) was not observed in approximately 20 percent [5]. No systematic evaluation has been undertaken reporting the prevalence of concealed ER in the general population, and the clinical importance, if any, of concealed ER remains unclear. ER pattern versus ER syndrome As noted above, ER is an ECG finding. Two terms, distinguished by the presence or absence of symptomatic arrhythmias, have been used to describe patients with this ECG finding: The ER pattern describes the patient with appropriate ECG findings in the absence of symptomatic arrhythmias. The ER syndrome applies to the patient with both appropriate ECG findings and symptomatic arrhythmias. Persons with either the ER pattern or ER syndrome can have identical findings on surface ECG. However, the mere presence of ER pattern on ECG should not lead to a classification of ER syndrome in the absence of symptoms or documented ventricular fibrillation (VF) [12]. Rarely, ER may be associated with the primary arrhythmic disorder idiopathic VF in the absence of structural heart disease [4,11]. Given the prevalence of ER pattern in the general population and the exceedingly low incidence of idiopathic VF, the diagnosis of idiopathic VF due to malignant ER is a diagnosis of exclusion. (See 'ER syndrome' below.) PREVALENCE OF ER AND INCIDENCE OF IDIOPATHIC VF https://www.uptodate.com/contents/early-repolarization/print 3/37 7/6/23, 3:25 PM Early repolarization - UpToDate Prevalence Several population studies have estimated that the prevalence of ER ranges from 5 to 18 percent of persons, with higher prevalence in younger patients [5,13-15]. In a multiethnic population, ER pattern was independently associated with greater LV mass [16]. Arrhythmic risk The perception that ER was a benign finding devoid of clinical significance changed as case reports, case-control studies, and population studies established a link between the presence of ER and an increased risk for arrhythmic death, in particular idiopathic ventricular fibrillation (VF) [4,5,8,13-15,17-23]. Even though ER is fairly common in the general population, idiopathic VF is rare. In one report which estimated the incidence of idiopathic VF, the estimated risk of developing idiopathic VF in an individual younger than 45 years was 3 in 100,000 [13,24]. The risk increased to 11 in 100,000 when J waves ( waveform 2) were present. Although ER increased the relative risk of SCD, the absolute risk was very low. In a meta-analysis, the relative risk of arrhythmic death in persons with the ER pattern was 1.70 (95% CI 1.19-2.42), and the estimated absolute risk for arrhythmic death was 70 per 100,000 person-years [25]. Therefore, the incidental identification of ER should not be interpreted as a high-risk marker for arrhythmic death due to the relatively low odds of SCD based on ER alone. Athletes with early repolarization The prevalence of J-point elevation among 121 young athletes was reported at 22 percent, a prevalence rate higher than seen in the general population [13]. However, higher ER prevalence rates ranging as high as 44 percent have also been reported in athletes [26,27]. The reported higher prevalence of ER in athletes likely is related to the physiological balance in autonomic tone favoring the parasympathetic tone and its regulation of the action potential [28]. Notably, the association of ER with arrhythmic risk is typically at rest or during sleep and not during physical activity when J-point elevation is typically markedly reduced or eliminated. In a study of 704 athletes (14 percent with ER) with six years follow-up, there were no arrhythmic events [29]. PROGNOSIS OF ER PATTERN Certain ECG characteristics may distinguish the benign ER pattern from patterns associated with an arrhythmic prognosis. Additionally, ER pattern may be modified by physiological variables with subsequent effect on prognosis. The coexistence of ER with other cardiac pathologies also likely influences prognosis/arrhythmic risk. Reports suggest that ER may be viewed as an https://www.uptodate.com/contents/early-repolarization/print 4/37 7/6/23, 3:25 PM Early repolarization - UpToDate adjunctive prognostic variable in the presence of other cardiac pathologies (ie, ER may incrementally worsen the prognosis of other more common conditions such as ischemic heart disease). Prognosis in the general population While the ER pattern is associated with an increased relative risk of adverse events, the prognostic implications described in this section should be viewed in the context of the overall very low risk of SCD in those with this asymptomatic ECG finding. Thus, even with a twofold increase in relative risk of SCD, the absolute risk remains exceedingly low. Additionally, in spite of the data discussed in this section, there is no current risk stratification strategy for asymptomatic patients with ER pattern in the general population and within families with ER pattern that would allow for the identification of higher risk individuals with the ER pattern who might be candidates for treatment. (See 'Prevalence' above and 'Arrhythmic risk' above and 'Treatment of ER pattern' below.) The presence of the ER pattern has generally been associated with adverse outcomes in numerous cohort and case-control studies, although some studies have suggested no overall impact on mortality after adjusting for comorbidities including coronary risk factors [4,5,13- 15,17,25,30-33]. Prognostic variables Variables thought to affect prognosis that have been investigated include: Distribution and amplitude of ER Morphology of the J wave, ST segment, T wave, T T interval peak end Age and sex Family history Slurring versus notching Ethnicity Association with other cardiac pathology Distribution and amplitude of early repolarization The inferior location of ER, in addition to higher J-point amplitude, have been described as variables associated with increased arrhythmic risk in both the general population and in patients with idiopathic ventricular fibrillation (VF), although some conflicting data have been reported in the general population. J-point elevation greater than 0.1 mV in the inferior leads in the large Finnish cohort study of 10,864 persons was weakly associated with an increased risk for death from cardiac causes (adjusted RR 1.28, 95% CI 1.04-1.59) [5]. While observed in only 0.3 percent of the cohort, J-point elevation greater than 0.2 mV in inferior leads ( waveform 3) was https://www.uptodate.com/contents/early-repolarization/print 5/37 7/6/23, 3:25 PM Early repolarization - UpToDate associated with a three times greater risk of death from cardiac causes (adjusted RR 2.98, 95% CI 1.85-4.92) [5]. In a population-based case-cohort study of 6213 persons (1945 persons with ECGs) with a mean follow-up of 19 years, ER was associated with higher cardiac mortality (hazard ratio 1.96, 95% CI 1.05-3.68) [14]. An inferior localization of ER further increased ER-attributable cardiac mortality (hazard ratio 3.15, 95% CI 1.58-6.28. However, these findings were not replicated in a cohort of 20,661 patients (90.5 percent male) with a median follow-up of 17.5 years, among whom the findings of ER were not associated with an increased risk of cardiovascular death [34]. Morphology of the ST segment The morphology of the ST segment may also determine the risk associated with ER, with a horizontal or downsloping ST segment following ER portending a higher risk in both the general population and in patients with idiopathic VF [24,26,31]. However, despite the increased risk of arrhythmia associated with the horizontal/downsloping ER pattern, the prevalence of this pattern in controls (approximately 3 percent) compared with the exceedingly low incidence of idiopathic VF renders this variable alone devoid of meaningful test accuracy [24,26]. In one study that compared 92 patients with ER and VF with 247 control patients with asymptomatic ER pattern, patients with ER and VF had a higher prevalence of low- amplitude T waves, lower T/R ratio (lead II or V5), and longer QTc interval [35]. The authors suggested the combination of these parameters with J-wave amplitude and distribution of J waves may further allow for improved identification of malignant ER. T to T interval has been reported to predict malignant ventricular arrhythmias in an ER peak end syndrome model [36], which is prolonged in patients with VF attributed to ER syndrome (86.7 14 ms versus 68 13.2 ms, p<0.001) [37]. J-wave duration (interval from Jo and the intersection of the tangent to the J wave with the isoelectric line >60 ms) and slope/j-angle (angle between an ideal line drawn from Jo perpendicular to the isoelectric line and the tangent to the J wave >30 ) have been reported to identify the malignant form of ER from the benign form [38]. Age and sex Although the data are conflicting, males with ER in the inferior leads may be at greater risk of cardiac mortality than males without ER or females with or without ER [14]. However in a conflicting study reporting on 6631 Finnish general population subjects (age 30 years) with ER ( 0.1 mV in 2 inferior/lateral leads), ER was associated with SCD in subjects younger than 50 years, particularly in women, but not in subjects 50 years and older [39]. Family history Conflicting data exist regarding the prognostic significance of a family history of SCD in persons with ER, such that no clear recommendations regarding risk https://www.uptodate.com/contents/early-repolarization/print 6/37 7/6/23, 3:25 PM Early repolarization - UpToDate assessment or treatment can be made [4,40]. Further studies are required to define the risk contribution of a family history of SCD to the prognosis of a patient with ER since no clear mechanism for inheritance of risk has been identified. Society guidelines support a possible role for an implantable cardioverter-defibrillator (ICD) in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST-segment elevation, or asymptomatic individuals with a high-risk ER pattern in the presence of a family history of early sudden death. The latter should be exceptional, in discussion with an expert versed in assessment of familial sudden death syndromes [41]. Slurring versus notching Although both slurring and notching type ER are observed and may exist in the same patient, the prognostic value of one compared with the other has not been clearly established ( waveform 1 and figure 2) [11,15,24,31,34,42]. However, a meta- analysis of 19 observational studies (7268 patients with 1127 cases of ventricular arrhythmias or SCD) demonstrated a higher risk with J waves in the inferior leads, with notching, and horizontal or descending ST segment [43]. Ethnicity Although ER pattern is more common in African Americans [44], there is no clear attributable risk associated with ethnicity, and African Americans are not specifically over represented in idiopathic VF cohorts compared with White Americans [45]. Thus, no clinically relevant risk stratification can be undertaken to identify the small subset at high risk for primary prevention. Modifying risk of underlying cardiac pathology In the context of structural heart disease or primary electrical disorders, the ER pattern may be a modifier of underlying arrhythmic risk associated with heterogeneous cardiac conditions (myocardial infarction [46,47], coronary disease [48], heart failure [49], SQTS [50,51], LVNC [52], LQTS [53,54], CPVT [55], Brugada [56]), in addition to the rare association with idiopathic VF (ie, in the absence of other cardiac conditions). Thus, the ER pattern is potentially a marker for increased arrhythmic mortality due to a vulnerable repolarization substrate when combined across a number of heterogeneous clinical conditions (eg, short QT syndrome, Brugada syndrome, or ischemic heart disease) in the general population, in addition to rarely being a primary arrhythmogenic disorder. Early repolarization may also indicate an underlying atrial electrical substrate for atrial fibrillation; however, studies are conflicting [57,58]. Risk stratification with invasive EP studies Invasive electrophysiologic studies (EPS) do not appear to improve the risk stratification of patients with the ER syndrome and prior VF arrest [59]. (See 'Chronic treatment of ER syndrome' below and "Invasive diagnostic cardiac electrophysiology studies".) https://www.uptodate.com/contents/early-repolarization/print 7/37 7/6/23, 3:25 PM Early repolarization - UpToDate GENETIC BASIS AND INHERITANCE OF ER The genetic basis of ER syndrome continues to be elucidated, with the evidence restricted to either case reports or preliminary studies that have not identified an accepted genetic basis of ER [60,61]. The reported implicated gene mutations involve the KCNJ8 gene (responsible for the ATP-sensitive potassium channel Kir6.1 - I current); CACNA1C, CACNB2, CACNA2D1 genes KATP (responsible for the cardiac L-type calcium channel - I current); and the SCN5A gene Ca.L (responsible for the sodium channel - I current) ( figure 3) [60-64]. First-degree relatives of Na patients with the ER pattern are more likely to also demonstrate the pattern, but this weak association has not been associated with clinical implications [65,66]. Inheritance of ER pattern The ER pattern may be sporadic or inherited, although first- degree relatives of a person with the ER pattern appear to have a two to threefold higher likelihood of also having the ER pattern on ECG [65,66]. While the vast majority of ER is likely sporadic, familial ER appears to be transmitted in an autosomal dominant fashion [67]. Gain of function mutations Consistent with the reports that I activation (KCNJ8 and KATP ABCC9) or I (KCNE5 mutation and rare polymorphism in DPP10) can generate an ER pattern on to the surface ECG, several investigators have detected a rare missense mutation, S422L in KCNJ8, to be associated with ER and idiopathic ventricular fibrillation (VF) [60,62,63,68]. The first report on this variant was a case report of a 14-year-old female who experienced numerous episodes of recurrent idiopathic VF unresponsive to beta-blockers, multiple anti- arrhythmic medications and verapamil [60]. Recurrences of VF were associated with a marked accentuation of ER. In a study of 87 patients with Brugada syndrome and 14 patients with ER syndrome, one Brugada syndrome case and one ER syndrome case hosted the identical missense mutation S422L. Investigators demonstrated that I was increased significantly in the KATP S422L variant compared with Kir6.1 wild type channels [62]. A separate study of 204 patients and family members with Brugada syndrome or ER syndrome also demonstrated a similar gain of function of the Kir6.1 channel (identified in three Brugada syndrome and one ER syndrome proband) [63]. KCNJ8-S422L is highly conserved across species and was absent in the reference alleles in these three studies [60,62,63]. This gain of function variant appears to be pathogenic in ER and idiopathic VF. https://www.uptodate.com/contents/early-repolarization/print 8/37 7/6/23, 3:25 PM Early repolarization - UpToDate Gain of function of I by missense variant (c.2240T > C/p. L747P) in DPP6 in four families with to SCA due to ER syndrome has been reported [69]. A heterozygous gain of function missense mutation in a highly conserved (K801T) residue in the hERG (KCNH2 gene) in a single Chinese family with ER syndrome involving four nocturnal SCD events has been reported involving the proband with ER syndrome and affected family members and was not present in a control population of 150 individuals [70]. Whole-cell patch-clamp methods were used to characterize the gain of function. A heterozygous gain of function mutation of KCND3 encoding Kv4.3, an -subunit (I ), Gly306Ala to (c.917g>c) was reported to be associated with ER syndrome in a 12-year-old male SCA survivor [71]. Isoproterenol and quinidine were effective in preventing VF recurrence with restoration of the J-point elevation. Furthermore, a genome wide association with ER on chromosome 1 in the KCND3 gene with rs1545300 as the lead polymorphism has been reported [72]. A total KCND3 duplication (with likely increase in I current) has been reported in a patient with to nonfatal nocturnal SCA and intermittent ER [73], responding to quinidine. Segregation analysis of available family members identified the proband's asymptomatic daughter as a carrier also demonstrating J-point elevation. Loss of function mutations Loss of function mutations of the inward sodium channel gene and cardiac L-type calcium channel gene have also been implicated in patients with ER (CACNA1C, CACNB2, and CACNA2D1 genes) ( figure 3). Two small studies (three and four patients with ER, respectively) have reported that mutations in these highly conserved residues were associated with ER, suggesting linkage of these genes with ER [61,64]. The complex genetic basis continues to be explored. Highlighting the complexity, a study indicated that the c.4297 G>C missense mutation in the SCN5A gene caused a "loss-of-function" of sodium channels accounting for the ER syndrome in a single case [74]. The reduction in INa density was due to a decreased number of sodium channels caused by abnormal translation processes. However, the synonymous T5457C polymorphism on the same allele partially restored the INa density of the mutant channels by the upregulation of mRNA levels. Furthermore, KCNE1 (and others) may be modulatory genes associated to ER syndrome [75]. A genome-wide association study was not able to reliably identify genetic variants predisposing to ER, presumably due to insufficient statistical power and phenotype heterogeneity [76]. This does however suggest that the genetic mechanisms may be multifactorial and that an ER gene or family of genes is an unlikely outcome of further ascertainment. Furthermore, a small proportion of reported genetic variants have undergone functional studies, and none has been https://www.uptodate.com/contents/early-repolarization/print 9/37 7/6/23, 3:25 PM Early repolarization - UpToDate studied in genetically engineered animal models. The poverty of validation of mutation effects remains a significant limitation when interpreting genetic test results. MECHANISM OF ER AND IDIOPATHIC VENTRICULAR FIBRILLATION There is controversy regarding whether the ER pattern represents abnormal repolarization or depolarization. The repolarization theory is based on the presence of a prominent action potential notch in the epicardium but not endocardium, which has been demonstrated to result in a voltage gradient that manifests as ER on the ECG ( figure 3 and figure 2) [77]. The depolarization theory is based on epicardial structural elements with conduction disturbances/delays in the epicardium [78-80]. The cause for this abnormal conduction leading to delayed and fractionated local epicardial electrograms remains unknown. A repolarization disparity secondary to the depolarization abnormality may also accentuate this mechanism. It is more likely that two mechanisms are contributing to ER. Clinical mapping data suggest two distinct substrates, delayed depolarization (with evident delayed local epicardial electrograms) and early repolarization abnormality (with absence of local delayed electrograms), underlie the J wave [78,79]. The term "J-wave syndromes" has been proposed in light of the heterogenous mechanisms to eliminate the implied mechanism in the term ER. Clinical studies also suggest the likelihood of two different substrates: In a study of 206 persons with idiopathic VF and the ER pattern, only a minority of cases (11 percent) had late potentials on signal-averaged ECG, with a prevalence similar to the control group who did not have the ER pattern (13 percent), suggesting that ER is not a depolarization phenomenon ( figure 4) [4]. However, in a smaller study of 22 patients with apparently idiopathic VF who were monitored using a signal-averaging system to record depolarization markers, repolarization markers, and autonomic modulation, the incidence of late potentials in persons with VF was significantly higher in those with the ER pattern (86 versus 27 percent in those without ER pattern) [18]. In contrast, repolarization markers did not differ between the two groups. These investigators concluded that ER might be more closely associated with a depolarization abnormality and autonomic modulation than with repolarization. https://www.uptodate.com/contents/early-repolarization/print 10/37 7/6/23, 3:25 PM Early repolarization - UpToDate Given that the mechanism for ER is likely heterogenous, the precise mechanism for ER- related idiopathic ventricular fibrillation (VF) is also likely heterogenous. The repolarization theory holds to endo-epicardial action potential gradients caused by gain or loss of function mutations by outward or inward currents respectively, causing phase 2 reentry and polymorphic VT/VF [81]. The depolarization theory holds to unidentified micro- structural abnormalities in the right ventricular (RV) epicardium, causing conduction delay and local triggers and reentry [78]. The two different mechanisms will likely have implications for therapy, with varied response to pharmacotherapy. The response to isoproterenol has been reported to be variable, with inferior J waves persisting in 35 percent, suggestive of a depolarization substrate, and normalizing (or decreasing) in 65 percent, suggestive of an early repolarization substrate [82]. Quinidine and isoproterenol have been demonstrated to restore electrical homogeneity by restoring the epicardial action potential dome, thus preventing VT/VF [82]. In contrast, those who fail to respond to quinidine tend to display depolarization abnormalities [78]. Furthermore, late depolarization may be associated with gene variants in the Na channel, connexins, and structural proteins, whereas mutations in I , IK-ATP, or ICa may be associated to with early repolarization [79]. Sodium channel blockers have been demonstrated to accentuate the ER in those with depolarization substrates and not in those devoid of depolarization substrate, further highlighting the heterogenous mechanism [78]. ER mechanistically demonstrates some similarities to Brugada syndrome and short QT syndrome (SQTS). (See "Short QT syndrome" and "Brugada syndrome: Epidemiology and pathogenesis", section on 'Pathogenesis'.) CLINICAL MANIFESTATIONS AND DIAGNOSIS ER pattern Given the relatively high prevalence of the ER pattern in the general population (5 to 13 percent) in comparison with the incidence of idiopathic ventricular fibrillation (VF) (approximately 10 cases per 100,000 population), the ER pattern is nearly always a benign incidental ECG finding. There are no specific signs or symptoms attributed to the ER pattern. In the absence of SCA, no additional testing is required in persons with the ER pattern. Asking patients to perform the Valsalva maneuver may unmask or accentuate the ER pattern. While performing this maneuver has been shown to aid in the identification of the ER pattern in high-risk familial ER, this has not been validated, and its applicability to broad populations of asymptomatic persons has not been evaluated [67]. The Valsalva maneuver is discussed in greater detail separately. (See "Vagal maneuvers".) https://www.uptodate.com/contents/early-repolarization/print 11/37 7/6/23, 3:25 PM Early repolarization - UpToDate ER syndrome Patients with ER syndrome typically present with SCA due to VF. Syncope has not been shown to be more common in patients with ER pattern [65,83]. The diagnosis of ER syndrome is most commonly considered in a survivor of SCD with ECG evidence of VF and an apparently structurally normal heart following extensive testing ( table 1). A systematic assessment of the survivors of SCD without evidence of infarction or left ventricular dysfunction is reported to establish a causative diagnosis in the majority of cases [11,84]. Systematic evaluation includes: Cardiac monitoring. Signal-averaged ECG. Exercise testing. Echocardiogram. Cardiac magnetic resonance imaging. Exclusion of coronary artery disease or anomalies. Intravenous sodium channel blocker challenge (discretionary epinephrine challenge). Targeted genetic testing should also be considered when a heritable phenotype is suggested. (See "Congenital long QT syndrome: Diagnosis" and "Catecholaminergic polymorphic ventricular tachycardia" and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) In patients whose evaluation revealed no identifiable cardiac pathology, idiopathic VF and the ER syndrome should be considered. A careful review of all available ECGs for evidence of ER is warranted, particularly around the time of the cardiac arrest [11]. ECGs often show variable and at times absent ER, so thorough review is important. VF storms in the idiopathic VF patients attributed to ER syndrome were highly associated with J wave augmentation prior to the VF onset [85]. ER syndrome causing VF may be diagnosed when: Other etiologies have been systematically excluded When J-point elevation is augmented immediately preceding VF ER syndrome causing VF is probable when: Other etiologies have been systematically excluded https://www.uptodate.com/contents/early-repolarization/print 12/37 7/6/23, 3:25 PM Early repolarization - UpToDate ER pattern exists or increased parasympathetic tone provokes ER Cardiac arrest occurs at rest or during sleep These patients may also display a high-risk ER pattern (J-point elevation >2 mm in the inferior or inferolateral leads or globally and/or horizontal or down sloping ST segment. (See 'Prognosis of ER pattern' above.) The ER pattern is not always identified on routine ECG due to the intermittent nature of ER. Bradycardia dependent and vagally dependent augmentation of ER has been reported [86]. However, no provocative test, such as pharmacologic augmentation of parasympathetic tone, is currently available and validated in this setting. Although the utility has not been studied systematically, tilt table testing may be of assistance to establish if vagal stimulation is associated with VF/syncope and/or if high-risk ER features are provoked. However, the diagnostic accuracy of this approach is unknown, and vasovagal syncope is far more common in comparison with VF due to ER syndrome. (See 'Prognostic variables' above and "Upright tilt table testing in the evaluation of syncope".) DIFFERENTIAL DIAGNOSIS ER versus Brugada syndrome Some individuals with Brugada syndrome (ECG findings of ST- segment elevation in leads V1 to V2 associated with SCD or sustained ventricular arrhythmia) also have ER (approximately 12 percent) as variants in genes encoding the L-type calcium channel, ATP-sensitive potassium channel, and sodium channels have been associated with both of these conditions [61,62,64,87-90]. Additionally, some ECG characteristics of ER resemble features of the Brugada ECG, including J waves, pause and bradycardia dependent accentuation, the dynamic nature of the ECG manifestations, short-coupled extra-systole-induced polymorphic ventricular tachycardia/ventricular fibrillation, and suppression of the ECG features and arrhythmia with isoproterenol and quinidine [8,82]. However, the provocation of the Brugada pattern by sodium channel blocker is not observed in ER [91]. In fact, sodium channel blockers in most patients with ER attenuate the J-point, whereas the J-point is augmented by sodium-channel blockers in the right precordial leads in patients with a Brugada ECG. Furthermore, a positive signal-averaged ECG and structural abnormalities in the RV outflow tract are not consistently observed and have not been reported in patients with ER, respectively [92-94]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) ER versus acute pericarditis As is seen in ER, there is J-point elevation with resultant ST segment elevation in patients with acute pericarditis. Symptom presentation is markedly https://www.uptodate.com/contents/early-repolarization/print 13/37 7/6/23, 3:25 PM Early repolarization - UpToDate different in the two conditions. Unlike ER, most patients with acute pericarditis have ST elevations diffusely in most or all limb and precordial leads. Additionally, patients with acute pericarditis often have deviation of the PR segment, which is not present in ER. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Electrocardiogram'.) ER versus acute myocardial injury While patients with acute myocardial injury due to ST- elevation myocardial infarction (STEMI) can initially have elevation of the J point with concave ST- segment elevation, the ST-segment elevation typically becomes more pronounced and convex (rounded upward) as the infarction persists. However, the primary distinguishing factor between ER and acute myocardial injury is the presence of clinical symptoms such as chest pain or dyspnea. The distinction between the ECG findings of ER and acute MI are discussed in greater detail elsewhere. (See "Electrocardiogram in the diagnosis of myocardial ischemia and infarction", section on 'Early repolarization'.) TREATMENT Treatment of ER pattern As discussed above, the ER pattern is nearly always a benign incidental ECG finding, with no specific signs or symptoms attributed to it. In addition, there is no current risk stratification strategy for asymptomatic patients with ER pattern in the general population and within families with ER pattern that would allow for the identification of higher risk individuals with the ER pattern who might be candidates for treatment. The 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline for management of patients with ventricular arrhythmias and the prevention of SCD recommends observation with no treatment, and the 2015 European Society of Cardiology guidelines on the treatment of ventricular arrhythmias and prevention of SCD found that there was "insufficient evidence" to make a recommendation on the management of the ER pattern without associated symptomatic ventricular arrhythmias [12,95]. As such, for patients with the incidental finding of the ER pattern on their ECG, we recommend observation without therapy ( table 1). Treatment of ER syndrome with idiopathic VF Among survivors of SCD due to idiopathic ventricular fibrillation (VF), the reported rate of recurrent VF ranges between 22 and 37 percent at two to four years [96-98]. Because these patients have no demonstrated structural heart disease, they have an excellent prognosis for long-term survival if VF is treated ( algorithm 1). As a result, such patients are best treated with an ICD [12,95-100]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) https://www.uptodate.com/contents/early-repolarization/print 14/37 7/6/23, 3:25 PM Early repolarization - UpToDate In patients with idiopathic VF, substrate and/or trigger ablation is feasible, safe, and effective in specialized centers [78,79]. In 43 patients undergoing ablation for recurrent VF episodes due to ER syndrome, two phenotypes were identified; one with late depolarization abnormalities predominantly in the epicardium of the RV outflow tract and RV inferolateral epicardium (group 1), and the other with VF triggers associated with Purkinje sites but without abnormal epicardial/endocardial depolarization substrates (group 2) [78]. Epicardial anterior RV, RV outflow tract, inferior RV, posterior and posterolateral LV and apical ablation guided by location of abnormal depolarization substrates +/- premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) triggers in group 1 and Purkinje PVC ablation in group 2 were effective with no VF recurrence in 91 percent at 31 +/- 26 months follow-up. Single procedure success was 67 percent. Ablation resulted in the disappearance of the ER pattern in 82 percent. Acute treatment of ER syndrome with VF storm For patients with ER syndrome and ongoing acute VF requiring frequent defibrillation, we suggest intravenous isoproterenol ( table 1). In a multicenter observational cohort study of 122 patients (90 males, mean age 37 12 years) with ER in the inferolateral leads and more than three episodes of idiopathic VF (including those with electrical storm), isoproterenol was effective for the acute suppression of VF, immediately suppressing electrical storms in seven of seven patients [101]. Theophylline has been described in a case report as eliminating ongoing malignant ventricular arrhythmias in spite of treatment with quinidine and high-rate ventricular pacing [102]. High-dose flecainide has also been reported to be effective at suppressing VF in ER syndrome in a case report [103]. In an experimental canine model of ER, quinidine, cilostazol, and milrinone, each administered individually, have been shown to suppress hypothermia-induced ventricular arrhythmias [104]. Furthermore in an ER syndrome wedge preparation, cilostazol and milrinone or isoproterenol were demonstrated to reverse the repolarization defects underlying the development of phase 2

Cardiac arrest occurs at rest or during sleep These patients may also display a high-risk ER pattern (J-point elevation >2 mm in the inferior or inferolateral leads or globally and/or horizontal or down sloping ST segment. (See 'Prognosis of ER pattern' above.) The ER pattern is not always identified on routine ECG due to the intermittent nature of ER. Bradycardia dependent and vagally dependent augmentation of ER has been reported [86]. However, no provocative test, such as pharmacologic augmentation of parasympathetic tone, is currently available and validated in this setting. Although the utility has not been studied systematically, tilt table testing may be of assistance to establish if vagal stimulation is associated with VF/syncope and/or if high-risk ER features are provoked. However, the diagnostic accuracy of this approach is unknown, and vasovagal syncope is far more common in comparison with VF due to ER syndrome. (See 'Prognostic variables' above and "Upright tilt table testing in the evaluation of syncope".) DIFFERENTIAL DIAGNOSIS ER versus Brugada syndrome Some individuals with Brugada syndrome (ECG findings of ST- segment elevation in leads V1 to V2 associated with SCD or sustained ventricular arrhythmia) also have ER (approximately 12 percent) as variants in genes encoding the L-type calcium channel, ATP-sensitive potassium channel, and sodium channels have been associated with both of these conditions [61,62,64,87-90]. Additionally, some ECG characteristics of ER resemble features of the Brugada ECG, including J waves, pause and bradycardia dependent accentuation, the dynamic nature of the ECG manifestations, short-coupled extra-systole-induced polymorphic ventricular tachycardia/ventricular fibrillation, and suppression of the ECG features and arrhythmia with isoproterenol and quinidine [8,82]. However, the provocation of the Brugada pattern by sodium channel blocker is not observed in ER [91]. In fact, sodium channel blockers in most patients with ER attenuate the J-point, whereas the J-point is augmented by sodium-channel blockers in the right precordial leads in patients with a Brugada ECG. Furthermore, a positive signal-averaged ECG and structural abnormalities in the RV outflow tract are not consistently observed and have not been reported in patients with ER, respectively [92-94]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) ER versus acute pericarditis As is seen in ER, there is J-point elevation with resultant ST segment elevation in patients with acute pericarditis. Symptom presentation is markedly https://www.uptodate.com/contents/early-repolarization/print 13/37 7/6/23, 3:25 PM Early repolarization - UpToDate different in the two conditions. Unlike ER, most patients with acute pericarditis have ST elevations diffusely in most or all limb and precordial leads. Additionally, patients with acute pericarditis often have deviation of the PR segment, which is not present in ER. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Electrocardiogram'.) ER versus acute myocardial injury While patients with acute myocardial injury due to ST- elevation myocardial infarction (STEMI) can initially have elevation of the J point with concave ST- segment elevation, the ST-segment elevation typically becomes more pronounced and convex (rounded upward) as the infarction persists. However, the primary distinguishing factor between ER and acute myocardial injury is the presence of clinical symptoms such as chest pain or dyspnea. The distinction between the ECG findings of ER and acute MI are discussed in greater detail elsewhere. (See "Electrocardiogram in the diagnosis of myocardial ischemia and infarction", section on 'Early repolarization'.) TREATMENT Treatment of ER pattern As discussed above, the ER pattern is nearly always a benign incidental ECG finding, with no specific signs or symptoms attributed to it. In addition, there is no current risk stratification strategy for asymptomatic patients with ER pattern in the general population and within families with ER pattern that would allow for the identification of higher risk individuals with the ER pattern who might be candidates for treatment. The 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline for management of patients with ventricular arrhythmias and the prevention of SCD recommends observation with no treatment, and the 2015 European Society of Cardiology guidelines on the treatment of ventricular arrhythmias and prevention of SCD found that there was "insufficient evidence" to make a recommendation on the management of the ER pattern without associated symptomatic ventricular arrhythmias [12,95]. As such, for patients with the incidental finding of the ER pattern on their ECG, we recommend observation without therapy ( table 1). Treatment of ER syndrome with idiopathic VF Among survivors of SCD due to idiopathic ventricular fibrillation (VF), the reported rate of recurrent VF ranges between 22 and 37 percent at two to four years [96-98]. Because these patients have no demonstrated structural heart disease, they have an excellent prognosis for long-term survival if VF is treated ( algorithm 1). As a result, such patients are best treated with an ICD [12,95-100]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) https://www.uptodate.com/contents/early-repolarization/print 14/37 7/6/23, 3:25 PM Early repolarization - UpToDate In patients with idiopathic VF, substrate and/or trigger ablation is feasible, safe, and effective in specialized centers [78,79]. In 43 patients undergoing ablation for recurrent VF episodes due to ER syndrome, two phenotypes were identified; one with late depolarization abnormalities predominantly in the epicardium of the RV outflow tract and RV inferolateral epicardium (group 1), and the other with VF triggers associated with Purkinje sites but without abnormal epicardial/endocardial depolarization substrates (group 2) [78]. Epicardial anterior RV, RV outflow tract, inferior RV, posterior and posterolateral LV and apical ablation guided by location of abnormal depolarization substrates +/- premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) triggers in group 1 and Purkinje PVC ablation in group 2 were effective with no VF recurrence in 91 percent at 31 +/- 26 months follow-up. Single procedure success was 67 percent. Ablation resulted in the disappearance of the ER pattern in 82 percent. Acute treatment of ER syndrome with VF storm For patients with ER syndrome and ongoing acute VF requiring frequent defibrillation, we suggest intravenous isoproterenol ( table 1). In a multicenter observational cohort study of 122 patients (90 males, mean age 37 12 years) with ER in the inferolateral leads and more than three episodes of idiopathic VF (including those with electrical storm), isoproterenol was effective for the acute suppression of VF, immediately suppressing electrical storms in seven of seven patients [101]. Theophylline has been described in a case report as eliminating ongoing malignant ventricular arrhythmias in spite of treatment with quinidine and high-rate ventricular pacing [102]. High-dose flecainide has also been reported to be effective at suppressing VF in ER syndrome in a case report [103]. In an experimental canine model of ER, quinidine, cilostazol, and milrinone, each administered individually, have been shown to suppress hypothermia-induced ventricular arrhythmias [104]. Furthermore in an ER syndrome wedge preparation, cilostazol and milrinone or isoproterenol were demonstrated to reverse the repolarization defects underlying the development of phase 2 reentry and VT/VF by inhibition of transient outward potassium current (Ito) and augmentation of L-type calcium current (Ica) [68]. Chronic treatment of ER syndrome Chronic treatment of the ER syndrome should include an ICD for rapid treatment of any recurrent VF ( table 1) [12,41]. Patients with frequent recurrent episodes of VF resulting in ICD shocks may require suppressive therapy with an antiarrhythmic drug and, rarely, ablation of a stereotypic initiating PVC. (See "Overview of catheter ablation of cardiac arrhythmias".) For patients with ER syndrome with prior resuscitated SCD due to VF, we recommend implantation of an ICD for secondary prevention of SCD. ICD therapy is highly effective in terminating ventricular arrhythmias in nearly all cases. https://www.uptodate.com/contents/early-repolarization/print 15/37 7/6/23, 3:25 PM Early repolarization - UpToDate Antiarrhythmic drug therapy is a therapeutic option for patients with recurrent VF following ICD implantation. For patients with ER syndrome and recurrent VF, we suggest the use of quinidine, a class IA antiarrhythmic drug, for chronic suppressive therapy. Class IA antiarrhythmic drugs have been shown to prevent reinduction of polymorphic ventricular arrhythmias both during electrophysiologic (EP) study and in long-term follow-up in patients with idiopathic VF [96,105]. The target dose should be 800 to 1600 mg per day, with a common target of 1200 to 1600 mg of quinidine sulfate divided in four doses. (See "Pharmacologic therapy in survivors of sudden cardiac arrest".) For patients with ER syndrome and prior idiopathic VF but no documented recurrent arrhythmias, we do not suggest chronic suppressive treatment with an antiarrhythmic drug as the frequency of recurrent VF attributed to ER syndrome is highly variable and not readily predicted. In an in vitro pharmacological model, the phosphodiesterase III inhibitors cilostazol or milrinone have been demonstrated to diminish ER manifestations and prevent the hypothermia-induced phase 2 reentry and ventricular tachycardia (VT)/VF [104]. Quinidine also demonstrated similar effects in this model. Patients with ER syndrome who participate in competitive athletics require further evaluation and appropriate precautions prior to returning to competition [106]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Early repolarization (ER) is defined as either a sharp well-defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST segment, or the presence of slurring at the terminal part of the QRS complex (since the J-wave or J-point elevation may be hidden in the terminal part of the QRS complex, resulting in the slurring of the terminal QRS complex) ( waveform 1). Most literature defines ER as being present on the ECG when there is J-point elevation of 0.1 mV in two adjacent leads with either a slurred or notched morphology. (See 'ECG findings' above.) https://www.uptodate.com/contents/early-repolarization/print 16/37 7/6/23, 3:25 PM Early repolarization - UpToDate ER is an ECG finding. Two terms, distinguished by the presence or absence of symptomatic arrhythmias, have been used to describe patients with this ECG finding (see 'ER pattern versus ER syndrome' above): The ER pattern describes the patient with appropriate ECG findings in the absence of symptomatic arrhythmias. The ER syndrome applies to the patient with both appropriate ECG findings and symptomatic arrhythmias (cardiac arrest). The mere presence of ER pattern on ECG should not lead to a classification of ER syndrome in the absence of symptoms or documented ventricular fibrillation (VF). Several population studies have estimated that the prevalence of ER ranges from 5 to 13 percent of persons. The perception that ER was a benign finding has changed, with numerous studies suggesting a two- to threefold increased risk of death in those with ER versus those without ER. While ER appears to increase one's risk of sudden cardiac death (SCD), the absolute risk of SCD remains exceedingly low in otherwise healthy people. (See 'Prevalence' above and 'Arrhythmic risk' above.) The genetic basis of ER continues to be elucidated, with the evidence restricted to either case reports or preliminary studies that fall short of clearly identifying the genetic basis of ER. (See 'Genetic basis and inheritance of ER' above.) The purported mechanisms of ER and idiopathic VF reflect either an imbalance in the ion channel currents responsible for the terminal portion of depolarization or the early portion of repolarization and/or abnormal epicardial RV depolarization abnormalities with conduction delay. (See 'Mechanism of ER and idiopathic ventricular fibrillation' above.) Given its relatively high prevalence in the general population in comparison with the incidence of idiopathic VF, the ER pattern is almost always an incidental ECG finding. The diagnosis of ER syndrome, however, should be considered in a survivor of SCD with ECG evidence of ER and VF and an apparently structurally normal heart following extensive testing. (See 'ER pattern' above and 'ER syndrome' above.) For patients with the incidental finding of the ER pattern on their ECG, we recommend observation without therapy (Grade 1A). (See 'Treatment of ER pattern' above.) For patients with ER and ongoing acute VF (VF storm) requiring frequent defibrillation, we suggest intravenous isoproterenol (Grade 2C). (See 'Acute treatment of ER syndrome with VF storm' above.) https://www.uptodate.com/contents/early-repolarization/print 17/37 7/6/23, 3:25 PM Early repolarization - UpToDate For patients with ER syndrome with prior resuscitated SCD due to VF, we recommend implantation of an implantable cardioverter-defibrillator (ICD) for secondary prevention of SCD (Grade 1A). (See 'Chronic treatment of ER syndrome' above.) For patients with ER syndrome and recurrent VF, we suggest the use of quinidine, a class IA antiarrhythmic drug, for chronic suppressive therapy (Grade 2C). (See 'Chronic treatment of ER syndrome' above.) Catheter ablation targeting epicardial substrates and/or Purkinje premature ventricular complex (PVC) triggers is appropriate in patients with recurrent VF not responding to quinidine. (See "Overview of catheter ablation of cardiac arrhythmias".) Patients with ER syndrome who have had an ICD placed but who have had no documented recurrent arrhythmias do not require chronic antiarrhythmic drug treatment. (See 'Chronic treatment of ER syndrome' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. Circulation 2009; 119:e241. 2. Patton KK, Ellinor PT, Ezekowitz M, et al. Electrocardiographic Early Repolarization: A Scientific Statement From the American Heart Association. Circulation 2016; 133:1520. 3. Macfarlane PW, Antzelevitch C, Haissaguerre M, et al. The Early Repolarization Pattern: A Consensus Paper. J Am Coll Cardiol 2015; 66:470. 4. Ha ssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008; 358:2016. 5. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009; 361:2529. 6. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010; 7:549. 7. Antzelevitch C, Yan GX, Viskin S. Rationale for the use of the terms J-wave syndromes and early repolarization. J Am Coll Cardiol 2011; 57:1587. https://www.uptodate.com/contents/early-repolarization/print 18/37 7/6/23, 3:25 PM Early repolarization - UpToDate 8. Nam GB, Ko KH, Kim J, et al. Mode of onset of ventricular fibrillation in patients with early repolarization pattern vs. Brugada syndrome. Eur Heart J 2010; 31:330. 9. Surawicz B, Macfarlane PW. Inappropriate and confusing electrocardiographic terms: J-wave syndromes and early repolarization. J Am Coll Cardiol 2011; 57:1584. 10. Wilde AA. "J-wave syndromes" bring the ATP-sensitive potassium channel back in the spotlight. Heart Rhythm 2012; 9:556. 11. Derval N, Simpson CS, Birnie DH, et al. Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol 2011; 58:722. 12. Priori SG, Blomstr m-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015; 36:2793. 13. Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol 2008; 52:1231. 14. Sinner MF, Reinhard W, M ller M, et al. Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA). PLoS Med 2010; 7:e1000314. 15. Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011; 123:2931. 16. McNamara DA, Bennett AJ, Ayers C, et al. Early Repolarization Pattern Is Associated With Increased Left Ventricular Mass: Insights From the Dallas Heart Study. JACC Clin Electrophysiol 2019; 5:395. 17. Olson KA, Viera AJ, Soliman EZ, et al. Long-term prognosis associated with J-point elevation in a large middle-aged biracial cohort: the ARIC study. Eur Heart J 2011; 32:3098. 18. Abe A, Ikeda T, Tsukada T, et al. Circadian variation of late potentials in idiopathic ventricular fibrillation associated with J waves: insights into alternative pathophysiology and risk stratification. Heart Rhythm 2010; 7:675. 19. Sugao M, Fujiki A, Nishida K, et al. Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide. J Cardiovasc Pharmacol 2005; 45:545. https://www.uptodate.com/contents/early-repolarization/print 19/37 7/6/23, 3:25 PM Early repolarization - UpToDate 20. Sahara M, Sagara K, Yamashita T, et al. J wave and ST segment elevation in the inferior leads: a latent type of variant Brugada syndrome? Jpn Heart J 2002; 43:55. 21. Kalla H, Yan GX, Marinchak R. Ventricular fibrillation in a patient with prominent J (Osborn) waves and ST segment elevation in the inferior electrocardiographic leads: a Brugada syndrome variant? J Cardiovasc Electrophysiol 2000; 11:95. 22. Aizawa Y, Tamura M, Chinushi M, et al. Idiopathic ventricular fibrillation and bradycardia- dependent intraventricular block. Am Heart J 1993; 126:1473. 23. Siebermair J, Sinner MF, Beckmann BM, et al. Early repolarization pattern is the strongest predictor of arrhythmia recurrence in patients with idiopathic ventricular fibrillation: results from a single centre long-term follow-up over 20 years. Europace 2016; 18:718. 24. Rosso R, Glikson E, Belhassen B, et al. Distinguishing "benign" from "malignant early repolarization": the value of the ST-segment morphology. Heart Rhythm 2012; 9:225. 25. Wu SH, Lin XX, Cheng YJ, et al. Early repolarization pattern and risk for arrhythmia death: a meta-analysis. J Am Coll Cardiol 2013; 61:645. 26. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011; 123:2666. 27. Serra-Grima R, Do ate M, lvarez-Garc a J, et al. Long-term follow-up of early repolarization pattern in elite athletes. Am J Med 2015; 128:192.e1. 28. Barbosa EC, Bomfim Ade S, Benchimol-Barbosa PR, Ginefra P. Ionic mechanisms and vectorial model of early repolarization pattern in the surface electrocardiogram of the athlete. Ann Noninvasive Electrocardiol 2008; 13:301. 29. Quattrini FM, Pelliccia A, Assorgi R, et al. Benign clinical significance of J-wave pattern (early repolarization) in highly trained athletes. Heart Rhythm 2014; 11:1974. 30. Klatsky AL, Oehm R, Cooper RA, et al. The early repolarization normal variant electrocardiogram: correlates and consequences. Am J Med 2003; 115:171. 31. Rollin A, Maury P, Bongard V, et al. Prevalence, prognosis, and identification of the malignant form of early repolarization pattern in a population-based study. Am J Cardiol 2012; 110:1302. 32. Ilkhanoff L, Soliman EZ, Prineas RJ, et al. Clinical characteristics and outcomes associated with the natural history of early repolarization in a young, biracial cohort followed to middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Circ Arrhythm Electrophysiol 2014; 7:392. 33. Cheng YJ, Lin XX, Ji CC, et al. Role of Early Repolarization Pattern in Increasing Risk of Death. J Am Heart Assoc 2016; 5. https://www.uptodate.com/contents/early-repolarization/print 20/37 7/6/23, 3:25 PM Early repolarization - UpToDate 34. Pargaonkar VS, Perez MV, Jindal A, et al. Long-term prognosis of early repolarization with J- wave and QRS slur patterns on the resting electrocardiogram: a cohort study. Ann Intern Med 2015; 163:747. 35. Roten L, Derval N, Maury P, et al. Benign vs. malignant inferolateral early repolarization: Focus on the T wave. Heart Rhythm 2016; 13:894. 36. Yoon N, Hong SN, Cho JG, et al. Experimental verification of the value of the Tpeak -Tend interval in ventricular arrhythmia inducibility in an early repolarization syndrome model. J Cardiovasc Electrophysiol 2019; 30:2098. 37. Karim Talib A, Sato N, Sakamoto N, et al. Enhanced transmural dispersion of repolarization in patients with J wave syndromes. J Cardiovasc Electrophysiol 2012; 23:1109. 38. Cristoforetti Y, Biasco L, Giustetto C, et al. J-wave duration and slope as potential tools to discriminate between benign and malignant early repolarization. Heart Rhythm 2016; 13:806. 39. Holkeri A, Eranti A, Haukilahti MAE, et al. Impact of age and sex on the long-term prognosis associated with early repolarization in the general population. Heart Rhythm 2020; 17:621. 40. Nunn LM, Bhar-Amato J, Lowe MD, et al. Prevalence of J-point elevation in sudden arrhythmic death syndrome families. J Am Coll Cardiol 2011; 58:286. 41. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013; 10:1932. 42. Merchant FM, Noseworthy PA, Weiner RB, et al. Ability of terminal QRS notching to distinguish benign from malignant electrocardiographic forms of early repolarization. Am J Cardiol 2009; 104:1402. 43. Cheng YJ, Li ZY, Yao FJ, et al. Early repolarization is associated with a significantly increased risk of ventricular arrhythmias and sudden cardiac death in patients with structural heart diseases. Heart Rhythm 2017; 14:1157. 44. Walsh JA 3rd, Ilkhanoff L, Soliman EZ, et al. Natural history of the early repolarization pattern in a biracial cohort: CARDIA (Coronary Artery Risk Development in Young Adults) Study. J Am Coll Cardiol 2013; 61:863. 45. Perez MV, Uberoi A, Jain NA, et al. The prognostic value of early repolarization with ST- segment elevation in African Americans. Heart Rhythm 2012; 9:558. 46. Rosso R, Adler A, Halkin A, Viskin S. Risk of sudden death among young individuals with J waves and early repolarization: putting the evidence into perspective. Heart Rhythm 2011; https://www.uptodate.com/contents/early-repolarization/print 21/37 7/6/23, 3:25 PM Early repolarization - UpToDate 8:923. 47. Patel RB, Ilkhanoff L, Ng J, et al. Clinical characteristics and prevalence of early repolarization associated with ventricular arrhythmias following acute ST-elevation myocardial infarction. Am J Cardiol 2012; 110:615. 48. Patel RB, Ng J, Reddy V, et al. Early repolarization associated with ventricular arrhythmias in patients with chronic coronary artery disease. Circ Arrhythm Electrophysiol 2010; 3:489. 49. Furukawa Y, Yamada T, Morita T, et al. Early repolarization pattern associated with sudden cardiac death: long-term follow-up in patients with chronic heart failure. J Cardiovasc Electrophysiol 2013; 24:632. 50. Watanabe H, Makiyama T, Koyama T, et al. High prevalence of early repolarization in short QT syndrome. Heart Rhythm 2010; 7:647. 51. Panicker GK, Manohar D, Karnad DR, et al. Early repolarization and short QT interval in healthy subjects. Heart Rhythm 2012; 9:1265. 52. Caliskan K, Ujvari B, Bauernfeind T, et al. The prevalence of early repolarization in patients with noncompaction cardiomyopathy presenting with malignant ventricular arrhythmias. J Cardiovasc Electrophysiol 2012; 23:938. 53. Laksman ZW, Gula LJ, Saklani P, et al. Early repolarization is associated with symptoms in patients with type 1 and type 2 long QT syndrome. Heart Rhythm 2014; 11:1632. 54. Sugrue A, Rohatgi RK, Bos M, et al. Clinical Significance of Early Repolarization in Long QT Syndrome. JACC Clin Electrophysiol 2018; 4:1238. 55. T l men E, Schulze-Bahr E, Zumhagen S, et al. Early repolarization pattern: a marker of increased risk in patients with catecholaminergic polymorphic ventricular tachycardia. Europace 2016; 18:1587. 56. Kaneko Y, Horie M, Niwano S, et al. Electrical storm in patients with brugada syndrome is associated with early repolarization. Circ Arrhythm Electrophysiol 2014; 7:1122. 57. Hasegawa Y, Watanabe H, Ikami Y, et al. Early repolarization and risk of lone atrial fibrillation. J Cardiovasc Electrophysiol 2019; 30:565. 58. McNair PW, Benenson DM, Ip JE, et al. Prevalence of early repolarization pattern in patients with lone atrial fibrillation. J Electrocardiol 2017; 50:545. 59. Mahida S, Derval N, Sacher F, et al. Role of electrophysiological studies in predicting risk of ventricular arrhythmia in early repolarization syndrome. J Am Coll Cardiol 2015; 65:151. 60. Ha ssaguerre M, Chatel S, Sacher F, et al. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol 2009; 20:93. https://www.uptodate.com/contents/early-repolarization/print 22/37 7/6/23, 3:25 PM Early repolarization - UpToDate 61. Watanabe H, Nogami A, Ohkubo K, et al. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. Circ Arrhythm Electrophysiol 2011; 4:874. 62. Medeiros-Domingo A, Tan BH, Crotti L, et al. Gain-of-function mutation S422L in the KCNJ8- encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm 2010; 7:1466. 63. Barajas-Mart nez H, Hu D, Ferrer T, et al. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm 2012; 9:548. 64. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm 2010; 7:1872. 65. Noseworthy PA, Tikkanen JT, Porthan K, et al. The early repolarization pattern in the general population: clinical correlates and heritability. J Am Coll Cardiol 2011; 57:2284. 66. Reinhard W, Kaess BM, Debiec R, et al. Heritability of early repolarization: a population- based study. Circ Cardiovasc Genet 2011; 4:134. 67. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large families in early repolarization syndrome. J Am Coll Cardiol 2013; 61:164. 68. Patocskai B, Barajas-Martinez H, Hu D, et al. Cellular and ionic mechanisms underlying the effects of cilostazol, milrinone, and isoproterenol to suppress arrhythmogenesis in an experimental model of early repolarization syndrome. Heart Rhythm 2016; 13:1326. 69. Ji CC, Yao FJ, Cheng YJ, et al. A novel DPP6 variant in Chinese families causes early repolarization syndrome. Exp Cell Res 2019; 384:111561. 70. Cheng YJ, Yao H, Ji CC, et al. A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome. Cell Physiol Biochem 2018; 51:1301. 71. Takayama K, Ohno S, Ding WG, et al. A de novo gain-of-function KCND3 mutation in early repolarization syndrome. Heart Rhythm 2019; 16:1698. 72. Teumer A, Trenkwalder T, Kessler T, et al. KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern. JCI Insight 2019; 4. 73. Chauveau S, Janin A, Till M, et al. Early repolarization syndrome caused by de novo duplication of KCND3 detected by next-generation sequencing. HeartRhythm Case Rep 2017; 3:574. 74. Li N, Wang R, Hou C, et al. A heterozygous missense SCN5A mutation associated with early repolarization syndrome. Int J Mol Med 2013; 32:661. https://www.uptodate.com/contents/early-repolarization/print 23/37 7/6/23, 3:25 PM Early repolarization - UpToDate 75. Yao H, Ji CC, Cheng YJ, et al. Mutation in KCNE1 associated to early repolarization syndrome by modulation of slowly activating delayed rectifier K+ current. Exp Cell Res 2018; 363:315. 76. Sinner MF, Porthan K, Noseworthy PA, et al. A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern. Heart Rhythm 2012; 9:1627. 77. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation 1996; 93:372. 78. Nademanee K, Haissaguerre M, Hocini M, et al. Mapping and Ablation of Ventricular Fibrillation Associated With Early Repolarization Syndrome. Circulation 2019; 140:1477. 79. Ha ssaguerre M, Nademanee K, Hocini M, et al. Depolarization versus repolarization abnormality underlying inferolateral J-wave syndromes: New concepts in sudden cardiac death with apparently normal hearts. Heart Rhythm 2019; 16:781. 80. Voskoboinik A, Hsia H, Moss J, et al. The many faces of early repolarization syndrome: A single-center case series. Heart Rhythm 2020; 17:273. 81. Koncz I, Gurabi Z, Patocskai B, et al. Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome. J Mol Cell Cardiol 2014; 68:20. 82. Roten L, Derval N, Sacher F, et al. Heterogeneous response of J-wave syndromes to beta- adrenergic stimulation. Heart Rhythm 2012; 9:1970. 83. Maury P, Sacher F, Rollin A, et al. Ventricular fibrillation in loop recorder memories in a patient with early repolarization syndrome. Europace 2012; 14:148. 84. Krahn AD, Healey JS, Chauhan V, et al. Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER). Circulation 2009; 120:278. 85. Aizawa Y, Chinushi M, Hasegawa K, et al. Electrical storm in idiopathic ventricular fibrillation is associated with early repolarization. J Am Coll Cardiol 2013; 62:1015. 86. Mizumaki K, Nishida K, Iwamoto J, et al. Vagal activity modulates spontaneous augmentation of J-wave elevation in patients with idiopathic ventricular fibrillation. Heart Rhythm 2012; 9:249. 87. Letsas KP, Sacher F, Probst V, et al. Prevalence of early repolarization pattern in inferolateral leads in patients with Brugada syndrome. Heart Rhythm 2008; 5:1685. 88. Sarkozy A, Chierchia GB, Paparella G, et al. Inferior and lateral electrocardiographic repolarization abnormalities in Brugada syndrome. Circ Arrhythm Electrophysiol 2009; 2:154. https://www.uptodate.com/contents/early-repolarization/print 24/37 7/6/23, 3:25 PM Early repolarization - UpToDate 89. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115:442. 90. Hong K, Berruezo-Sanchez A, Poungvarin N, et al. Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A:. J Cardiovasc Electrophysiol 2004; 15:64. 91. Kawata H, Noda T, Yamada Y, et al. Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndrome. Heart Rhythm 2012; 9:77. 92. Nam GB, Kim YH, Antzelevitch C. Augmentation of J waves and electrical storms in patients with early repolarization. N Engl J Med 2008; 358:2078. 93. Roten L, Derval N, Sacher F, et al. Ajmaline attenuates electrocardiogram characteristics of inferolateral early repolarization. Heart Rhythm 2012; 9:232. 94. Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011; 123:1270. 95. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 96. Viskin S, Belhassen B. Idiopathic ventricular fibrillation. Am Heart J 1990; 120:661. 97. Wever EF, Hauer RN, Oomen A, et al. Unfavorable outcome in patients with primary electrical disease who survived an episode of ventricular fibrillation. Circulation 1993; 88:1021. 98. Marcus FI. Idiopathic ventricular fibrillation. J Cardiovasc Electrophysiol 1997; 8:1075. 99. Survivors of out-of-hospital cardiac arrest with apparently normal heart. Need for definition and standardized clinical evaluation. Consensus Statement of the Joint Steering Committees of the Unexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular Fibrillation Registry of the United States. Circulation 1997; 95:265. 100. Meissner MD, Lehmann MH, Steinman RT, et al. Ventricular fibrillation in patients without significant structural heart disease: a multicenter experience with implantable cardioverter- defibrillator therapy. J Am Coll Cardiol 1993; 21:1406. https://www.uptodate.com/contents/early-repolarization/print 25/37 7/6/23, 3:25 PM Early repolarization - UpToDate 101. Ha ssaguerre M, Sacher F, Nogami A, et al. Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization role of drug therapy. J Am Coll Cardiol 2009; 53:612. 102. Perrin T, Guieu R, Koutbi L, et al. Theophylline as an adjunct to control malignant ventricular arrhythmia associated with early repolarization. Pacing Clin Electrophysiol 2018; 41:444. 103. Ahn J, Roh SY, Lee DI, et al. Effect of flecainide on suppression of ventricular fibrillation in a patient with early repolarization syndrome. Heart Rhythm 2016; 13:1724. 104. Gurabi Z, Koncz I, Patocskai B, et al. Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine, cilostazol, and milrinone. Circ Arrhythm Electrophysiol 2014; 7:134. 105. Belhassen B, Viskin S, Fish R, et al. Effects of electrophysiologic-guided therapy with Class IA antiarrhythmic drugs on the long-term outcome of patients with idiopathic ventricular fibrillation with or without the Brugada syndrome. J Cardiovasc Electrophysiol 1999; 10:1301. 106. Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 10: The Cardiac Channelopathies: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2424. Topic 83199 Version 27.0 https://www.uptodate.com/contents/early-repolarization/print 26/37 7/6/23, 3:25 PM Early repolarization - UpToDate GRAPHICS Expert consensus recommendations regarding early repolarization from the HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes Expert consensus statement on diagnosis 1. ER syndrome is diagnosed in the presence of J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG in a patient resuscitated from otherwise unexplained VF/polymorphic VT. 2. ER syndrome can be diagnosed in an SCD victim with a negative autopsy and medical chart review with a previous ECG demonstrating J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG. 3. ER pattern can be diagnosed in the presence of J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG. Expert consensus statement on therapeutic intervention CLASS I 1. ICD implantation is recommended in patients with a diagnosis of ER syndrome who have survived a cardiac arrest. CLASS IIa 2. Isoproterenol infusion can be useful in suppressing electrical storms in patients with a diagnosis of ER syndrome. 3. Quinidine in addition to an ICD can be useful for secondary prevention of VF in patients with a diagnosis of ER syndrome. CLASS IIb 4. ICD implantation may be considered in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST-segment elevation >1 mm in 2 inferior or lateral leads. 5. ICD implantation may be considered in asymptomatic individuals who demonstrate a high-risk ER ECG pattern (high J-wave amplitude, horizontal/descending ST segment) in the presence of a strong family history of juvenile unexplained sudden death with or without a pathogenic mutation. CLASS III 6. ICD implantation is not recommended in asymptomatic patients with an isolated ER ECG pattern. ECG: electrocardiogram; VF: ventricular fibrillation; VT: ventricular tachycardia; ER: early repolarization; SCD: sudden cardiac death; ICD: implantable cardioverter defibrillator. https://www.uptodate.com/contents/early-repolarization/print 27/37 7/6/23, 3:25 PM Early repolarization - UpToDate Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes. Heart Rhythm 2013; 10:1932. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 93392 Version 2.0 https://www.uptodate.com/contents/early-repolarization/print 28/37 7/6/23, 3:25 PM Early repolarization - UpToDate Early repolarization end-QRS notch and slur terminology (A) Illustration of the amplitudes J onset (Jo), J peak (Jp), and J termination (Jt), as well as durations D and D , in relation to an end-QRS notch, as defined in the text. 1 2 (B) Illustration of Jp and Jt, as well as D , in relation to an end-QRS slur. 2

86. Mizumaki K, Nishida K, Iwamoto J, et al. Vagal activity modulates spontaneous augmentation of J-wave elevation in patients with idiopathic ventricular fibrillation. Heart Rhythm 2012; 9:249. 87. Letsas KP, Sacher F, Probst V, et al. Prevalence of early repolarization pattern in inferolateral leads in patients with Brugada syndrome. Heart Rhythm 2008; 5:1685. 88. Sarkozy A, Chierchia GB, Paparella G, et al. Inferior and lateral electrocardiographic repolarization abnormalities in Brugada syndrome. Circ Arrhythm Electrophysiol 2009; 2:154. https://www.uptodate.com/contents/early-repolarization/print 24/37 7/6/23, 3:25 PM Early repolarization - UpToDate 89. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115:442. 90. Hong K, Berruezo-Sanchez A, Poungvarin N, et al. Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A:. J Cardiovasc Electrophysiol 2004; 15:64. 91. Kawata H, Noda T, Yamada Y, et al. Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndrome. Heart Rhythm 2012; 9:77. 92. Nam GB, Kim YH, Antzelevitch C. Augmentation of J waves and electrical storms in patients with early repolarization. N Engl J Med 2008; 358:2078. 93. Roten L, Derval N, Sacher F, et al. Ajmaline attenuates electrocardiogram characteristics of inferolateral early repolarization. Heart Rhythm 2012; 9:232. 94. Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011; 123:1270. 95. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 96. Viskin S, Belhassen B. Idiopathic ventricular fibrillation. Am Heart J 1990; 120:661. 97. Wever EF, Hauer RN, Oomen A, et al. Unfavorable outcome in patients with primary electrical disease who survived an episode of ventricular fibrillation. Circulation 1993; 88:1021. 98. Marcus FI. Idiopathic ventricular fibrillation. J Cardiovasc Electrophysiol 1997; 8:1075. 99. Survivors of out-of-hospital cardiac arrest with apparently normal heart. Need for definition and standardized clinical evaluation. Consensus Statement of the Joint Steering Committees of the Unexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular Fibrillation Registry of the United States. Circulation 1997; 95:265. 100. Meissner MD, Lehmann MH, Steinman RT, et al. Ventricular fibrillation in patients without significant structural heart disease: a multicenter experience with implantable cardioverter- defibrillator therapy. J Am Coll Cardiol 1993; 21:1406. https://www.uptodate.com/contents/early-repolarization/print 25/37 7/6/23, 3:25 PM Early repolarization - UpToDate 101. Ha ssaguerre M, Sacher F, Nogami A, et al. Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization role of drug therapy. J Am Coll Cardiol 2009; 53:612. 102. Perrin T, Guieu R, Koutbi L, et al. Theophylline as an adjunct to control malignant ventricular arrhythmia associated with early repolarization. Pacing Clin Electrophysiol 2018; 41:444. 103. Ahn J, Roh SY, Lee DI, et al. Effect of flecainide on suppression of ventricular fibrillation in a patient with early repolarization syndrome. Heart Rhythm 2016; 13:1724. 104. Gurabi Z, Koncz I, Patocskai B, et al. Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine, cilostazol, and milrinone. Circ Arrhythm Electrophysiol 2014; 7:134. 105. Belhassen B, Viskin S, Fish R, et al. Effects of electrophysiologic-guided therapy with Class IA antiarrhythmic drugs on the long-term outcome of patients with idiopathic ventricular fibrillation with or without the Brugada syndrome. J Cardiovasc Electrophysiol 1999; 10:1301. 106. Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 10: The Cardiac Channelopathies: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2424. Topic 83199 Version 27.0 https://www.uptodate.com/contents/early-repolarization/print 26/37 7/6/23, 3:25 PM Early repolarization - UpToDate GRAPHICS Expert consensus recommendations regarding early repolarization from the HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes Expert consensus statement on diagnosis 1. ER syndrome is diagnosed in the presence of J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG in a patient resuscitated from otherwise unexplained VF/polymorphic VT. 2. ER syndrome can be diagnosed in an SCD victim with a negative autopsy and medical chart review with a previous ECG demonstrating J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG. 3. ER pattern can be diagnosed in the presence of J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG. Expert consensus statement on therapeutic intervention CLASS I 1. ICD implantation is recommended in patients with a diagnosis of ER syndrome who have survived a cardiac arrest. CLASS IIa 2. Isoproterenol infusion can be useful in suppressing electrical storms in patients with a diagnosis of ER syndrome. 3. Quinidine in addition to an ICD can be useful for secondary prevention of VF in patients with a diagnosis of ER syndrome. CLASS IIb 4. ICD implantation may be considered in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST-segment elevation >1 mm in 2 inferior or lateral leads. 5. ICD implantation may be considered in asymptomatic individuals who demonstrate a high-risk ER ECG pattern (high J-wave amplitude, horizontal/descending ST segment) in the presence of a strong family history of juvenile unexplained sudden death with or without a pathogenic mutation. CLASS III 6. ICD implantation is not recommended in asymptomatic patients with an isolated ER ECG pattern. ECG: electrocardiogram; VF: ventricular fibrillation; VT: ventricular tachycardia; ER: early repolarization; SCD: sudden cardiac death; ICD: implantable cardioverter defibrillator. https://www.uptodate.com/contents/early-repolarization/print 27/37 7/6/23, 3:25 PM Early repolarization - UpToDate Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes. Heart Rhythm 2013; 10:1932. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 93392 Version 2.0 https://www.uptodate.com/contents/early-repolarization/print 28/37 7/6/23, 3:25 PM Early repolarization - UpToDate Early repolarization end-QRS notch and slur terminology (A) Illustration of the amplitudes J onset (Jo), J peak (Jp), and J termination (Jt), as well as durations D and D , in relation to an end-QRS notch, as defined in the text. 1 2 (B) Illustration of Jp and Jt, as well as D , in relation to an end-QRS slur. 2 Reproduced from: Macfarlane PW, Antzelevitch C, Haissaguerre M, et al. The Early Repolarization Pattern: A Consensus Paper. J Am Coll Cardiol 2015; 66:470. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 118056 Version 1.0 https://www.uptodate.com/contents/early-repolarization/print 29/37 7/6/23, 3:25 PM Early repolarization - UpToDate Early repolarization 12 lead ECG Early repolarization manifest as inferior J-point slurring and lateral J-point notching, each >1 mm in two contiguous leads. Graphic 83883 Version 2.0 https://www.uptodate.com/contents/early-repolarization/print 30/37 7/6/23, 3:25 PM Early repolarization - UpToDate J or Osborn wave ECG change with hypothermia, including presence of J wave. Reproduced with permission from: Hickey R, De Caen A. Warming Procedures. In: Textbook of Pediatric Emergency Procedures, 2nd ed, King C, Henretig FM (Eds), Lippincott Williams & Wilkins, Philadelphia 2008. Copyright 2008 Lippincott Williams & Wilkins. www.lww.com. Graphic 56369 Version 11.0 https://www.uptodate.com/contents/early-repolarization/print 31/37 7/6/23, 3:25 PM Early repolarization - UpToDate Early repolarization 12-lead electrocardiogram Marked inferior and lateral ER of 3 mm. ER: early repolarization. Graphic 83891 Version 3.0 https://www.uptodate.com/contents/early-repolarization/print 32/37 7/6/23, 3:25 PM Early repolarization - UpToDate Action potentials in early repolarization A disproportionately abbreviated epicardial action potential compared with the endocardial action potential causes J-point elevation. Graphic 83884 Version 1.0 https://www.uptodate.com/contents/early-repolarization/print 33/37 7/6/23, 3:25 PM Early repolarization - UpToDate Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/early-repolarization/print 34/37 7/6/23, 3:25 PM Early repolarization - UpToDate Signal-averaged ECG in early repolarization Signal-averaged ECG in a patient with ER demonstrating normal parameters (filtered QRS duration 124 milliseconds, duration of high frequency low amplitude signal less than 40 microvolts of 37 milliseconds, and root mean square voltage in the terminal 40 milliseconds of 19 microvolts). Graphic 83890 Version 2.0 https://www.uptodate.com/contents/early-repolarization/print 35/37 7/6/23, 3:25 PM Early repolarization - UpToDate Approach for the acute management of ventricular arrhythmia An algorithmic approach for the acute management of ventricular arrhythmia associated with genetic disorders. VF: ventricular fibrillation; PMVT: polymorphic ventricular tachycardia, possible torsade de pointes; ERS: early repolarization syndrome. Refer to UpToDate text for details. Graphic 83895 Version 3.0 https://www.uptodate.com/contents/early-repolarization/print 36/37 7/6/23, 3:25 PM Early repolarization - UpToDate Contributor Disclosures Andrew Krahn, MD No relevant financial relationship(s) with ineligible companies to disclose. Manoj Obeyesekere, MBBS, MD No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/early-repolarization/print 37/37

7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Electrical storm and incessant ventricular tachycardia : Rod Passman, MD, MSCE : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2023. INTRODUCTION Electrical storm, also referred to as arrhythmic storm, refers to multiple recurrences of ventricular arrhythmias over a short period of time. In most instances, the arrhythmia is ventricular tachycardia (VT), but polymorphic VT and ventricular fibrillation (VF) can also result in electrical storm. The arrhythmias can be self-terminating but frequently are terminated using antiarrhythmic drugs or device-related therapies (defibrillation or anti-tachycardia pacing). In contrast to repetitive ventricular arrhythmias occurring in electrical storm, incessant VT is defined as hemodynamically stable VT which persists for longer than one hour. This topic will discuss the incidence, triggers, clinical significance and treatment of electric storm and incessant VT. The general approach to the diagnosis and management of VT, as well as the use of implantable cardioverter-defibrillators, are discussed separately in various topics. (See "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) DEFINITION Electrical storm refers to a state of cardiac electrical instability characterized by multiple episodes of ventricular tachycardia (VT storm) or ventricular fibrillation (VF storm) within a https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 1/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate relatively short period of time, typically 24 hours [1]. The clinical definition of electrical storm is varied, somewhat arbitrary, and is a source of ongoing debate [2]. In patients without an implantable cardioverter-defibrillator (ICD), electrical storm has been variously defined as [1,3-5]: The occurrence of three or more hemodynamically stable ventricular tachyarrhythmias within 24 hours VT recurring soon after (within five minutes) termination of another VT episode Sustained and non-sustained VT resulting in a total number of ventricular ectopic beats greater than sinus beats in a 24-hour period In patients with an ICD, the most widely accepted definition of electrical storm is three or more appropriate therapies for ventricular tachyarrhythmias, including antitachycardia pacing or shocks, within 24 hours [2,5-9]. However, this definition is not comprehensive as it fails to account for: VT that is slower than the programmed detection rate of the ICD VT that fails to terminate with appropriate ICD therapy and remain undetected by the patient VT that recurs soon after (within five minutes) a successful therapy are included by only some authors [7,10] While electrical storm is defined by recurrent ventricular arrhythmia episodes or recurrent ICD therapies, incessant VT is defined as hemodynamically stable VT lasting longer than one hour. INCIDENCE The reported incidence of electrical storm varies widely based on the differences in the definition used, characteristics of the study population, device programming, and interpretation of intracardiac electrograms. The indication for implantable cardioverter-defibrillator (ICD) implantation (ie, primary versus secondary prevention) and type of underlying heart disease appear to be the most likely to influence the reported incidence of electrical storm. Most patients with electrical storm or incessant VT have severe underlying structural heart disease, although electrical storm or incessant VT has been less frequently reported in patients with structurally normal hearts (eg, Brugada syndrome or long QT syndrome). (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 2/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate When electrical storm is defined by >2 VT/VF episodes requiring device intervention over a 24- hour period, the incidence is approximately 2 to 10 percent per year follow-up period in patients with ICDs [2,6-8,11-17]. As examples: In an analysis of 719 patients from the MADIT II study of primary prevention ICD implantation who were followed for an average of 21 months, 4 percent experienced electrical storm (2.3 percent per year) [8]. In a single-center cohort of 955 patients who received an ICD (81 percent for primary prevention) and were followed for 4.5 years, 6.6 percent experienced electrical storm (1.5 percent per year) [17]. TRIGGERS OF ELECTRICAL STORM Most patients with electrical storm or incessant VT have severe underlying structural heart disease, and studies have revealed an inciting factor in only a minority of patients with electrical storm. However, careful assessment is required as some of the known triggers are reversible, including [9]: Drug toxicity Electrolyte disturbances (ie, hypokalemia and hypomagnesemia) New or worsened heart failure Acute myocardial ischemia Thyrotoxicosis QT prolongation (which may be related to drug toxicity, electrolyte imbalance, or an underlying syndrome such as long QT syndrome) A circadian pattern of electrical storm seems likely as well, as shown in a meta-analysis of 246 patients from five cohorts, in which 29 percent of electrical storm episodes occurred between 8 AM and 10 AM (and 61 percent occurred between 8 AM and 4 PM) [18]. These varied triggers highlight the complex interactions among anatomic substrate, autonomic tone, and cellular milieu that result in electrical storm. CLINICAL PRESENTATION The clinical presentation of electrical storm is highly variable but rarely if ever asymptomatic. One or more ventricular arrhythmias may be present, but monomorphic VT is the inciting arrhythmia in the vast majority of patients. https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 3/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Symptoms The type and severity of symptoms from electrical storm depends on the ventricular rate, the presence of underlying heart disease, the degree of left ventricular systolic dysfunction, and the presence or absence of therapies delivered by an implantable cardioverter- defibrillator (ICD). In patients without an ICD, the range of clinical presentations due to electrical storm spans from relatively minor symptoms such as repeated episodes of palpitations, presyncope, or syncope if the patient remains hemodynamically stable to cardiac arrest in those patients with hemodynamically unstable ventricular arrhythmias. In patients with a preexisting ICD, electrical storm typically presents with multiple ICD therapies (some combination of anti-tachycardia pacing and ICD shocks depending on how the device is programmed to deliver therapy). However, patients with ventricular arrhythmias that are slower than the detection settings of the ICD may present in similar fashion as patients without an ICD. Patients with incessant VT may present with similar symptoms (eg, presyncope, syncope, palpitations, chest pain, dyspnea, etc), which again will vary depending on the ventricular rate and hemodynamic instability related to the VT. Rarely, when patients have incessant VT at slower rates (<150 beats per minute), they may remain asymptomatic and hemodynamically stable for days or longer. In such cases, the initial presentation may be heart failure symptoms, suggesting that the incessant VT has resulted in tachycardia-mediated cardiomyopathy. (See "Arrhythmia- induced cardiomyopathy".) Electrocardiographic monitoring Electrical storm is not likely to be captured on a standard 12-lead electrocardiogram (ECG), given the brief 10-second window of time recorded with an ECG. Alternatively, continuous monitoring with either surface ECG (continuous ambulatory telemetry monitoring) or intracardiac electrograms (as recorded by an ICD) is required to document the presence, frequency, and duration of VT. A 12-lead ECG during incessant VT should be obtained whenever possible to help identify the mechanism and anatomic site of VT origin in order to help guide treatment. The electrocardiographic characteristics that are consistent with VT include a wide QRS complex occurring regularly at a rate of more than 100 beats per minute in association with one or more other distinct ECG characteristics (ie, AV dissociation, fusion beats, capture beats, etc). The ECG characteristics of VT are discussed in greater detail elsewhere. (See "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'Evaluation of the electrocardiogram'.) Type of ventricular arrhythmia Analyses of stored intracardiac electrograms (in patients with preexisting ICDs) recorded at the time of delivered therapies have provided insight into the https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 4/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate arrhythmias responsible for electrical storm. The frequency of various ventricular arrhythmias is as follows [6-8,10-13,15,16,19,20]: Monomorphic VT 86 to 97 percent Primary VF 1 to 21 percent Mixed VT/VF 3 to 14 percent Polymorphic VT 2 to 8 percent In patients with documented sustained arrhythmias prior to ICD implantation, there exists a significant correlation between the initial arrhythmia and that recorded during electrical storm. Patients with a prior history of VT are more likely to experience VT storm and a similar correlation is reported for patients with VF [8,15]. DIAGNOSIS The diagnosis of electrical storm is made when a patient has three or more confirmed episodes of ventricular tachyarrhythmia resulting in symptoms or implantable cardioverter-defibrillator (ICD) therapy within a 24-hour period. Typically, the episodes of arrhythmia are confirmed using continuous telemetry monitoring or by reviewing stored intracardiac electrograms from a patient's ICD. Given the likelihood of significant symptoms associated with electrical storm, the diagnosis is usually made in hospitalized patients (or in patients who have presented to the emergency department), though it is possible to make the diagnosis in outpatients whose cardiac activity is being continuously monitored (eg, patients with an ICD or wearing an ambulatory telemetry monitor). The diagnosis of incessant VT is made by confirming the presence of continuous VT for greater than one hour. As with electrical storm, given the likelihood of significant symptoms with incessant VT, the diagnosis is usually made in hospitalized patients (or in patients who have presented to the emergency department), though it is possible to make the diagnosis in outpatients whose cardiac activity is being continuously monitored (eg, patients with an ICD or wearing an ambulatory telemetry monitor). Rarely, when patients have incessant VT at slower rates (<150 beats per minute), remaining asymptomatic and hemodynamically stable, the initial presentation may be related to tachycardia-mediated cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".) DIFFERENTIAL DIAGNOSIS https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 5/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate The differential diagnosis of electrical storm should be thought of differently depending on the presence or absence of an implantable cardioverter-defibrillator (ICD): In patients without an ICD, the differential diagnosis includes the usual causes of a wide QRS complex tachycardia ( table 1). In patients with an ICD who receive multiple ICD shocks, the differential diagnosis includes the usual causes of a wide QRS complex tachycardia as well as the possibility of ICD malfunction (eg, electrical noise, oversensing, lead fracture, etc). (See "Cardiac implantable electronic devices: Long-term complications", section on 'Inappropriate shocks'.) Differentiating supraventricular tachycardia (SVT) with aberrant conduction from VT can usually be done by identifying P waves associated with every QRS complex (in contrast to the AV dissociation seen with VT) on a surface ECG or atrial activity associated with each ventricular activity on intracardiac electrogram. In patients who have received multiple ICD shock, device interrogation can quickly determine in the shocks were appropriate (in response to ventricular tachyarrhythmia) or inappropriate (ie, in response to an SVT or device malfunction). The differential diagnosis of incessant VT is similar to that of any wide QRS complex tachycardia ( table 1). Most commonly, this would include atrial tachycardia or atrial flutter (with aberrant conduction), although any type of SVT must be considered. TREATMENT In patients with an acute and ongoing episode of electrical storm or incessant VT, initial treatment is based on hemodynamic stability or instability [9]. Patients with hemodynamically unstable ventricular arrhythmias should initially undergo electrical cardioversion according to advanced cardiac life support protocol ( algorithm 1) [5]. (See "Advanced cardiac life support (ACLS) in adults", section on 'Pulseless ventricular tachycardia and ventricular fibrillation'.) Patients with electrical storm or incessant VT who are hemodynamically stable should be treated with both intravenous (IV) antiarrhythmic therapy and a beta blocker. We recommend IV amiodarone as the initial antiarrhythmic agent given its superior efficacy for terminating most ventricular arrhythmias. Additionally, because of the adrenergic surge associated with frequent ventricular tachyarrhythmias and defibrillator shocks, we recommend co-administration of a beta blocker, usually oral propranolol. (See 'Initial management' below.) https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 6/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate For patients with electrical storm or incessant VT in whom active myocardial ischemia is felt to be a contributing factor, urgent coronary revascularization should be pursued. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction".) Initial management ACLS and defibrillation Patients with electrical storm or incessant VT should be rapidly assessed for evidence of hemodynamic stability. Patients without a pulse or with other signs/symptoms of hemodynamic instability (ie, hypotension, active anginal-type chest pain or dyspnea, new changes in mental status, etc) should be promptly treated according to advanced cardiac life support (ACLS) protocol ( algorithm 1) with electrical cardioversion/defibrillation [5,21]. ACLS is discussed in greater detail separately. (See "Advanced cardiac life support (ACLS) in adults", section on 'Pulseless ventricular tachycardia and ventricular fibrillation'.) Patients who are successfully resuscitated from cardiac arrest associated with a ventricular arrhythmia are usually treated with antiarrhythmic therapy as well. (See 'Initial antiarrhythmic medical therapy' below.) Initial antiarrhythmic medical therapy While patients with electrical storm or incessant VT who are hemodynamically stable do not usually require emergent electrical cardioversion, urgent therapy is necessary to treat the ventricular arrhythmia(s) and reduce the effect of the adrenergic nervous system on the heart. Patients should be treated with both IV antiarrhythmic therapy and a beta blocker. Our approach to initial medical therapy is as follows: We recommend IV amiodarone (150 mg IV over 10 minutes, followed by 1 mg/minute IV infusion for 6 hours, followed by 0.5 mg/minute IV infusion for 18 additional hours), rather than lidocaine, procainamide, or no antiarrhythmic drug, as the initial antiarrhythmic agent given its superior efficacy for terminating most ventricular arrhythmias. We recommend oral propranolol (40 mg every 6 hours for the first 48 hours, with additional IV doses as needed for recurrent breakthrough ventricular arrhythmias) rather than a beta-1 selective beta blocker. Once the patient has stabilized, the patient should be transitioned to an oral beta blocker for long-term management. (See 'Maintenance antiarrhythmic therapy' below.) This approach is in agreement with the 2017 AHA/ACC/HRS guidelines for the management of ventricular arrhythmias and the prevention of sudden cardiac death as well as the 2014 position paper from the European Heart Rhythm Association, both of which included recommendations for the management of electrical storm and incessant VT [5,22]. Following stabilization, options https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 7/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate for long-term arrhythmia control include catheter ablation or chronic oral antiarrhythmic therapy. (See 'Subsequent management' below.) Amiodarone Amiodarone has been shown in numerous trials to significantly improve survival from cardiac arrest and reduce the frequency of ventricular tachyarrhythmias [23-26]. As examples: Among a group of 504 patients with out-of-hospital cardiac arrest due to VF/VT who were not resuscitated following three or more external shocks and who were randomized to either IV amiodarone (300 mg) or placebo, patients who received amiodarone were significantly more like to survive to hospital admission (odds ratio 1.6, 95% CI 1.1-2.4) [23]. In a randomized, double-blind dose ranging trial of 342 patients with electrical storm who received one of three IV doses of amiodarone (125 mg, 500 mg, or 1000 mg over the first 24 hours, with supplemental 150 mg IV doses as needed for recurrent VF/VT), patients in the 1000 mg group had an 88 percent reduction in ventricular arrhythmias in the initial 24 hours of therapy (compared with the 24 hours preceding therapy with amiodarone) [24]. Among a group of 273 patients with recurrent VF/VT refractory to therapy with lidocaine, procainamide, and bretylium who received amiodarone, 40 percent survived for 24 hours without any recurrent hemodynamically significant ventricular arrhythmias [25]. Beta blockers Beta blockers are utilized to reduce the adrenergic surge associated with frequent ventricular tachyarrhythmias and defibrillator shocks. There is extensive evidence of the efficacy of beta blockers in patients with various cardiac conditions (eg, heart failure with reduced left ventricular systolic function, acute myocardial ischemia and/or infarction, etc) in which beta blockers reduced the impact of the sympathetic nervous system on the heart. Patients with electrical storm or incessant VT, particularly those who have received multiple defibrillations, will have increased sympathetic nervous system output, which can further predispose to additional arrhythmias, and they should be treated with a beta blocker along with antiarrhythmic drugs [22]. Propranolol, a nonselective beta blocker, appears to be more effective than metoprolol, which is beta-1 selective. In a single-center, double-blind study of 60 patients with electrical storm, all patients received IV amiodarone and were randomized to propranolol (40 mg every 6 hours) or metoprolol (50 mg every 6 hours) for the first 48 hours [27]. The primary end point (time to termination of ventricular arrhythmias) occurred significantly earlier in patients receiving propranolol (3 versus 18 hours with metoprolol), with 27 of 30 patients receiving propranolol free of ventricular arrhythmias within 24 hours (compared with 16 of 30 receiving metoprolol). Additionally, compared with the patients receiving metoprolol, patients receiving propranolol https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 8/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate had significant improvement in several secondary end points, including lower rates of ventricular arrhythmias (incidence rate ratio 0.38, 95% CI 0.21-0.68) and implantable cardioverter-defibrillator (ICD) shocks (incidence rate ratio 0.43, 95% CI 0.23-0.89) during the ICU stay and shorter hospitalizations. The efficacy of sympathetic blockade was compared with conventional antiarrhythmic drugs in an observational study of 49 patients with electrical storm occurring up to 50 days after an acute myocardial infarction [28]. Patients treated with sympathetic blockade (beta blockers or stellate ganglionic blockade) had a lower overall mortality compared with patients treated with conventional antiarrhythmics both at one week (22 versus 82 percent) and at one year (33 versus 95 percent). Patients with an ICD Careful implantable cardiac-defibrillator (ICD) interrogation and assessment of programming are necessary in the setting of electrical storm. This ensures that delivered therapies are appropriate and that the ICD itself is not contributing to the event. Rare cases of pacing "permitted" or "facilitated" ventricular tachycardia (VT) or ventricular fibrillation (VF) have been reported where the pacing mode or programmed rate allows for proarrhythmic pauses or short-long-short sequences. [29]. Anti-tachycardia pacing can also be proarrhythmic in that it may accelerate VT to ventricular flutter or VF. Coronary revascularization For patients with electrical storm or incessant VT in whom active myocardial ischemia is felt to be a contributing factor, urgent coronary revascularization should be pursued as revascularization, and restoration of adequate coronary perfusion may be enough to resolve the ventricular tachyarrhythmias [22,30,31]. Urgent coronary revascularization is discussed in greater detail elsewhere. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction".) Subsequent management Catheter ablation Catheter ablation of ventricular tachyarrhythmias is an important and effective therapy for electrical storm or incessant VT [5,22,32-34]. For patients with electrical storm or incessant VT that persists or recurs in spite of medical therapy with amiodarone and a beta blocker, we recommend catheter ablation. Ablation for these conditions is a complex procedure with significant risk and should be performed in experienced centers capable of treating the recognized complications. Catheter ablation may also be considered in patients whose ventricular tachyarrhythmias are controlled with medical therapy but who are intolerant of medical therapy due to side effects. (See "Overview of catheter ablation of cardiac https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 9/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate arrhythmias" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.) Elimination of recurrent VT using catheter ablation techniques has long been available. Most reports of catheter ablation in electrical storm or incessant VT have been case reports or small retrospective single-center cohort studies. In a meta-analysis of 471 patients with electrical storm compiled from 39 publications (case reports and cohort studies), there was a high initial success rate for ablation of all ventricular arrhythmias (72 percent) along with a low procedural mortality rate (0.6 percent) and a relatively low recurrence rate of 6 percent over 61 weeks mean follow-up [35]. In this review, the recurrence rate was significantly higher after ablation for electrical storm due to monomorphic VT compared with VF or polymorphic VT with underlying cardiomyopathy (odds ratio 3.8, 95% CI 1.7-8.6). In a multicenter case series of 1940 patients undergoing VT ablation, which was published after the meta-analysis, 677 patients (35 percent) had electrical storm; patients with electrical storm had a greater number of inducible VTs, required longer procedure times, and had a higher hospital mortality compared with those without storm (6.2 versus 1.4 percent) [36]. At one-year follow-up, the risk of VT recurrence as detected by ICD interrogation was higher in the electrical storm group (32 versus 23 percent). Catheter ablation has also been used with reasonable success in patients with cardiogenic shock and refractory VT that together necessitated mechanical circulatory support; in one single-center experience with 21 such patients, 17 patients were successfully weaned from mechanical circulatory support following ablation, with 15 patients surviving to discharge and 13 surviving for at least one year post-ablation [37]. The impact of catheter ablation on mortality in patients with electrical storm or incessant VT is not as clearly defined. In one single-center retrospective study of 52 patients with a first episode of electrical storm between 1995 and 2011 who were initially treated with pharmacologic therapy alone (29 patients) or catheter ablation (23 patients), the risk of recurrent electrical storm was significantly lower following catheter ablation, but there was no significant difference in survival over a median follow-up of 28 months [38]. Compared with patients undergoing VT ablation in the absence of electrical storm in a large case series of 1940 patients, those with electrical storm had a higher one-year mortality (20.1 versus 8.5 percent; hazard ratio 1.5, 95% CI 1.1-2.1) [36]. The high mortality seen in these patients is most likely related to the severity of underlying cardiac pathology in patients who present with electrical storm or incessant VT. The potential role of prophylactic catheter ablation for primary prevention of electrical storm in high-risk individuals is discussed separately. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.) https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 10/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Maintenance antiarrhythmic therapy Antiarrhythmic therapy should be maintained in the following patients: Patients who have undergone catheter ablation of their ventricular tachyarrhythmia, until there is evidence of no recurrent arrhythmias following the procedure, at which point the treating clinician may consider stopping the antiarrhythmic medication. Patients who have not undergone catheter ablation in whom stopping antiarrhythmic therapy would put them at risk for recurrent arrhythmias. Maintenance antiarrhythmic therapy is discussed in greater detail separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Antiarrhythmic drugs' and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Antiarrhythmic drugs'.) ICD implantation ICD implantation is contraindicated in patients with acute uncontrolled ventricular arrhythmias. However, once the patient has been treated successfully with maintenance antiarrhythmic therapy and catheter ablation, many patients will meet criteria for ICD implantation. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Indications'.) In the small minority of patients with electrical storm due to reversible triggers, eventual ICD implantation will not be necessary once the trigger is removed. These patients should also have no other indication for ICD implantation. (See 'Triggers of electrical storm' above.) Condition-specific therapies While general measures are appropriate for most patients, targeted therapies are indicated for specific conditions. Specific arrythmias Pause-dependent torsades de pointes can be effectively treated with pacing, and incessant arrhythmias associated with Brugada syndrome may be suppressed with quinidine or isoproterenol. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Brugada syndrome or pattern: Management and approach to screening of relatives".) Cardiomyopathy For the majority of patients in whom a cardiomyopathy will be present, appropriate heart failure therapies should be prescribed and titrated to maximally tolerated doses. (See "Overview of the management of heart failure with reduced ejection fraction in adults".) Ischemia For patients in whom myocardial ischemia was the precipitating factor and who underwent revascularization, appropriate antithrombotic and anti-ischemic therapies https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 11/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate should be prescribed. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction".) Toxic and/or metabolic factors Correction of any identified inciting factors should occur. This may include removal of any offending drugs (eg, prescription or illicit drugs that prolong the QT interval) and correction of any electrolyte disturbances (ie, hypokalemia, hypomagnesemia, etc). Management of refractory cases Rarely, patients will continue to have refractory electrical storm or incessant VT in spite of medical therapy and catheter ablation attempts. A variety of salvage therapies may be considered, in conjunction with the standard therapies discussed above, when the other treatments have been unsuccessful, including [39-44]: Thoracic epidural anesthesia and/or general anesthesia [40,42]. Insertion of an intraaortic balloon pump or a temporary ventricular assist device. In appropriate patients, these devices may help stabilize patients with refractory recurrent VT until ablation or surgical treatment can be performed. (See "Intraaortic balloon pump counterpulsation", section on 'Refractory ventricular arrhythmias' and "Short-term mechanical circulatory assist devices".) Stellate ganglion block (SGB; usually left-sided). In aggregate, case series of patients treated with SGB show a reduction in episodes of VT and ICD shocks [44-49]. In the largest reported case series of 30 patients with drug-refractory electrical storm, among whom 15 underwent left and 15 underwent bilateral SGB, 18 patients (60 percent) were free of VT at 24 hours, with an overall reduction in VT burden of 92 percent over the initial 72 hours [50]. A study of 11 patients who underwent an SGB for electrical storm followed patients for sustained cessation of electrical storm for 24 hours. Cessation of electrical storm for 24 hours was achieved in 90 percent of patients after left SGB. Similarly, 90 percent of patients had no documented episodes of ventricular arrhythmias requiring intervention within six hours after SGB [49]. In a first-in-man case series, transcutaneous magnetic stimulation of the left stellate ganglion significantly reduced episodes of VT and shocks for 48 to 72 hours in five patients with VT storm [51]. SGB is a temporizing measure, and terminal sympathectomy via surgical cardiac sympathetic denervation (CSD) or orthotopic heart transplantation may be needed for eligible non-responders in whom other treatments have also failed. CSD, with one series suggesting bilateral CSD, is more efficacious than isolated left CSD [5,39-41,43,45,52-54]. https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 12/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Cardiac transplantation. (See "Heart transplantation in adults: Indications and contraindications", section on 'Indications for transplantation'.) Renal artery denervation (RDN), with one small series of four patients showing marked decrease in the frequency of VT episodes following RDN [55,56]. In a study of five patients with refractory VT, stereotactic body radiation therapy reduced the number of VT episodes by 99.9 percent, although the benefit was not quite as significant in a second study of 10 patients (88 percent reduction in VT) [57,58]. PROGNOSIS Electrical storm is generally associated with poor outcomes, with most studies reporting an association between electrical storm and cardiovascular mortality [7,10,15]. As examples: In the AVID trial, electrical storm was a significant independent risk factor for cardiac, non- sudden death (relative risk 2.4), which occurred most frequently within three months [7]. The MADIT II trial found that patients with electrical storm had a 7.4-fold higher risk of death when compared with those without electrical storm, with a 17.8-fold increased risk of death within the first three months after storm onset [8]. What is not clear is whether the ventricular tachyarrhythmias or repeated implantable cardioverter-defibrillator (ICD) shocks themselves contribute to cardiac mortality or are secondary to a degenerating cardiac status. A potential mechanism was suggested by the experimental observation that recurrent ventricular fibrillation (VF) results in increases in intracellular calcium concentrations which might contribute to deterioration of left ventricular systolic function [59,60]. Additionally, repeated shocks can cause myocardial injury leading to acute inflammation and fibrosis [61-63]. Lastly, myocardial injury or stunning from recurrent defibrillations may activate the neurohormonal cascade responsible for worsening heart failure and cardiovascular mortality [28,64,65]. Additional studies are needed to clarify these issues. Electrical storm, particularly when associated with repeated ICD discharges, may induce long- term anxiety that impacts overall health-related quality of life [6,10,11,13,66]. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Quality of life'.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 13/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Catheter ablation of arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics links (see "Patient education: Ventricular tachycardia (The Basics)") SUMMARY AND RECOMMENDATIONS Electrical storm, also referred to as arrhythmic storm, refers to multiple recurrences of ventricular arrhythmias over a short period of time, while incessant ventricular tachycardia (VT) is defined as hemodynamically stable VT which persists for hours. In most instances, the arrhythmia is monomorphic VT, but polymorphic VT and ventricular fibrillation (VF) can also result in electrical storm. The definition of electrical storm is different in patients with and without an implantable cardioverter-defibrillator (ICD). (See 'Definition' above.) Common triggers of electrical storm or incessant VT include drug toxicity, electrolyte disturbances, new or worsened heart failure, and acute myocardial ischemia, although a single inciting factor is not identified in the majority of patients. (See 'Triggers of electrical storm' above.) The clinical presentations of electrical storm and incessant are highly variable but rarely if ever asymptomatic. (See 'Clinical presentation' above.) https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 14/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate In patients without an ICD, the range of clinical presentations due to electrical storm spans from relatively minor symptoms such as repeated episodes of palpitations, presyncope, or syncope if the patient remains hemodynamically stable to cardiac arrest in those patients with hemodynamically unstable ventricular arrhythmias. In patients with a preexisting ICD, electrical storm typically presents with multiple ICD therapies (some combination of anti-tachycardia pacing and ICD shocks depending on how the device is programmed to deliver therapy). However, patients with ventricular arrhythmias that are slower than the detection settings of the ICD may present in similar fashion as patients without an ICD. The diagnosis of electrical storm is made when a patient has three or more confirmed episodes of ventricular tachyarrhythmia resulting in symptoms or ICD therapy within a 24- hour period. Typically, the episodes of arrhythmia are confirmed using continuous telemetry monitoring or by reviewing stored intracardiac electrograms from a patient's ICD. The diagnosis of incessant VT is made by confirming the presence of continuous VT for greater than one hour. (See 'Diagnosis' above.) The initial treatment approach to patients with electrical storm or incessant VT is based on hemodynamic stability or instability. Patients with hemodynamically unstable ventricular arrhythmias should initially undergo electrical cardioversion according to advanced cardiac life support protocol (

24 hours, with an overall reduction in VT burden of 92 percent over the initial 72 hours [50]. A study of 11 patients who underwent an SGB for electrical storm followed patients for sustained cessation of electrical storm for 24 hours. Cessation of electrical storm for 24 hours was achieved in 90 percent of patients after left SGB. Similarly, 90 percent of patients had no documented episodes of ventricular arrhythmias requiring intervention within six hours after SGB [49]. In a first-in-man case series, transcutaneous magnetic stimulation of the left stellate ganglion significantly reduced episodes of VT and shocks for 48 to 72 hours in five patients with VT storm [51]. SGB is a temporizing measure, and terminal sympathectomy via surgical cardiac sympathetic denervation (CSD) or orthotopic heart transplantation may be needed for eligible non-responders in whom other treatments have also failed. CSD, with one series suggesting bilateral CSD, is more efficacious than isolated left CSD [5,39-41,43,45,52-54]. https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 12/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Cardiac transplantation. (See "Heart transplantation in adults: Indications and contraindications", section on 'Indications for transplantation'.) Renal artery denervation (RDN), with one small series of four patients showing marked decrease in the frequency of VT episodes following RDN [55,56]. In a study of five patients with refractory VT, stereotactic body radiation therapy reduced the number of VT episodes by 99.9 percent, although the benefit was not quite as significant in a second study of 10 patients (88 percent reduction in VT) [57,58]. PROGNOSIS Electrical storm is generally associated with poor outcomes, with most studies reporting an association between electrical storm and cardiovascular mortality [7,10,15]. As examples: In the AVID trial, electrical storm was a significant independent risk factor for cardiac, non- sudden death (relative risk 2.4), which occurred most frequently within three months [7]. The MADIT II trial found that patients with electrical storm had a 7.4-fold higher risk of death when compared with those without electrical storm, with a 17.8-fold increased risk of death within the first three months after storm onset [8]. What is not clear is whether the ventricular tachyarrhythmias or repeated implantable cardioverter-defibrillator (ICD) shocks themselves contribute to cardiac mortality or are secondary to a degenerating cardiac status. A potential mechanism was suggested by the experimental observation that recurrent ventricular fibrillation (VF) results in increases in intracellular calcium concentrations which might contribute to deterioration of left ventricular systolic function [59,60]. Additionally, repeated shocks can cause myocardial injury leading to acute inflammation and fibrosis [61-63]. Lastly, myocardial injury or stunning from recurrent defibrillations may activate the neurohormonal cascade responsible for worsening heart failure and cardiovascular mortality [28,64,65]. Additional studies are needed to clarify these issues. Electrical storm, particularly when associated with repeated ICD discharges, may induce long- term anxiety that impacts overall health-related quality of life [6,10,11,13,66]. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Quality of life'.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 13/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Catheter ablation of arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics links (see "Patient education: Ventricular tachycardia (The Basics)") SUMMARY AND RECOMMENDATIONS Electrical storm, also referred to as arrhythmic storm, refers to multiple recurrences of ventricular arrhythmias over a short period of time, while incessant ventricular tachycardia (VT) is defined as hemodynamically stable VT which persists for hours. In most instances, the arrhythmia is monomorphic VT, but polymorphic VT and ventricular fibrillation (VF) can also result in electrical storm. The definition of electrical storm is different in patients with and without an implantable cardioverter-defibrillator (ICD). (See 'Definition' above.) Common triggers of electrical storm or incessant VT include drug toxicity, electrolyte disturbances, new or worsened heart failure, and acute myocardial ischemia, although a single inciting factor is not identified in the majority of patients. (See 'Triggers of electrical storm' above.) The clinical presentations of electrical storm and incessant are highly variable but rarely if ever asymptomatic. (See 'Clinical presentation' above.) https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 14/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate In patients without an ICD, the range of clinical presentations due to electrical storm spans from relatively minor symptoms such as repeated episodes of palpitations, presyncope, or syncope if the patient remains hemodynamically stable to cardiac arrest in those patients with hemodynamically unstable ventricular arrhythmias. In patients with a preexisting ICD, electrical storm typically presents with multiple ICD therapies (some combination of anti-tachycardia pacing and ICD shocks depending on how the device is programmed to deliver therapy). However, patients with ventricular arrhythmias that are slower than the detection settings of the ICD may present in similar fashion as patients without an ICD. The diagnosis of electrical storm is made when a patient has three or more confirmed episodes of ventricular tachyarrhythmia resulting in symptoms or ICD therapy within a 24- hour period. Typically, the episodes of arrhythmia are confirmed using continuous telemetry monitoring or by reviewing stored intracardiac electrograms from a patient's ICD. The diagnosis of incessant VT is made by confirming the presence of continuous VT for greater than one hour. (See 'Diagnosis' above.) The initial treatment approach to patients with electrical storm or incessant VT is based on hemodynamic stability or instability. Patients with hemodynamically unstable ventricular arrhythmias should initially undergo electrical cardioversion according to advanced cardiac life support protocol ( algorithm 1). (See "Advanced cardiac life support (ACLS) in adults", section on 'Pulseless ventricular tachycardia and ventricular fibrillation'.) Patients with electrical storm or incessant VT who are hemodynamically stable should be treated with both intravenous (IV) antiarrhythmic therapy and a beta blocker. We recommend IV amiodarone, rather than lidocaine, procainamide, or no antiarrhythmic drug, as the initial antiarrhythmic agent given its superior efficacy for terminating most ventricular arrhythmias (Grade 1B). Amiodarone should be given as 150 mg IV over 10 minutes, followed by 1 mg/minute IV infusion for 6 hours, followed by 0.5 mg/minute IV infusion for 18 additional hours. We recommend the nonselective beta blocker propranolol rather than a beta-1 selective beta blocker because of its increased efficacy in terminating VT (Grade 1B). Propranolol should be given as 40 mg oral doses every 6 hours for the first 48 hours, with additional IV doses as needed for recurrent breakthrough ventricular arrhythmias. (See 'Initial management' above.) https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 15/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate For patients with electrical storm or incessant VT in whom active myocardial ischemia is felt to be a contributing factor, urgent coronary revascularization should be pursued. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction".) The subsequent management of patients with electrical storm or incessant VT is focused on the prevention of recurrent ventricular tachyarrhythmias. For patients with electrical storm or incessant VT that persists or recurs in spite of medical therapy with amiodarone and a beta blocker, we recommend catheter ablation (Grade 1B). (See 'Catheter ablation' above.) Most patients will require at least a short course of maintenance antiarrhythmic therapy. (See 'Maintenance antiarrhythmic therapy' above.) Patients should also receive medical therapy aimed at the likely underlying cardiac pathology (eg, beta blockers and ACE-inhibitors in patients with heart failure and cardiomyopathy, anti-thrombotic and anti-ischemic therapy for patients with myocardial ischemia). (See 'Condition-specific therapies' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kowey PR. An overview of antiarrhythmic drug management of electrical storm. Can J Cardiol 1996; 12 Suppl B:3B. 2. Israel CW, Barold SS. Electrical storm in patients with an implanted defibrillator: a matter of definition. Ann Noninvasive Electrocardiol 2007; 12:375. 3. Kowey PR, Levine JH, Herre JM, et al. Randomized, double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995; 92:3255. 4. Hariman RJ, Hu DY, Gallastegui JL, et al. Long-term follow-up in patients with incessant ventricular tachycardia. Am J Cardiol 1990; 66:831. 5. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 16/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 6. Credner SC, Klingenheben T, Mauss O, et al. Electrical storm in patients with transvenous implantable cardioverter-defibrillators: incidence, management and prognostic implications. J Am Coll Cardiol 1998; 32:1909. 7. Exner DV, Pinski SL, Wyse DG, et al. Electrical storm presages nonsudden death: the antiarrhythmics versus implantable defibrillators (AVID) trial. Circulation 2001; 103:2066. 8. Sesselberg HW, Moss AJ, McNitt S, et al. Ventricular arrhythmia storms in postinfarction patients with implantable defibrillators for primary prevention indications: a MADIT-II substudy. Heart Rhythm 2007; 4:1395. 9. Haegeli LM, Della Bella P, Brunckhorst CB. Management of a Patient With Electrical Storm: Role of Epicardial Catheter Ablation. Circulation 2016; 133:672. 10. Gatzoulis KA, Andrikopoulos GK, Apostolopoulos T, et al. Electrical storm is an independent predictor of adverse long-term outcome in the era of implantable defibrillator therapy. Europace 2005; 7:184. 11. B nsch D, B cker D, Brunn J, et al. Clusters of ventricular tachycardias signify impaired survival in patients with idiopathic dilated cardiomyopathy and implantable cardioverter defibrillators. J Am Coll Cardiol 2000; 36:566. 12. Stuber T, Eigenmann C, Delacr taz E. Characteristics and relevance of clustering ventricular arrhythmias in defibrillator recipients. Pacing Clin Electrophysiol 2005; 28:702. 13. Hohnloser SH, Al-Khalidi HR, Pratt CM, et al. Electrical storm in patients with an implantable defibrillator: incidence, features, and preventive therapy: insights from a randomized trial. Eur Heart J 2006; 27:3027. 14. Arya A, Haghjoo M, Dehghani MR, et al. Prevalence and predictors of electrical storm in patients with implantable cardioverter-defibrillator. Am J Cardiol 2006; 97:389. 15. Verma A, Kilicaslan F, Marrouche NF, et al. Prevalence, predictors, and mortality significance of the causative arrhythmia in patients with electrical storm. J Cardiovasc Electrophysiol 2004; 15:1265. 16. Brigadeau F, Kouakam C, Klug D, et al. Clinical predictors and prognostic significance of electrical storm in patients with implantable cardioverter defibrillators. Eur Heart J 2006; 27:700. 17. Streitner F, Kuschyk J, Veltmann C, et al. Predictors of electrical storm recurrences in patients with implantable cardioverter-defibrillators. Europace 2011; 13:668. https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 17/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate 18. Guerra F, Bonelli P, Flori M, et al. Temporal Trends and Temperature-Related Incidence of Electrical Storm: The TEMPEST Study (Temperature-Related Incidence of Electrical Storm). Circ Arrhythm Electrophysiol 2017; 10. 19. Greene M, Newman D, Geist M, et al. Is electrical storm in ICD patients the sign of a dying heart? Outcome of patients with clusters of ventricular tachyarrhythmias. Europace 2000; 2:263. 20. Fries R, Heisel A, Huwer H, et al. Incidence and clinical significance of short-term recurrent ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillator. Int J Cardiol 1997; 59:281. 21. Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S729. 22. Gorenek B, Blomstr m Lundqvist C, Brugada Terradellas J, et al. Cardiac arrhythmias in acute coronary syndromes: position paper from the joint EHRA, ACCA, and EAPCI task force. Europace 2014; 16:1655. 23. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999; 341:871. 24. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995; 92:3264. 25. Levine JH, Massumi A, Scheinman MM, et al. Intravenous amiodarone for recurrent sustained hypotensive ventricular tachyarrhythmias. Intravenous Amiodarone Multicenter Trial Group. J Am Coll Cardiol 1996; 27:67. 26. Eifling M, Razavi M, Massumi A. The evaluation and management of electrical storm. Tex Heart Inst J 2011; 38:111. 27. Chatzidou S, Kontogiannis C, Tsilimigras DI, et al. Propranolol Versus Metoprolol for Treatment of Electrical Storm in Patients With Implantable Cardioverter-Defibrillator. J Am Coll Cardiol 2018; 71:1897. 28. Nademanee K, Taylor R, Bailey WE, et al. Treating electrical storm : sympathetic blockade versus advanced cardiac life support-guided therapy. Circulation 2000; 102:742. 29. Sweeney MO, Ruetz LL, Belk P, et al. Bradycardia pacing-induced short-long-short sequences at the onset of ventricular tachyarrhythmias: a possible mechanism of proarrhythmia? J Am Coll Cardiol 2007; 50:614. https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 18/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate 30. Authors/Task Force members, Windecker S, Kolh P, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35:2541. 31. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019; 40:87. 32. Carbucicchio C, Santamaria M, Trevisi N, et al. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverter-defibrillators: short- and long- term outcomes in a prospective single-center study. Circulation 2008; 117:462. 33. Deneke T, Shin DI, Lawo T, et al. Catheter ablation of electrical storm in a collaborative hospital network. Am J Cardiol 2011; 108:233. 34. Tan VH, Yap J, Hsu LF, Liew R. Catheter ablation of ventricular fibrillation triggers and electrical storm. Europace 2012; 14:1687. 35. Nayyar S, Ganesan AN, Brooks AG, et al. Venturing into ventricular arrhythmia storm: a systematic review and meta-analysis. Eur Heart J 2013; 34:560. 36. Vergara P, Tung R, Vaseghi M, et al. Successful ventricular tachycardia ablation in patients with electrical storm reduces recurrences and improves survival. Heart Rhythm 2018; 15:48. 37. Ballout JA, Wazni OM, Tarakji KG, et al. Catheter Ablation in Patients With Cardiogenic Shock and Refractory Ventricular Tachycardia. Circ Arrhythm Electrophysiol 2020; 13:e007669. 38. Izquierdo M, Ruiz-Granell R, Ferrero A, et al. Ablation or conservative management of electrical storm due to monomorphic ventricular tachycardia: differences in outcome. Europace 2012; 14:1734. 39. Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 2004; 109:1826. 40. Bourke T, Vaseghi M, Michowitz Y, et al. Neuraxial modulation for refractory ventricular arrhythmias: value of thoracic epidural anesthesia and surgical left cardiac sympathetic denervation. Circulation 2010; 121:2255. 41. Ajijola OA, Lellouche N, Bourke T, et al. Bilateral cardiac sympathetic denervation for the management of electrical storm. J Am Coll Cardiol 2012; 59:91. 42. Burjorjee JE, Milne B. Propofol for electrical storm; a case report of cardioversion and suppression of ventricular tachycardia by propofol. Can J Anaesth 2002; 49:973. https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 19/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate 43. Vaseghi M, Gima J, Kanaan C, et al. Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: intermediate and long-term follow- up. Heart Rhythm 2014; 11:360. 44. Meng L, Tseng CH, Shivkumar K, Ajijola O. Efficacy of Stellate Ganglion Blockade in Managing Electrical Storm: A Systematic Review. JACC Clin Electrophysiol 2017; 3:942. 45. Cardona-Guarache R, Padala SK, Velazco-Davila L, et al. Stellate ganglion blockade and bilateral cardiac sympathetic denervation in patients with life-threatening ventricular arrhythmias. J Cardiovasc Electrophysiol 2017; 28:903. 46. Fudim M, Boortz-Marx R, Ganesh A, et al. Stellate ganglion blockade for the treatment of refractory ventricular arrhythmias: A systematic review and meta-analysis. J Cardiovasc Electrophysiol 2017; 28:1460. 47. Sanghai S, Abbott NJ, Dewland TA, et al. Stellate Ganglion Blockade With Continuous Infusion Versus Single Injection for Treatment of Ventricular Arrhythmia Storm. JACC Clin Electrophysiol 2021; 7:452. 48. Reinertsen E, Sabayon M, Riso M, et al. Stellate ganglion blockade for treating refractory electrical storm: a historical cohort study. Can J Anaesth 2021; 68:1683. 49. Patel RA, Condrey JM, George RM, et al. Stellate ganglion block catheters for refractory electrical storm: a retrospective cohort and care pathway. Reg Anesth Pain Med 2023; 48:224. 50. Tian Y, Wittwer ED, Kapa S, et al. Effective Use of Percutaneous Stellate Ganglion Blockade in Patients With Electrical Storm. Circ Arrhythm Electrophysiol 2019; 12:e007118. 51. Markman TM, Hamilton RH, Marchlinski FE, Nazarian S. Case Series of Transcutaneous Magnetic Stimulation for Ventricular Tachycardia Storm. JAMA 2020; 323:2200. 52. Vaseghi M, Barwad P, Malavassi Corrales FJ, et al. Cardiac Sympathetic Denervation for Refractory Ventricular Arrhythmias. J Am Coll Cardiol 2017; 69:3070. 53. Assis FR, Sharma A, Shah R, et al. Long-Term Outcomes of Bilateral Cardiac Sympathetic Denervation for Refractory Ventricular Tachycardia. JACC Clin Electrophysiol 2021; 7:463. 54. Cauti FM, Rossi P, Bianchi S, et al. Outcome of a Modified Sympathicotomy for Cardiac Neuromodulation of Untreatable Ventricular Tachycardia. JACC Clin Electrophysiol 2021; 7:442. 55. Remo BF, Preminger M, Bradfield J, et al. Safety and efficacy of renal denervation as a novel treatment of ventricular tachycardia storm in patients with cardiomyopathy. Heart Rhythm 2014; 11:541. https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 20/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate 56. Garg J, Shah S, Shah K, et al. Renal sympathetic denervation for the treatment of recurrent ventricular arrhythmias-ELECTRAM investigators. Pacing Clin Electrophysiol 2021; 44:865. 57. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. N Engl J Med 2017; 377:2325. 58. Neuwirth R, Cvek J, Knybel L, et al. Stereotactic radiosurgery for ablation of ventricular tachycardia. Europace 2019; 21:1088. 59. Zaugg CE, Wu ST, Barbosa V, et al. Ventricular fibrillation-induced intracellular Ca2+ overload causes failed electrical defibrillation and post-shock reinitiation of fibrillation. J Mol Cell Cardiol 1998; 30:2183. 60. Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev 1999; 79:215. 61. Epstein AE, Kay GN, Plumb VJ, et al. Gross and microscopic pathological changes associated with nonthoracotomy implantable defibrillator leads. Circulation 1998; 98:1517. 62. Hurst TM, Hinrichs M, Breidenbach C, et al. Detection of myocardial injury during transvenous implantation of automatic cardioverter-defibrillators. J Am Coll Cardiol 1999; 34:402. 63. Joglar JA, Kessler DJ, Welch PJ, et al. Effects of repeated electrical defibrillations on cardiac troponin I levels. Am J Cardiol 1999; 83:270. 64. Poelaert J, Jordaens L, Visser CA, et al. Transoesophageal echocardiographic evaluation of ventricular function during transvenous defibrillator implantation. Acta Anaesthesiol Scand 1996; 40:913. 65. Runsi M, Bergfeldt L, Brodin LA, et al. Left ventricular function after repeated episodes of ventricular fibrillation and defibrillation assessed by transoesophageal echocardiography. Eur Heart J 1997; 18:124. 66. Sears SE Jr, Conti JB. Understanding implantable cardioverter defibrillator shocks and storms: medical and psychosocial considerations for research and clinical care. Clin Cardiol 2003; 26:107. Topic 1058 Version 47.0 https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 21/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate GRAPHICS Causes of a wide QRS complex tachycardia Ventricular tachycardia (VT) Any type of supraventricular tachycardia (SVT) with a preexistent bundle branch block or a rate-related (functional) bundle branch block Sinus tachycardia Atrial tachycardia Atrial flutter Atrioventricular nodal reentrant tachycardia Atrioventricular reentrant tachycardia (orthodromic) Any SVT which occurs in a patient receiving an antiarrhythmic drug, primarily class IA or IC, or in a patient with severe hyperkalemia Any SVT with antegrade conduction via an accessory pathway (Wolff-Parkinson-White syndrome) Sinus tachycardia Atrial tachycardia Atrial flutter Atrioventricular reentrant tachycardia (antidromic) Electronic pacemaker in certain specific settings Graphic 51512 Version 2.0 https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 22/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Adult tachycardia with a pulse algorithm 2020 update Reprinted with permission. ACLS Provider Manual. Copyright 2020 American Heart Association, Inc. Graphic 130747 Version 10.0 https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 23/24 7/6/23, 3:26 PM Electrical storm and incessant ventricular tachycardia - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/electrical-storm-and-incessant-ventricular-tachycardia/print 24/24

7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk : Martin S Maron, MD : Samuel L vy, MD, William J McKenna, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 24, 2020. INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease caused by mutations in one of several sarcomere genes that encode components of the contractile apparatus of the heart. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".) HCM is characterized by left ventricular (LV) hypertrophy of various morphologies, with a wide array of clinical manifestations and hemodynamic abnormalities ( figure 1). Depending in part upon the site and extent of cardiac hypertrophy, patients with HCM can develop one or more of the following abnormalities: LV outflow obstruction. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction".) Diastolic and systolic dysfunction. Myocardial ischemia. Mitral regurgitation. These structural and functional abnormalities can produce a variety of symptoms, including: Fatigue Dyspnea Chest pain Palpitations https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 1/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Presyncope or syncope In broad terms, the symptoms related to HCM can be categorized as those related to heart failure (HF), chest pain, or arrhythmias. Patients with HCM are prone to both atrial and ventricular arrhythmias. Many of these arrhythmias are asymptomatic, but some can precipitate hemodynamic collapse and sudden cardiac death (SCD). SCD is a catastrophic and unpredictable complication of HCM and in some patients may be the first presentation of the disease. The management of patients following risk assessment and following a documented ventricular arrhythmia will be reviewed here. The assessment of risk for arrhythmic SCD is a critical component of the clinical evaluation of nearly all patients with HCM and is reviewed separately. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".) Other issues related to ventricular arrhythmias and SCD, as well as other clinical manifestations, natural history, diagnosis and evaluation, and treatment of patients with HCM, are discussed separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation" and "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation" and "Hypertrophic cardiomyopathy: Natural history and prognosis" and "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".) MANAGEMENT The management of the risk for SCD and ventricular arrhythmias in patients with HCM is centered around minimizing risk associated with physical activity and targeted interventions, primarily implantation of an ICD when indicated. There are limited roles for other nonpharmacologic therapies (eg, septal reduction therapy and catheter ablation) and medical therapy in the management of ventricular arrhythmias and risk of SCD. The overall role of nonpharmacologic therapies and medical therapy in patients with HCM is discussed in detail separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction".) Implantable cardioverter-defibrillators (ICDs) The ICD is the best available therapy for patients with HCM who have survived SCD or who are at high risk of ventricular arrhythmias and SCD. Randomized trials of ICD therapy have not been performed in patients with HCM; as a result, the indications for an ICD are derived from largely retrospective observational data that define strength of the noninvasive risk factors in identifying high-risk patients. In addition, efficacy of ICDs in patients with HCM is also derived from the incidence of appropriate ICD https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 2/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate therapies in patients who have had an ICD implanted [1-3]. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Recommendations for ICD therapy For patients who survive an episode of sustained ventricular tachycardia (VT) or SCD, we recommend implantation of an ICD for the secondary prevention of SCD. (See 'Secondary prevention ICD' below.) In patients with HCM with 1 of the major noninvasive risk markers ( table 1), it is reasonable to offer an ICD for primary prevention of SCD, taking into account the individual patient's age, clinical profile, and values/preferences regarding device therapy. (See 'Primary prevention ICD' below.) In patients with 1 major risk marker, but who remain ambivalent or uncertain regarding ICD implantation, magnitude of LV outflow tract gradient, abnormal blood pressure response to exercise, and the results of contrast-enhanced cardiovascular magnetic resonance imaging are important arbitrators in resolving high-risk status and the need for primary prevention ICD therapy. Age is also an important factor in considering patients at risk. Patients with HCM who have achieved an advanced age of 60 years are at very low risk for disease-related adverse events, including SCD, even in the presence of conventional risk factors. Therefore, a high threshold is necessary to consider older patients with HCM at high risk and candidates for ICD therapy for primary prevention of SCD. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".) If a patient with HCM develops a clinical indication for permanent pacing, and is otherwise low risk for SCD based on risk stratification strategy, there would be no indication for upgrading the pacemaker to include ICD functionality. Certain other subsets of patients with HCM, namely patients with end-stage HCM with LV ejection fraction <50 percent and patients with HCM and an LV apical aneurysm, are at high risk for SCD [4]. Patients with HCM and an LV apical aneurysm have a fivefold higher risk of life-threatening ventricular arrhythmias and SCD compared with patients with HCM who do not have an LV apical aneurysm. For this reason, many HCM patients with apical aneurysms have sufficiently increased risk of SCD to warrant implantation of an ICD for primary prevention of SCD. As is the case in similar management scenarios where prospective randomized trials are not possible, decisions regarding high-risk status should be made on an individual basis, taking into consideration the entire clinical profile of the patient. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 3/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Secondary prevention ICD Patients with HCM who have survived cardiac arrest due to VT or ventricular fibrillation (VF) are at an increased risk for recurrent events and should undergo ICD implantation for secondary prevention [1,5-12]. This risk was illustrated in a series of 33 patients successfully resuscitated from a cardiac arrest prior to the widespread use of ICDs [8]. They were treated with a variety of strategies, including septal myotomy and medical therapy. Despite treatment, recurrent arrhythmias were common. The survival rates free of recurrent cardiac arrest or death after 1, 5, and 10 years were 83, 65, and 53 percent, respectively. A high rate of recurrent ventricular arrhythmias in patients with HCM and a history of cardiac arrest or sustained VT are further supported by the frequency of appropriate shocks in patients who received an ICD for secondary prevention of SCD [10]. In a study of 160 selected high-risk patients with HCM and an ICD, including 94 patients with 24- or 48-hour ambulatory electrocardiogram (ECG) monitoring pre-ICD implant, nonsustained VT (NSVT) was detected in 86 patients (54 percent) during an average follow-up of four years [13]. Patients with documented NSVT were significantly more likely to develop sustained VT/VF requiring ICD therapy (21 versus 8 percent; adjusted hazard ratio [HR] 3.6, 95% CI 1.3-10.2). Factors associated with a significantly higher likelihood of requiring ICD therapy include NSVT duration >7 beats, rate >200 beats per minute, or more than one NSVT run. Primary prevention ICD In HCM patients with 1 major risk marker, an ICD can be beneficial for primary prevention of SCD. ( algorithm 1) [5,6,12]. The American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guidelines for the management of ventricular arrhythmias and the prevention of SCD note that an ICD is reasonable in patients with one or more major risk factors [12]. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Impact of number of risk factors' and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk modifiers'.) In a multicenter registry of 506 patients with HCM and an ICD (24 percent for secondary prevention) who were followed for an average of 3.7 years, 20 percent of patients received appropriate ICD interventions [2]. The rate of appropriate device activation was 10.6 percent per year when used for secondary prevention of SCD, and 3.6 percent per year when used for primary prevention. Similar rates of ICD intervention have been reported using registry data in a pediatric population; among 224 children and adolescents with HCM and an ICD (including 188 patients [84 percent] placed for primary prevention) who were followed for an average of 4.3 years, 43 patients (19 percent; 4.5 percent per year) received an appropriate ICD intervention [14]. Choice of device Traditionally, most patients with HCM who underwent ICD implantation received a transvenous ICD system, with the vast majority of long-term safety and efficacy of ICD https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 4/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate therapy in HCM patients being derived from studies with transvenous ICDs. Some patients with HCM may also be candidates for a subcutaneous ICD (S-ICD) rather than the standard ICD with transvenous leads [15]. The S-ICD provides patients the opportunity to avoid intravascular complications from long-term lead placement, a particular relevant point for patients with HCM who are young and often have many decades of risk and the need for primary prevention ICDs. In addition, the S-ICD can be extracted with minimal risk if an indication for device removal emerges at any point in patients' clinical course. However, prior to implantation, the surface ECG must be rigorously scrutinized to determine eligibility for the S- ICD in order to avoid inappropriate shocks related to T-wave oversensing [16]. (See "Subcutaneous implantable cardioverter defibrillators".) Early data from small cohort studies of S-ICD use in patients with HCM are promising: In a cohort of 872 patients (99 with HCM), similar implantation success and one-year complication rates following S-ICD implantation were seen for patients with and without HCM; additionally, 3 of the 99 patients with HCM had VT that was successfully terminated following the initial shock [17]. In a multicenter cohort of 88 patients with HCM who received an S-ICD and were followed for an average of 2.7 years, two patients received appropriate shocks terminating VT, while inappropriate shocks occurred in five patients (due to T-wave oversensing or supraventricular tachycardias with rates in the shock range) [18]. Among 122 consecutive patients with HCM who met criteria for ICD implantation (3 for secondary prevention, 119 for primary prevention based on one or more major risk markers) and were eligible for either S-ICD or transvenous ICD, 47 patients chose S-ICD while 75 chose transvenous ICD [19]. Rate of appropriate shocks was not different between S-ICD and transvenous ICD. Five patients (11 percent) with S-ICD received a total of 10 appropriate shocks, while 15 patients (20 percent) with a transvenous ICD received appropriate therapies (shocks in three patients, antitachycardia pacing in 12 patients). Inappropriate shocks were more common in S-ICD recipients (eight patients [17 percent) versus two patients [3 percent]). Although preliminary, this study demonstrates that despite the absence of antitachycardia pacing with the S-ICD, appropriate shock rates were not greater with the S-ICD compared to transvenous ICD. Our approach to device selection in high-risk HCM patients In patients with an indication for bradycardia pacing, or in whom monomorphic VT is most likely the initiating ventricular arrhythmia (ie, patients with HCM with LV apical aneurysm), https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 5/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate we place a transvenous ICD given the ability to provide bradycardia pacing and antitachycardia pacing. In patients with massive LV hypertrophy (LVH), defined as LV wall thickness 30 mm anywhere in the LV wall, we favor the transvenous ICD given that patients with HCM and massive LVH have not yet been well-represented in prospective S-ICD studies and the theoretical concern regarding long-term efficacy of the S-ICD in aborting life-threatening arrhythmias, particularly in patients with extreme disease expression. In patients with apical aneurysm, monomorphic VT is the most common initiating ventricular tachyarrhythmia, and for this reason we favor transvenous ICD, given the opportunity this device provides for anti-tachycardia pacing treatment to abort VT. For younger, active HCM patients without massive LVH in whom device therapy will be required over many decades of life, we employ a shared decision-making strategy in which patients are fully informed about the strengths and limitations of both devices to enable a transparent and reliable choice regarding selection of ICD. In middle-aged or older high-risk patients with HCM, the overall benefit of S-ICD is generally less compared with the transvenous device and for this reason we generally favor transvenous ICD for this subgroup, although it is reasonable to evaluate for S-ICD placement, incorporating similar shared decision-making strategy as discussed with younger patients. Complications of device therapy Long-term complications following ICD placement include the following [20-22]: Approximately 25 percent of patients experience inappropriate ICD discharge 6 to 13 percent experience lead complications (eg, fracture, dislodgment, oversensing) 4 to 5 percent develop device-related infection 2 to 3 percent experience bleeding or thrombosis By contrast to the experience among ICD recipients with other nonischemic and ischemic etiologies for cardiomyopathy, patients with HCM implanted for primary prevention ICDs do not appear to have a significant increase in all-cause or cardiac mortality following appropriate ICD shocks. Among a cohort of 486 patients with HCM felt to be at high risk for SCD and who received primary prevention ICDs, 94 patients (19 percent) received an appropriate ICD intervention (shock or antitachycardia pacing) over an average follow-up of 6.4 years (3.7 percent per year risk of appropriate ICD intervention) [23]. Freedom from HCM-related mortality at 1, 5, and 10 years was 100, 97, and 92 percent, respectively. The favorable outcome after https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 6/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate appropriate ICD shocks in HCM is likely related to the otherwise preserved myocardial substrate in HCM, in which systolic function is normal and risk of developing advanced HF is low. The rate of inappropriate shocks and lead fractures appears to be higher in children than in adults, largely because their activity level and body growth place continual strain on the leads, which are the weakest link in the system [22]. This issue is of particular concern, given the long periods that young patients will have prophylactically implanted devices. (See "Cardiac implantable electronic devices: Long-term complications".) Nonpharmacologic treatment of LV outflow tract obstruction Nonpharmacologic therapies for LV outflow tract obstruction are discussed separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".) Medical treatment Medical therapy for ventricular arrhythmias in patients with HCM has an important role in select clinical scenarios, including: Patients with symptomatic arrhythmias Patients with an ICD who have frequent arrhythmias or antitachyarrhythmia therapies Patients at high risk of ventricular arrhythmias who are not candidates for, or choose not to have, an ICD There is no evidence that pharmacologic therapy provides absolute protection against sudden death due to malignant ventricular arrhythmias in patients with HCM [24]. Thus, for patients with asymptomatic ventricular premature beats (VPBs) or NSVT, we recommend that pharmacologic therapy not be given for the purpose of arrhythmia suppression. However, for patients with symptoms due to VPBs or NSVT, we suggest pharmacologic treatment for symptom control, typically with a beta blocker or an antiarrhythmic drug. Patients with frequent sustained ventricular arrhythmias resulting in ICD shocks should be treated with adjunctive antiarrhythmic therapy, most often sotalol or amiodarone. Our general approach is as follows: For patients with symptomatic VPBs, we use beta blockers. (See "Premature ventricular complexes: Treatment and prognosis".) Patients with symptomatic NSVT can be treated with beta blockers, or in selected patients, sotalol or amiodarone, for the purpose of symptom control [25,26]. If antiarrhythmic therapy is required, we generally prefer sotalol in younger patients (<50 years of age) due to the potential toxicities associated with the long-term use (ie, years to decades) of amiodarone. There is a small risk of proarrhythmia with sotalol due to the potential for QT prolongation, although our experts feel the risks of sotalol in younger patients are https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 7/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate generally lower than the potential long-term toxicities of amiodarone. As such, sotalol remains an option, even in the absence of an ICD, although clinical experience and published data are limited. Because NSVT is associated with an increased risk of SCD, its presence should be taken into account when considering an individual's risk for SCD and the need for ICD therapy. Pharmacologic therapies directed at symptomatic NSVT do not reduce the risk of SCD and should not be used alone as an alternative to ICD therapy. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk stratification'.) Sustained VT in the absence of an identifiable provoking factor is generally regarded as a major risk factor for SCD. Nearly all such patients receive an ICD for secondary prevention. For patients with frequent arrhythmia recurrences who experience multiple shocks, adjunctive antiarrhythmic therapy is indicated, with sotalol or amiodarone and/or a beta blocker as therapeutic options [6,12,26]. Electrical storm and/or incessant VT are highly unusual in patients with HCM, and given the diffusely abnormal myocardial substrate in this disease, the efficacy of radiofrequency ablation is uncertain. One exception is those patients with HCM and LV apical aneurysms, in whom the focus of incessant ventricular tachyarrhythmias can often be reliably identified with mapping techniques (junction of the aneurysm rim with myocardium) and successfully treated with radiofrequency ablation [27,28]. (See "Electrical storm and incessant ventricular tachycardia", section on 'Catheter ablation'.) Catheter ablation Radiofrequency catheter ablation for recurrent VT in patients with HCM has largely been reserved for the subgroup of patients with LV apical aneurysm [28]. Among 13 patients with LV apical aneurysm and recurrent VT, seven underwent catheter ablation for VT, with six of the seven remaining free of subsequent VT at an average of 1.9 years of follow-up [29]. The success of catheter ablation in this subgroup of patients is due to the fact that the structural nidus for VT is commonly at the junction of the aneurysm rim and LV myocardium, providing an identifiable target for ablation. On the other hand, in the remainder of the HCM population, the diffuse abnormal myocardial substrate results in multiple foci for VT and therefore little evidence that catheter ablation would be successful [28]. The use of catheter ablation for ventricular arrhythmias is largely focused in other populations (eg, post-myocardial infarction) and is discussed in detail separately. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 8/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Restriction of physical activity Due to the potential risk of SCD associated with exercise in patients with HCM, activity restriction is an important component of patient management. Competitive athletes with a probable or unequivocal clinical diagnosis of HCM should not participate in most competitive sports, with the possible exception of those that are low intensity ( figure 2). Activity restriction in competitive athletes with HCM is discussed separately. (See "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Hypertrophic cardiomyopathy'.) Among patients with HCM who are not competitive athletes, there is frequently a desire to exercise for both recreation and personal fitness. Additionally, exercise may be an important mechanism to prevent cardiometabolic heart disease as most patients with HCM have an expected longevity that is similar to the general population. Historically, patients with HCM have been instructed to confine themselves to mild to moderate recreational level activities, always engaging in a noncompetitive manner. To provide a more concrete guide to the appropriate limits of exercise in HCM patients, some experts have suggested that at peak exertion, HCM patients should still be able to complete full sentences without straining to complete words. Several studies have suggested that exercise, either moderate- or high-intensity, is safe in carefully selected patients with HCM [30-34]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices" and "Society guideline links: Catheter ablation of arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 9/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hypertrophic cardiomyopathy in adults (The Basics)") Beyond the Basics topic (see "Patient education: Hypertrophic cardiomyopathy (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Patients with hypertrophic cardiomyopathy (HCM) are prone to ventricular arrhythmias. Ventricular arrhythmias can range from isolated ventricular premature beats (VPBs) to nonsustained ventricular tachycardia (NSVT) to sustained VT and ventricular fibrillation (VF). While the frequency of ventricular arrhythmias is highly variable, the annual incidence of sudden cardiac death (SCD) in the clinically identified general HCM patient population is approximately 1 percent. (See 'Introduction' above and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Epidemiology'.) SCD is the most-feared complication of HCM. The implantable cardioverter-defibrillator (ICD) is the best available therapy for patients with HCM who have survived SCD or who are at high risk of life-threatening ventricular arrhythmias. Persons with a probable or unequivocal clinical diagnosis of HCM should not participate in most competitive sports, with the possible exception of those that are low intensity ( figure 2). (See "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Hypertrophic cardiomyopathy'.) For patients who survive an episode of sustained VT or sudden cardiac arrest, we recommend implantation of an ICD for secondary prevention of SCD (Grade 1B). (See 'Implantable cardioverter-defibrillators (ICDs)' above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) In patients with HCM with 1 of the major noninvasive risk markers, we suggest implantation of an ICD for primary prevention of SCD (Grade 2C). ICD decision making in HCM should almost always take into account the individual patient's age, clinical profile, and values/preferences regarding device therapy. (See 'Recommendations for ICD therapy' above and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Established major risk markers'.) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 10/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate In patients with one major risk marker, but who remain ambivalent or uncertain regarding ICD implantation, magnitude of LV outflow tract gradient, abnormal blood pressure response to exercise, and the results of contrast-enhanced cardiovascular magnetic resonance imaging are important arbitrators in resolving high-risk status and the need for primary prevention ICD therapy. Age is also an important factor in considering patients at risk. (See 'Recommendations for ICD therapy' above and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk modifiers'.) Certain other subsets of patients with HCM, namely patients with end-stage HCM with LV ejection fraction <50 percent and patients with HCM and an LV apical aneurysm, are at high risk for SCD and therefore are also candidates for ICD therapy [4]. In patients with HCM and an LV apical aneurysm, we suggest implantation of an ICD for primary prevention of SCD (Grade 2C). (See 'Recommendations for ICD therapy' above and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Established major risk markers'.) Our approach to the selection of a particular type of ICD is presented in the text. (See 'Our approach to device selection in high-risk HCM patients' above.) There is no evidence that pharmacologic therapy provides absolute protection against SCD due to malignant ventricular arrhythmias in patients with HCM. However, medical therapy for ventricular arrhythmias in patients with HCM has an important role in select clinical scenarios: For patients with asymptomatic VPBs or NSVT, we recommend that pharmacologic therapy not be given for the purpose of arrhythmia suppression (Grade 1B). However, because NSVT is associated with an increased risk of SCD, its presence should be taken into account when considering the need for ICD therapy for primary prevention of sudden death. (See 'Medical treatment' above.) For patients with symptoms due to VPBs or NSVT, we suggest pharmacologic treatment for symptom control (Grade 2C). Beta blockers are the preferred initial therapy, and in refractory cases, we suggest sotalol or amiodarone. The purpose of medical therapy is the control of symptoms; it should not be considered an alternative to an ICD in patients at high risk of SCD. (See 'Medical treatment' above.) Patients with frequent sustained ventricular arrhythmias resulting in ICD shocks should be treated with adjunctive antiarrhythmic therapy, most often sotalol or amiodarone. Radiofrequency ablation is an option to abolish or mitigate recurrent ventricular https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 11/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate arrhythmias in patients with HCM and an apical aneurysm, although the efficacy of VT ablation in patients without an apical aneurysm is uncertain. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Other treatment options'.) ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Perry Elliott, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Elliott PM, Sharma S, Varnava A, et al. Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1999; 33:1596. 2. Maron BJ, Spirito P, Shen WK, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007; 298:405. 3. Begley DA, Mohiddin SA, Tripodi D, et al. Efficacy of implantable cardioverter defibrillator therapy for primary and secondary prevention of sudden cardiac death in hypertrophic cardiomyopathy. Pacing Clin Electrophysiol 2003; 26:1887. 4. Spirito P, Autore C. Management of hypertrophic cardiomyopathy. BMJ 2006; 332:1251. 5. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 124:e783. 6. Authors/Task Force members, Elliott PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014; 35:2733. 7. Maron BJ, Shen WK, Link MS, et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000; 342:365. 8. Cecchi F, Maron BJ, Epstein SE. Long-term outcome of patients with hypertrophic cardiomyopathy successfully resuscitated after cardiac arrest. J Am Coll Cardiol 1989; 13:1283. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 12/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate 9. Primo J, Geelen P, Brugada J, et al. Hypertrophic cardiomyopathy: role of the implantable cardioverter-defibrillator. J Am Coll Cardiol 1998; 31:1081. 10. Magnusson P, Gadler F, Liv P, M rner S. Risk Markers and Appropriate Implantable Defibrillator Therapy in Hypertrophic Cardiomyopathy. Pacing Clin Electrophysiol 2016; 39:291. 11. Thavikulwat AC, Tomson TT, Knight BP, et al. Appropriate Implantable Defibrillator Therapy in Adults With Hypertrophic Cardiomyopathy. J Cardiovasc Electrophysiol 2016; 27:953. 12. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 13. Wang W, Lian Z, Rowin EJ, et al. Prognostic Implications of Nonsustained Ventricular Tachycardia in High-Risk Patients With Hypertrophic Cardiomyopathy. Circ Arrhythm Electrophysiol 2017; 10. 14. Maron BJ, Spirito P, Ackerman MJ, et al. Prevention of sudden cardiac death with implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 2013; 61:1527. 15. Weinstock J, Bader YH, Maron MS, et al. Subcutaneous Implantable Cardioverter Defibrillator in Patients With Hypertrophic Cardiomyopathy: An Initial Experience. J Am Heart Assoc 2016; 5. 16. Maurizi N, Olivotto I, Olde Nordkamp LR, et al. Prevalence of subcutaneous implantable cardioverter-defibrillator candidacy based on template ECG screening in patients with hypertrophic cardiomyopathy. Heart Rhythm 2016; 13:457. 17. Lambiase PD, Gold MR, Hood M, et al. Evaluation of subcutaneous ICD early performance in hypertrophic cardiomyopathy from the pooled EFFORTLESS and IDE cohorts. Heart Rhythm 2016; 13:1066. 18. Nazer B, Dale Z, Carrassa G, et al. Appropriate and inappropriate shocks in hypertrophic cardiomyopathy patients with subcutaneous implantable cardioverter-defibrillators: An international multicenter study. Heart Rhythm 2020; 17:1107. 19. Maron MS, Steiger N, Burrows A, et al. Evidence That Subcutaneous Implantable Cardioverter-Defibrillators Are Effective and Reliable in Hypertrophic Cardiomyopathy. JACC Clin Electrophysiol 2020; 6:1019. 20. Schinkel AF, Vriesendorp PA, Sijbrands EJ, et al. Outcome and complications after implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: systematic https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 13/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate review and meta-analysis. Circ Heart Fail 2012; 5:552. 21. Vriesendorp PA, Schinkel AF, Van Cleemput J, et al. Implantable cardioverter-defibrillators in hypertrophic cardiomyopathy: patient outcomes, rate of appropriate and inappropriate interventions, and complications. Am Heart J 2013; 166:496. 22. Berul CI, Van Hare GF, Kertesz NJ, et al. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. J Am Coll Cardiol 2008; 51:1685. 23. Maron BJ, Casey SA, Olivotto I, et al. Clinical Course and Quality of Life in High-Risk Patients With Hypertrophic Cardiomyopathy and Implantable Cardioverter-Defibrillators. Circ Arrhythm Electrophysiol 2018; 11:e005820. 24. Maron BJ, Maron MS. Contemporary strategies for risk stratification and prevention of sudden death with the implantable defibrillator in hypertrophic cardiomyopathy. Heart Rhythm 2016; 13:1155. 25. McKenna WJ, Oakley CM, Krikler DM, Goodwin JF. Improved survival with amiodarone in patients with hypertrophic cardiomyopathy and ventricular tachycardia. Br Heart J 1985; 53:412. 26. McKenna WJ, Harris L, Rowland E, et al. Amiodarone for long-term management of patients with hypertrophic cardiomyopathy. Am J Cardiol 1984; 54:802. 27. Mantica M, Della Bella P, Arena V. Hypertrophic cardiomyopathy with apical aneurysm: a case of catheter and surgical therapy of sustained monomorphic ventricular tachycardia. Heart 1997; 77:481. 28. Rodriguez LM, Smeets JL, Timmermans C, et al. Radiofrequency catheter ablation of sustained monomorphic ventricular tachycardia in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 1997; 8:803. 29. Rowin EJ, Maron BJ, Haas TS, et al. Hypertrophic Cardiomyopathy With Left Ventricular Apical Aneurysm: Implications for Risk Stratification and Management. J Am Coll Cardiol 2017; 69:761. 30. Saberi S, Wheeler M, Bragg-Gresham J, et al. Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy: A Randomized Clinical Trial. JAMA 2017; 317:1349. 31. Klempfner R, Kamerman T, Schwammenthal E, et al. Efficacy of exercise training in symptomatic patients with hypertrophic cardiomyopathy: results of a structured exercise training program in a cardiac rehabilitation center. Eur J Prev Cardiol 2015; 22:13. 32. Sheikh N, Papadakis M, Schnell F, et al. Clinical Profile of Athletes With Hypertrophic https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 14/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Cardiomyopathy. Circ Cardiovasc Imaging 2015; 8:e003454.

ablation in patients without an apical aneurysm is uncertain. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Other treatment options'.) ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Perry Elliott, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Elliott PM, Sharma S, Varnava A, et al. Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1999; 33:1596. 2. Maron BJ, Spirito P, Shen WK, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007; 298:405. 3. Begley DA, Mohiddin SA, Tripodi D, et al. Efficacy of implantable cardioverter defibrillator therapy for primary and secondary prevention of sudden cardiac death in hypertrophic cardiomyopathy. Pacing Clin Electrophysiol 2003; 26:1887. 4. Spirito P, Autore C. Management of hypertrophic cardiomyopathy. BMJ 2006; 332:1251. 5. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 124:e783. 6. Authors/Task Force members, Elliott PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014; 35:2733. 7. Maron BJ, Shen WK, Link MS, et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000; 342:365. 8. Cecchi F, Maron BJ, Epstein SE. Long-term outcome of patients with hypertrophic cardiomyopathy successfully resuscitated after cardiac arrest. J Am Coll Cardiol 1989; 13:1283. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 12/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate 9. Primo J, Geelen P, Brugada J, et al. Hypertrophic cardiomyopathy: role of the implantable cardioverter-defibrillator. J Am Coll Cardiol 1998; 31:1081. 10. Magnusson P, Gadler F, Liv P, M rner S. Risk Markers and Appropriate Implantable Defibrillator Therapy in Hypertrophic Cardiomyopathy. Pacing Clin Electrophysiol 2016; 39:291. 11. Thavikulwat AC, Tomson TT, Knight BP, et al. Appropriate Implantable Defibrillator Therapy in Adults With Hypertrophic Cardiomyopathy. J Cardiovasc Electrophysiol 2016; 27:953. 12. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 13. Wang W, Lian Z, Rowin EJ, et al. Prognostic Implications of Nonsustained Ventricular Tachycardia in High-Risk Patients With Hypertrophic Cardiomyopathy. Circ Arrhythm Electrophysiol 2017; 10. 14. Maron BJ, Spirito P, Ackerman MJ, et al. Prevention of sudden cardiac death with implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 2013; 61:1527. 15. Weinstock J, Bader YH, Maron MS, et al. Subcutaneous Implantable Cardioverter Defibrillator in Patients With Hypertrophic Cardiomyopathy: An Initial Experience. J Am Heart Assoc 2016; 5. 16. Maurizi N, Olivotto I, Olde Nordkamp LR, et al. Prevalence of subcutaneous implantable cardioverter-defibrillator candidacy based on template ECG screening in patients with hypertrophic cardiomyopathy. Heart Rhythm 2016; 13:457. 17. Lambiase PD, Gold MR, Hood M, et al. Evaluation of subcutaneous ICD early performance in hypertrophic cardiomyopathy from the pooled EFFORTLESS and IDE cohorts. Heart Rhythm 2016; 13:1066. 18. Nazer B, Dale Z, Carrassa G, et al. Appropriate and inappropriate shocks in hypertrophic cardiomyopathy patients with subcutaneous implantable cardioverter-defibrillators: An international multicenter study. Heart Rhythm 2020; 17:1107. 19. Maron MS, Steiger N, Burrows A, et al. Evidence That Subcutaneous Implantable Cardioverter-Defibrillators Are Effective and Reliable in Hypertrophic Cardiomyopathy. JACC Clin Electrophysiol 2020; 6:1019. 20. Schinkel AF, Vriesendorp PA, Sijbrands EJ, et al. Outcome and complications after implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: systematic https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 13/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate review and meta-analysis. Circ Heart Fail 2012; 5:552. 21. Vriesendorp PA, Schinkel AF, Van Cleemput J, et al. Implantable cardioverter-defibrillators in hypertrophic cardiomyopathy: patient outcomes, rate of appropriate and inappropriate interventions, and complications. Am Heart J 2013; 166:496. 22. Berul CI, Van Hare GF, Kertesz NJ, et al. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. J Am Coll Cardiol 2008; 51:1685. 23. Maron BJ, Casey SA, Olivotto I, et al. Clinical Course and Quality of Life in High-Risk Patients With Hypertrophic Cardiomyopathy and Implantable Cardioverter-Defibrillators. Circ Arrhythm Electrophysiol 2018; 11:e005820. 24. Maron BJ, Maron MS. Contemporary strategies for risk stratification and prevention of sudden death with the implantable defibrillator in hypertrophic cardiomyopathy. Heart Rhythm 2016; 13:1155. 25. McKenna WJ, Oakley CM, Krikler DM, Goodwin JF. Improved survival with amiodarone in patients with hypertrophic cardiomyopathy and ventricular tachycardia. Br Heart J 1985; 53:412. 26. McKenna WJ, Harris L, Rowland E, et al. Amiodarone for long-term management of patients with hypertrophic cardiomyopathy. Am J Cardiol 1984; 54:802. 27. Mantica M, Della Bella P, Arena V. Hypertrophic cardiomyopathy with apical aneurysm: a case of catheter and surgical therapy of sustained monomorphic ventricular tachycardia. Heart 1997; 77:481. 28. Rodriguez LM, Smeets JL, Timmermans C, et al. Radiofrequency catheter ablation of sustained monomorphic ventricular tachycardia in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 1997; 8:803. 29. Rowin EJ, Maron BJ, Haas TS, et al. Hypertrophic Cardiomyopathy With Left Ventricular Apical Aneurysm: Implications for Risk Stratification and Management. J Am Coll Cardiol 2017; 69:761. 30. Saberi S, Wheeler M, Bragg-Gresham J, et al. Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy: A Randomized Clinical Trial. JAMA 2017; 317:1349. 31. Klempfner R, Kamerman T, Schwammenthal E, et al. Efficacy of exercise training in symptomatic patients with hypertrophic cardiomyopathy: results of a structured exercise training program in a cardiac rehabilitation center. Eur J Prev Cardiol 2015; 22:13. 32. Sheikh N, Papadakis M, Schnell F, et al. Clinical Profile of Athletes With Hypertrophic https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 14/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Cardiomyopathy. Circ Cardiovasc Imaging 2015; 8:e003454. 33. Dejgaard LA, Haland TF, Lie OH, et al. Vigorous exercise in patients with hypertrophic cardiomyopathy. Int J Cardiol 2018; 250:157. 34. Pelliccia A, Solberg EE, Papadakis M, et al. Recommendations for participation in competitive and leisure time sport in athletes with cardiomyopathies, myocarditis, and pericarditis: position statement of the Sport Cardiology Section of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2019; 40:19. Topic 119625 Version 9.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 15/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate GRAPHICS Morphologic variants of hypertrophic cardiomyopathy HCM typically presents with asymmetric or localized areas of LV hypertrophy, which are diagrammed in B to J. (A) Normal LV wall thickness. (B) ASH. (C) Sigmoid septum, which is more common in older adults. (D) Midcavity hypertrophy associated with midcavity obstruction. (E) Predominantly free wall hypertrophy, an unusual pattern in HCM. (F) LV wall thinning (associated with low LV ejection fraction) and biatrial enlargement. (G) Predominantly apical LV hypertrophy. (H) Severe concentric hypertrophy with cavity obliteration. (I) Biventricular hypertrophy. (J) Mild to moderate symmetric hypertrophy. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 16/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate HCM: hypertrophic cardiomyopathy; LV: left ventricular; ASH: asymmetrical septal hypertrophy. Graphic 58156 Version 6.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 17/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Established major risk markers and risk modifiers associated with increased risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) Risk factor Comment Major risk factors Family history of HCM- related SCD SCD due to HCM in a close relative, particularly if <40 years of age, should be considered evidence for increased risk of SCD in other related family members. Syncope Unexplained syncope that, based on clinical history, appears to be due to arrhythmia (and not neurally mediated) is associated with increased SCD risk, particularly in young patients and when the event occurred close to the time of evaluation (<6 months). Massive LV hypertrophy An increased risk of SCD in patients with HCM is seen in patients with echocardiographic evidence of 30 mm wall thickness anywhere in the LV chamber. If maximal wall thickness is not clearly defined using echocardiography, additional evaluation with CMR to clarify the extent of LV wall thickening may be warranted. LV apical aneurysm Uncommon subgroup with thin-walled dyskinetic LV apex with regional scarring. LV apical aneurysm is associated with increased risk for sustained monomorphic VT and warrants consideration for ICD. End-stage HCM (LVEF <50 percent) Higher incidence of life-threatening VT associated with this uncommon phase of HCM. These patients often develop advanced heart failure at a young age and therefore are often considered for ICD as a bridge to definitive therapy with heart transplant. Risk Modifiers Extensive LGE (ie, myocardial fibrosis) occupying 15 percent of LV mass is associated with markers of disease severity and adverse Extensive LGE by contrast-enhanced CMR outcomes including increased risk for SCD and should be considered an important arbitrator to resolving ICD decision-making when uncertain following assessment with established major risk markers. Age at time of SCD risk assessment Risk of SCD is greatest in young patients <30 years old and lessens through mid-life. In patients who have achieved advanced age ( 60 years), risk of SCD is low, even in the presence of other risk factors. Defined as 3 consecutive ventricular beats at >120 beats per minute, lasting less than 30 seconds. Multiple bursts identified on ambulatory monitoring are associated with increased risk, particularly in younger patients. Although the data relating characteristics of NSVT to SCD risk NSVT on ambulatory monitoring remain poorly defined, it would be reasonable to give greater weight to increased SCD risk in those patients with HCM with NSVT that is https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 18/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate frequent (>1 burst), of long duration (>7 beats), or particularly fast (>200 beats per minute). LVEF: left ventricular ejection fraction; CMR: cardiovascular magnetic resonance; NSVT: nonsustained ventricular tachycardia; BP: blood pressure; ICD: implantable cardioverter-defibrillator; LGE: late gadolinium enhancement; LVOT: left ventricular outflow tract obstruction. Graphic 102357 Version 9.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 19/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Algorithm showing the indications for implantable cardioverter-defibrillator (ICD) placement in patients with hypertrophic cardiomyopathy (HCM) Regardless of the level of recommendation put forth in these guidelines, the decision for placement of an ICD must involve prudent application of individual clinical judgment, thorough discussions of the strength of evidence, the benefits, and the risks (including but not limited to inappropriate discharges, lead and procedural complications) to allow active participation of the fully informed patient in ultimate decision making. ICD: implantable cardioverter-defibrillator; HCM: hypertrophic cardiomyopathy; VT: ventricular tachycardia; SD: sudden death; LV: left ventricular; BP: blood pressure; SCD: sudden cardiac death. SCD risk modifiers include established risk factors and emerging risk modifiers. Reproduced from: Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 20/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Coll Cardiol 2011; 58:e212. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 102271 Version 3.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 21/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Classification of sports based on peak static and dynamic components during competition This classification is based on peak static and dynamic components achieved during competition; however, higher values may be reached during training. The increasing dynamic component is defined in terms of the estimated percentage of maximal oxygen uptake (VO max) achieved and results in an increasing cardiac output. The increasing static component is related to the estimated percentage of maximal voluntary contraction reached and results in an increasing blood pressure load. The lowest total cardiovascular demands (cardiac output and blood pressure) are shown 2 in the palest color, with increasing dynamic load depicted by increasing blue intensity and increasing static load by increasing red intensity. Note the graded transition between categories, which should be individualized on the basis of player position and style of play. Danger of bodily collision (refer to UpToDate content regarding sports according to risk of impact and educational background). https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 22/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Increased risk if syncope occurs. Reproduced from: Levine BD, Baggish AL, Kovacs RJ. Eligibility and disquali cation recommendations for competitive athletes with cardiovascular abnormalities: Task force 1: Classi cation of sports: Dynamic, static, and impact: A scienti c statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2350. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 105651 Version 9.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 23/24 7/6/23, 3:27 PM Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk - UpToDate Contributor Disclosures Martin S Maron, MD Grant/Research/Clinical Trial Support: iRhythm [Hypertrophic cardiomyopathy]. Consultant/Advisory Boards: Cytokinetics [Steering committee, REDWOOD-HCM]; Edgewise Pharmaceuticals [Myosin inhibitor for treatment of symptomatic hypertrophic cardiomyopathy]; Imbria Pharmaceuticals [Hypertrophic cardiomyopathy]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. William J McKenna, MD Consultant/Advisory Boards: Bristol Meyers Squibb [Novel pharmacological treatments for HCM]; Cytokinetics [Novel pharmacological treatments for HCM]; Health in Code [Genetic testing in inherited cardiac disease]; Tenaya Therapeutics [Gene therapy in cardiomyopathy]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-management-of-ventricular-arrhythmias-and-sudden-cardiac-death-risk/print 24/24

7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death : Martin S Maron, MD : Samuel L vy, MD, William J McKenna, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 26, 2020. INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease caused by mutations in one of several sarcomere genes that encode components of the contractile apparatus of the heart. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".) HCM is characterized by left ventricular (LV) hypertrophy of various morphologies, with a wide array of clinical manifestations and hemodynamic abnormalities ( figure 1). Depending in part upon the site and extent of cardiac hypertrophy, patients with HCM can develop one or more of the following abnormalities: LV outflow obstruction. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction".) Diastolic and systolic dysfunction. Myocardial ischemia. Mitral regurgitation. These structural and functional abnormalities can produce a variety of symptoms, including: Fatigue Dyspnea Chest pain Palpitations https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 1/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Presyncope or syncope In broad terms, the symptoms related to HCM can be categorized as those related to heart failure (HF), chest pain, or arrhythmias. Patients with HCM are prone to both atrial and ventricular arrhythmias. Many of these arrhythmias are asymptomatic, but some can precipitate hemodynamic collapse and sudden cardiac death (SCD). SCD is a catastrophic and unpredictable complication of HCM and in some patients may be the first presentation of the disease. The assessment of risk for arrhythmic SCD is a critical component of the clinical evaluation of nearly all patients with HCM and will be reviewed here. The management of patients following risk assessment and following a documented ventricular arrhythmia is discussed separately. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".) Other issues related to ventricular arrhythmias and SCD, as well as other clinical manifestations, natural history, diagnosis and evaluation, and treatment of patients with HCM, are discussed separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation" and "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation" and "Hypertrophic cardiomyopathy: Natural history and prognosis" and "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".) EPIDEMIOLOGY Ventricular arrhythmias are common in patients with HCM and can range from isolated ventricular premature beats (VPBs) to nonsustained ventricular tachycardia (NSVT) to sustained VT and ventricular fibrillation. While the frequency of ventricular arrhythmias is highly variable, clinically documented sustained VT is relatively rare, with the annual incidence of sudden cardiac arrest (SCA) in clinically identified HCM referral populations being approximately 1 percent, with even lower reported rate in HCM patients in the general community [1-5]. The frequency of ventricular tachyarrhythmias detected by ambulatory monitoring in patients with HCM has been evaluated in a variety of studies [1,6-12]. As an example, in a study of 178 patients who underwent 24-hour ambulatory monitoring, VPBs were highly prevalent (seen in 88 percent; 12 percent had 500 VPBs) and NSVT was present in 31 percent [1]. However, there is no evidence to suggest that frequent VPBs are, by themselves, indicative of an increased risk of sustained ventricular arrhythmia. This is similar to other forms of heart disease in which treatment of VPBs alone is warranted only in symptomatic patients. (See "Premature ventricular complexes: Treatment and prognosis".) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 2/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Other studies have shown lower rates of NSVT (typically asymptomatic), with ranges of 15 to 31 percent of patients with HCM [1,6-8]. NSVT is more likely in older patients and is associated with greater LV wall thickening and New York Heart Association (NYHA) class III or IV symptoms ( table 1). Episodes are most frequent during sleep and other periods of heightened vagal tone. The prevalence of NSVT is less common in young patients (<40 years old) with HCM, and therefore when present is of greater predictive value for SCD than when it occurs in older patients. Among one cohort of 428 patients 60 years of age with HCM, the risk of arrhythmic SCD was 0.2 percent per year, lower than the younger HCM population and significantly lower than the risk of non-HCM-related death [13]. PATHOGENESIS OF ARRHYTHMIAS An abnormal myocardial substrate comprised of myocyte disarray ( picture 1), interstitial fibrosis, and replacement fibrosis provides the likely structural nidus for the generation of ventricular arrhythmias in patients with HCM. This substrate can be acted upon by potential triggers and/or modifiers, including myocardial ischemia, LV outflow tract obstruction, and abnormal vascular response with inappropriate vasodilatation, as well as the impact of high adrenergic states (eg, during competitive sports, etc) that can lower the threshold for initiating VT/ventricular fibrillation. CLINICAL MANIFESTATIONS The presentation of ventricular arrhythmias in patients with HCM is highly variable, ranging from an absence of symptoms to palpitations to SCA, but in general the presentation of ventricular arrhythmias is similar to their presentation in other types of patients without HCM. Most patients with ventricular premature beats (VPBs) or nonsustained VT (NSVT) will be asymptomatic or have intermittent palpitations. Sustained VT most often results in palpitations, presyncope, or syncope. SCA, although rare, can be the initial presentation of sustained VT or ventricular fibrillation (VF). More detailed discussions of the presenting symptoms of VPBs, NSVT, sustained VT, and VF are discussed elsewhere. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Symptoms' and "Nonsustained ventricular tachycardia: https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 3/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Clinical manifestations, evaluation, and management", section on 'History and associated symptoms' and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'History and associated symptoms'.) EVALUATION Since the underlying abnormal myocardial substrate in HCM can evolve over time, nearly all patients with known or suspected HCM should undergo serial evaluations assessing SCD risk every 12 to 24 months, particularly young and middle-aged HCM patients who were previously considered low or intermediate risk, but who still remain eligible for primary prevention implantable cardioverter-defibrillator (ICD) therapy [14]. Such evaluations should include the following (see "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Diagnostic evaluation'): History and physical examination. Interim family history, with emphasis on any relatives with SCD, syncope, or ICD placement, as well as any new diagnoses of HCM. Echocardiography. 24- to 48-hour ambulatory electrocardiographic (ECG) monitoring. Although the benefit of performing longer-term ambulatory monitoring initially to identify nonsustained ventricular tachycardia (NSVT) can be considered, this strategy has not been systematically evaluated. Exercise (stress) echocardiography testing at initial evaluation to assess for symptoms, provoked LV outflow tract (LVOT) obstruction, arrhythmias, myocardial ischemia, and blood pressure (BP) response. Exercise testing is not generally repeated on an annual basis, unless warranted by the presence of new limiting symptoms, for the purpose of evaluating for a provoked LVOT gradient. Cardiac magnetic resonance (CMR) imaging. Our experts have differing approaches to utilizing CMR in HCM, with currently no clear consensus on how to best apply this advanced imaging technique for HCM diagnosis. Some experts proceed with CMR only when diagnosis of HCM remains uncertain following echocardiography while other experts perform CMR in all patients with suspected or diagnosed HCM to most reliably assess LV morphology, including maximal LV wall thickness, as well as to further inform risk https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 4/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate stratification with assessment of extent of late gadolinium enhancement. (See 'Risk stratification' below.) In a patient who has an ICD, tests for the purpose of risk stratification of sudden death (eg, ambulatory monitoring for NSVT and exercise testing to assess BP response) are not typically repeated. RISK STRATIFICATION Patients with HCM have an increased risk of death from several causes, including SCD, HF, and stroke. Established major risk factors and risk modifiers for SCD include: Prior cardiac arrest or sustained ventricular arrhythmias Family history of first-degree or close relative <50 years of age with SCD judged definitely or likely due to HCM Recent syncope suspected to be arrhythmic in origin Massive LV hypertrophy (LVH) 30 mm anywhere in LV wall LV apical aneurysm of any size End-stage HCM with LV ejection fraction (LVEF) <50 percent Risk modifiers include: Late gadolinium enhancement on cardiac magnetic resonance imaging Patient Age Multiple bursts of NSVT on ambulatory monitoring These established risk factors have greatest weight in young and middle age patients, but risk stratification for SCD should still be performed in all patients with HCM, independent of symptoms or hemodynamic status. The risk factors associated with SCD have also been evaluated for their more general association with overall mortality and outcomes. Several society guidelines for HCM as well as ventricular arrhythmias and SCD have outlined the risk factors for SCD in patients with HCM ( figure 2) [3,6,14-18]. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality'.) Prior arrhythmic events Patients with HCM who are at the highest risk of SCD are those with prior SCA or sustained ventricular tachyarrhythmias [14]. In the absence of a clearly identifiable and reversible cause for SCD, such patients do not require additional risk stratification and should undergo implantation of an ICD for secondary prevention of SCD. (See "Hypertrophic https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 5/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Implantable cardioverter-defibrillators (ICDs)'.) Established major risk markers Because ventricular arrhythmias can be life-threatening, the ability to identify patients at high risk for SCD due to ventricular arrhythmias is critical among patients with HCM. Retrospective observational cohort studies have demonstrated that the presence of 1 of the major risk factors is associated with an elevated SCD risk, and it is reasonable to consider primary prevention ICD therapy ( table 2) after taking into account the overall clinical profile of the individual patient, including age and the benefits and risks of long- term device therapy. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Implantable cardioverter-defibrillators (ICDs)'.) The major risk factors for SCD that are most commonly cited include the following ( table 3) [3,14-16,19]: Family history of SCD A family history of HCM-related SCD is associated with an increased risk of SCD in other affected family members [20,21]. This risk is particularly high if there are multiple SCD events in one family, and if the events occurred in younger patients [20,21]. In a report of 41 relatives from eight families, 31 (75 percent) died from their heart disease, including 18 before 25 years of age, 23 with SCD, and in 15 of these 23 patients, SCD was the initial manifestation of the disease [21]. Families with multiple sudden deaths under the age of 40 years, however, are uncommon (approximately 5 percent), whereas a single sudden death is seen in up to 25 percent of families, but is of low positive predictive accuracy (<15 percent) [6,22]. Syncope Syncope, if it is not clearly attributable to another cause (eg, neurocardiogenic syncope), is a risk factor for SCD in patients with HCM [6,23]. The predictive power for syncope is greatest when it occurs in relatively close proximity to the clinical evaluation (<6 months) and in young patients. Its predictive strength is significantly less when the event has occurred remote to the time of visit and/or it has occurred in older patients [23]. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".) Massive LVH LV wall thickness 30 mm is seen in approximately 10 percent of patients with HCM and is associated in the majority of studies with an increased risk of SCD, particularly in patients less than 30 years of age [24-28]. The positive predictive value of massive LVH, however, is relatively low [24,25], although expert opinion would support strong consideration for ICD if massive LVH is confirmed, particularly in young patients [26]. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 6/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Both echocardiography and cardiac magnetic resonance (CMR) imaging are used in clinical practice to determine maximal wall thickness [29]. One report from a large HCM referral center suggested a discrepancy between echocardiography and CMR imaging in the classification of massive LVH in 70 percent of patients (44 of 63 patients), with massive LVH identified more commonly on CMR (83 versus 48 percent) [30]. However, the data pertaining to increased sudden death risk in patients with HCM and massive LVH are derived from echocardiographic studies. For this reason, we recommend that if massive LVH ( 30 mm) is identified by echocardiography, using reliable measurements, the patients should be considered high risk with consideration of primary prevention ICD therapy. In patients with echo-derived measurements that are <30 mm but in whom CMR demonstrates massive LVH (echocardiography underestimated wall thickness), it would be reasonable to consider an increased risk for SCD as well, with consideration given to placement of an ICD for primary prevention. The relation of massive LVH and sudden death has been highlighted in a number of studies: In a single-center referral population of 1766 patients with HCM, including 92 with massive LVH, who were initially seen between 2004 and 2015 and followed for an average of 5.3 years, SCD events were significantly more common in patients with massive LVH (3 versus 0.8 percent per year) [31]. In a study of 480 patients, including 43 with massive LVH, who were followed for a mean of 6.5 years, the risk of SCD was zero for a wall thickness 15 mm, compared with 1.8 percent per year for a wall thickness 30 mm; the incidence of SCD almost doubled for each 5 mm increase in wall thickness ( figure 3) [24]. The cumulative risk 20 years after the initial diagnosis was close to 0 for those with a thickness 19 mm, compared with 40 percent for a wall thickness 30 mm. In a similar study of 630 patients, maximal wall thickness 30 mm was associated with sudden death, but only in the cohort who had an additional risk factor (ie, adverse family history, NSVT on Holter, syncope, or abnormal BP response on exercise) [25]. LV apical aneurysm Patients with HCM who have an LV apical aneurysm include a cohort in whom the risk of life-threatening arrhythmia appears increased [29,32,33]. Patients with HCM and LV apical aneurysm constitute a small number of patients, with outcome data supported by a small number of observational studies. Therefore, decisions regarding high-risk status should be considered on an individual basis, taking into consideration the entire clinical profile of the patient. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 7/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Thin-walled apical aneurysms are almost always associated with transmural scar (ie, apical late gadolinium enhancement [LGE]), which represent a structural nidus for the generation of sustained monomorphic VT. Apical aneurysms most notably occur in association with midventricular hypertrophy, which often produces mid-cavitary obstruction resulting in high apical systolic pressures, which likely promotes the adverse LV remodeling that ultimately develops into a thin-walled scarred akinetic apex. Patients with apical aneurysms often come to medical attention because of the dramatically abnormal ECG with precordial ST segment elevation and giant T wave inversions, most notably in leads V3 and V4, a similar ECG pattern to HCM patients with only hypertrophy at the apex (without aneurysm). This phenotype is distinct from HCM patients with increased wall thickness confined to the apex, without associated wall thinning (ie, apical HCM). (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Apical HCM'.) Among a cohort of 1940 consecutive patients with HCM seen at one of two high-volume referral centers and who underwent echocardiography with LV opacification and/or CMR, 93 patients (4.8 percent) were found to have an LV apical aneurysm [33]. Of the 54 patients who received an ICD for primary prevention, 18 patients (33 percent) experienced a life- threatening ventricular arrhythmia requiring ICD intervention, resulting in an arrhythmic event rate of 4.7 percent per year (compared with 0.9 percent per year in the patients without an LV apical aneurysm), with no difference in the risk of SCD based on the size of the aneurysm. In contrast to the general population of patients with HCM without an apical aneurysm, risk of SCD persists into the seventh decade of life (and beyond) among patients with HCM and LV apical aneurysm. In one cohort of 118 such patients, 36 percent of SCD (and aborted SCD) events occurred in patients 60 years of age [34]. In addition, patients with HCM with apical aneurysm represent the only subgroup of patients with HCM in whom radiofrequency ablation appears successful at treating life- threatening recurrent VT. In this series, recurrent VT requiring 2 ICD shocks occurred in 13 patients, of which six underwent radiofrequency ablation with no recurrence of VT. Of note, the high-risk phenotype of HCM with apical aneurysm stands in contrast to apical HCM patients who, in the absence of any of the conventional sudden death risk factors, are in fact at low risk for experiencing life-threatening VT/VF. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Apical HCM' and "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Implantable cardioverter- defibrillators (ICDs)' and "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Catheter ablation'.) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 8/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate End-stage with LVEF <50 percent A small proportion of patients with HCM (<5 percent) eventually progress to a stage of disease associated with adverse LV remodeling with reduced systolic performance (LVEF <50 percent). This phase has been termed "end-stage" or "burned out" HCM. Once end-stage HCM develops, further deterioration is progressive in a subset of patients, with death from progressive HF, SCD, or the need for heart transplantation. With conventional cardiovascular therapies, some end-stage patients can experience a relatively benign course in which HF symptoms can remain stable over many years. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'HCM with LV systolic dysfunction (ejection fraction <50 percent)'.) Risk modifiers Several other factors contribute to the overall SCD risk profile of patients with HCM: LGE on CMR imaging LGE on CMR imaging is common in HCM and appears to represent the structural nidus for ventricular tachyarrhythmias in patients with HCM with myocardial fibrosis [35,36]. The presence and extent of LGE is associated with markers of disease severity, including the magnitude of LVH and the presence of nonsustained ventricular arrhythmias. How best to integrate LGE in HCM management strategies remains controversial, even among HCM experts. However, based on the totality of data evaluating LGE and outcomes in HCM, we suggest considering the results of contrast-enhanced CMR with LGE in assessing risk of SCD to provide a more complete evaluation of patients who may benefit from primary prevention ICD therapy. More data to inform this management issue will also be forthcoming following the completion of a Nation Institutes of Health (NIH)-funded study, Novel Markers of Prognosis in Hypertrophic Cardiomyopathy (HCMR), involving 40 centers and more than 2500 patients, anticipated to be completed over the next seven years [37]. In addition, there are a number of methods that have been used to quantify LGE in HCM, but there is no expert consensus on which technique should be universally employed in clinical practice. The lack of standardization with respect to the preferred strategy for quantification of LGE in HCM represents a challenge. The two most commonly employed methods to identify high-signal intensity LGE pixels in the LV wall include applying a grayscale threshold several standard deviations (five or six) above mean signal intensity within a region of "nulled" myocardium and the full-width at half maximum method. Both of these techniques are highly reproducible and reliably represent total fibrosis burden as demonstrated by histopathologic analysis of ventricular septal tissue removed in HCM patients undergoing surgical myectomy [38]. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 9/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate In patients without any of the conventional SCD risk markers, the presence of extensive LGE on CMR may identify high-risk status and prompt consideration for primary prevention ICD therapy. In patients with HCM in whom risk assessment remains ambiguous or uncertain after assessment with the conventional risk factors, extensive LGE can be utilized as a potential arbitrator to help resolve difficult ICD decision-making, with extensive LGE swaying decision-making potentially toward ICD, and no (or minimal) LGE swaying decision-making potentially away from an ICD. The absolute amount of LGE is highly predictive of SCD. However, the pattern of LGE is more variable, with the only consistent LGE pattern observed in HCM being LGE confined to the right ventricular insertion point area, where it has been shown not to be associated with increased risk for SCD. Of note, decisions regarding device therapy in both of these clinical scenarios should be made in the context of a fully informed patient, taking into account the desires and wishes of the patient in a shared decision-making manner. In a cohort of 1293 patients with HCM who underwent CMR and were followed for a median of 3.3 years, LGE was present in 548 patients (42 percent), and the primary end point of SCD events (including SCD and appropriate ICD shocks for documented VT or VF) occurred in 37 patients (3 percent) [39]. Risk of SCD events increased with the amount of LGE present (adjusted hazard ratio 1.46 for each 10 percent increase in LGE, 95% CI 1.12-1.92), particularly among patients with apparent low risk based on the traditional clinical features. In addition, the absence of LGE was associated with lower risk and a source of reassurance for patients. In a 2018 cohort study from a single, high-volume referral center, which included 1423 adult patients (age 18 years) who underwent CMR between 2008 and 2015, 706 patients (50 percent) had LGE identified on CMR imaging [40]. LGE involving 15 percent of the myocardium was associated with a significantly greater risk of SCD or appropriate ICD therapy. In a 2016 meta-analysis, which included 2993 patients from five cohorts, the presence of LGE on CMR imaging was associated with significantly greater risk for total mortality (OR 1.8, 95% CI 1.2-2.7), cardiovascular mortality (OR 2.9, 95% CI 1.5-5.6), and SCD (OR 3.4, 95% CI 2.0-5.9) [41]. For every additional 10 percent of the myocardium affected by LGE, there was an incremental increase in total mortality of approximately 30 percent, with an incremental increase of nearly 60 percent in cardiovascular mortality, SCD, and https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 10/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate HF death. Patients with LGE have also been shown to be more likely to have SCD or aborted SCD with an ICD shock [42]. Age at time of SCD risk assessment Risk of SCD is greatest in young patients with HCM (<30 years of age), and this risk decreases but is not eliminated through mid-life [20]. Patients with HCM who are >60 years of age are at a very low risk for any HCM-related adverse events, including SCD [13]. Indeed, risk of SCD in older patients is very low (<1 percent), even among those patients with one or more of the conventional risk factors [13,43,44]. Conversely, the presence of the major risk factors is of greater prognostic significance in young and middle-aged patients with HCM. The impact of age at HCM diagnosis on overall mortality risk (ie, in addition to SCD) is discussed separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Age at diagnosis'.) NSVT The presence of multiple asymptomatic runs of NSVT (most commonly defined as 3 beats at >120 beats per minute) is associated with an increased risk for SCD in patients with HCM, although the effect of a patient's age plays a role in the associated risk [8-11,45]. Multiple bursts of NSVT are associated with increased risk, particularly in young patients and in patients with symptoms of impaired consciousness [1,7-10,46,47]. Although the data for relating characteristics of NSVT to SCD risk are scant, it would be reasonable to give greater weight to increased risk of SCD in patients with HCM with NSVT that is frequent, prolonged, and particularly fast, while a single, slow, short burst of NSVT on ambulatory monitoring is itself not associated with increased risk of future life-threatening VT/ventricular fibrillation (VF), and in the absence of any other conventional risk factors does not form the basis for primary prevention ICD. For patients with HCM and an ICD, NSVT is associated with an increased risk of appropriate ICD therapies for VT/VF [48]. In a study of 178 adult patients with HCM aged 20 to 50 years who underwent 24-hour ambulatory ECG monitoring and were followed for an average of 5.5 years, NSVT was common (31 percent), with a relatively low annual sudden death rate (1.1 percent). In this cohort of older patients, there was a smaller increase in risk with NSVT (1.6 versus 0.9 percent per year in patients with and without NSVT, defined as 3 beats at 120 beats per minute) [1]. In a series of 531 patients with HCM, of whom 104 had NSVT, the presence of NSVT was associated with an increased risk of SCD in patients less than 30 years of age (odds ratio [OR] 4.4 compared with no NSVT, 95% CI 1.5-12.3) [8]. There was, however, no relation among duration, frequency, or rate of NSVT episodes and prognosis at any age. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 11/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Uncertain risk modifiers Several other clinical factors contribute in an uncertain way to the overall SCD risk profile of patients with HCM: Myocardial ischemia There are conflicting data as to whether myocardial ischemia is a risk factor for SCD in patients with HCM. In a series of 23 young patients with HCM (age 6 to 23 years), ischemia was associated with a history of cardiac arrest or syncope [49]. In contrast, there was no relation between the presence of ischemia and outcomes in a larger prospective series of 216 unselected patients with HCM [50]. The relationship between ischemia and outcomes is likely dependent upon both the age of the patient and the etiology of ischemia (eg, severe small vessel-mediated ischemia versus atherosclerotic obstructive coronary artery disease [CAD]). Patients with HCM and coincident CAD have mortality rates that exceed those of CAD patients with normal LV function [51]. The impact of stress-induced ischemia on overall mortality risk (ie, in addition to SCD) is presented separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality'.) Genotype There appear to be high-risk genotypes for SCD, particularly related to troponin T disease and several of the beta myosin-heavy chain mutations [52]. However, the available data are derived from a small number of families and may be skewed on this basis [14,16]. Moreover, most mutations are novel (ie, "private mutations"), and thus a certain genotype may be associated with higher risk in a specific family but would not be associated with the same consequences in other unrelated patients and families. For this reason, clinical decisions about risk for sudden death and need for primary prevention ICD are not made based on the results of genetic testing. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".) LV outflow tract (LVOT) gradient The majority of natural history studies involving patients with HCM have failed to show an association between LVOT gradient and adverse prognosis [20,44,46,47,53]. Two large studies, however, have shown a weak association of LVOT gradients with overall disease-related mortality and sudden death [54,55]. The impact of LVOT obstruction on overall morbidity (ie, HF symptoms and risk for atrial fibrillation) is discussed separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality'.) In a multicenter, multinational study of 1101 patients (273 [25 percent] with resting LVOT gradient 30 mmHg) followed for a mean of six years, the probability of HCM- related death and of SCD was slightly greater in those with LVOT gradient of at least 30 mmHg (relative risk [RR] 2) [55]. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 12/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate In a single-center study of 917 patients (288 [31 percent] with resting LVOT gradient 30 mmHg) followed for a median of 61 months, survival free from mortality/transplant was significantly lower in patients with LVOT gradients (87 versus 90 percent), as was survival free from sudden death/ICD discharge (91 versus 96 percent) [54]. LVOT obstruction was independently associated with SCD, and there was a significant trend towards lower sudden death/ICD survival in patients with increasing LVOT obstruction. The incidence of SCD in patients with obstruction also varies substantially based upon the number of additional risk factors ( figure 4) [54]. For patients with an outflow gradient 30 mmHg but no additional risk factors, the annual incidence of SCD or ICD discharge was low. There are also a number of practical limitations to using LVOT gradient as a clinical risk factor for sudden death. Gradients are present in large numbers of patients, which would ultimately lead to significant overtreatment with ICDs in this disease. Additionally, gradients can be abolished and/or significantly mitigated with drugs or invasive septal reduction therapy. Nonrandomized retrospective cohort studies suggest that risk of SCD or appropriate ICD shocks is very low following septal myectomy [56,57]. However, surgical myectomy in asymptomatic or mildly symptomatic patients is not indicated solely as a therapy to decrease sudden death risk. In contrast, septal ablation has not been demonstrated to reduce SCD or ICD discharge rates. However, for those patients in whom risk remains ambiguous after assessment with the conventional sudden death risk factors, the presence of a high LVOT gradient can be used as a potential arbitrator to help resolve difficult ICD decision-making. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Nonpharmacologic treatment of LV outflow tract obstruction'.) Impact of number of risk factors It is reasonable to consider ICD in patients with one major risk factor, since SCD risk is increased. Decisions about high-risk status in patients with one risk factor should be individualized based on the strength of the specific risk factor and the individual patient situation. The presence of two or more risk factors for SCD is associated with even greater SCD risk. In patients in whom sudden death risk remains uncertain after assessment with the major risk markers or who are uncertain about pursuing ICD therapy, the presence of a risk modifier may be associated with additional sudden death risk and therefore may help resolve ICD decision-making. Identification of high-risk patients may be improved by using multiple factors [6,54,58,59]. In a study of 368 patients (mean age 37 years) who were followed for a mean of 3.6 years, estimated https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 13/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate six-year SCD-free survival was associated with the number of risk factors ( figure 5) [6]: Zero risk factors (55 percent of the cohort) 95 percent survival One risk factor (33 percent of the cohort) 93 percent survival Two or three risk factors (12 percent of the cohort) 72 percent survival Data from a multicenter registry of ICDs in patients with HCM published in 2007 suggested that a single risk factor may be sufficient justification for consideration of ICD implantation [60]. Subsequently, in a 2019 single-center study of 2094 consecutive patients evaluated over a 17- year period at a tertiary HCM referral center, 527 patients were implanted with a primary prevention ICD based on clinical evaluation and the presence of one or more high-risk markers [61]. Cumulative five-year likelihood of appropriate ICD intervention was 10.5 percent, with 82 primary prevention ICD recipients (15.6 percent) experiencing VT or VF requiring ICD therapy, whereas only five patients (0.3 percent) without an ICD experienced SCD (including two patients in whom primary prevention ICD was declined by the patient). Data in low-risk patients are limited, but those meeting the following profile probably have an incidence of SCD of <0.5 percent per year [14,16,62]: None of the five major risk factors No or only mild symptoms of HF Left atrium 45 mm LV wall thickness <20 mm LV outflow gradient <50 mmHg Risk prediction model While the risk of SCD in patients with HCM can be estimated from large populations, individualized risk prediction offers the hope of the most accurate risk assessment and appropriate interventions. Given the complexity of SCD risk assessment in patients with HCM and the mixed data on the HCM Risk-SCD calculator, we feel that additional studies are warranted to further validate and refine this risk model in other HCM populations, along with the need for additional comparisons with the current United States guideline-based approach using a number of noninvasive risk markers [63,64]. As with risk prediction in any situation, the ability to discriminate patients with HCM at risk of SCD has been most successful in patients deemed at higher risk. In a retrospective cohort study involving 3675 patients from six European centers (2082 in the development cohort and 1593 in the validation cohort) with a median follow-up of 5.7 years, the primary outcome of SCD or appropriate ICD shock occurred in 198 patients (118 patients with SCD, 27 with aborted SCD, and 53 with appropriate ICD shock) [65]. Using the derived model (which incorporated parameters of age, maximal LV wall thickness, left atrial diameter, LVOT https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 14/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate gradient, family history of SCD, NSVT, and unexplained syncope), which can be accessed online, investigators predicted that for every 16 ICDs implanted, one patient would be saved from SCD every five years. Subsequent studies looking at validation of the HCM Risk-SCD calculator have reported widely varying results in terms of the accuracy of the score for predicting SCD [66-69]. In the largest reported validation cohort (International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy [EVIDENCE-HCM] cohort), which included 2147 patients with

reason, clinical decisions about risk for sudden death and need for primary prevention ICD are not made based on the results of genetic testing. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".) LV outflow tract (LVOT) gradient The majority of natural history studies involving patients with HCM have failed to show an association between LVOT gradient and adverse prognosis [20,44,46,47,53]. Two large studies, however, have shown a weak association of LVOT gradients with overall disease-related mortality and sudden death [54,55]. The impact of LVOT obstruction on overall morbidity (ie, HF symptoms and risk for atrial fibrillation) is discussed separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality'.) In a multicenter, multinational study of 1101 patients (273 [25 percent] with resting LVOT gradient 30 mmHg) followed for a mean of six years, the probability of HCM- related death and of SCD was slightly greater in those with LVOT gradient of at least 30 mmHg (relative risk [RR] 2) [55]. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 12/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate In a single-center study of 917 patients (288 [31 percent] with resting LVOT gradient 30 mmHg) followed for a median of 61 months, survival free from mortality/transplant was significantly lower in patients with LVOT gradients (87 versus 90 percent), as was survival free from sudden death/ICD discharge (91 versus 96 percent) [54]. LVOT obstruction was independently associated with SCD, and there was a significant trend towards lower sudden death/ICD survival in patients with increasing LVOT obstruction. The incidence of SCD in patients with obstruction also varies substantially based upon the number of additional risk factors ( figure 4) [54]. For patients with an outflow gradient 30 mmHg but no additional risk factors, the annual incidence of SCD or ICD discharge was low. There are also a number of practical limitations to using LVOT gradient as a clinical risk factor for sudden death. Gradients are present in large numbers of patients, which would ultimately lead to significant overtreatment with ICDs in this disease. Additionally, gradients can be abolished and/or significantly mitigated with drugs or invasive septal reduction therapy. Nonrandomized retrospective cohort studies suggest that risk of SCD or appropriate ICD shocks is very low following septal myectomy [56,57]. However, surgical myectomy in asymptomatic or mildly symptomatic patients is not indicated solely as a therapy to decrease sudden death risk. In contrast, septal ablation has not been demonstrated to reduce SCD or ICD discharge rates. However, for those patients in whom risk remains ambiguous after assessment with the conventional sudden death risk factors, the presence of a high LVOT gradient can be used as a potential arbitrator to help resolve difficult ICD decision-making. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Nonpharmacologic treatment of LV outflow tract obstruction'.) Impact of number of risk factors It is reasonable to consider ICD in patients with one major risk factor, since SCD risk is increased. Decisions about high-risk status in patients with one risk factor should be individualized based on the strength of the specific risk factor and the individual patient situation. The presence of two or more risk factors for SCD is associated with even greater SCD risk. In patients in whom sudden death risk remains uncertain after assessment with the major risk markers or who are uncertain about pursuing ICD therapy, the presence of a risk modifier may be associated with additional sudden death risk and therefore may help resolve ICD decision-making. Identification of high-risk patients may be improved by using multiple factors [6,54,58,59]. In a study of 368 patients (mean age 37 years) who were followed for a mean of 3.6 years, estimated https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 13/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate six-year SCD-free survival was associated with the number of risk factors ( figure 5) [6]: Zero risk factors (55 percent of the cohort) 95 percent survival One risk factor (33 percent of the cohort) 93 percent survival Two or three risk factors (12 percent of the cohort) 72 percent survival Data from a multicenter registry of ICDs in patients with HCM published in 2007 suggested that a single risk factor may be sufficient justification for consideration of ICD implantation [60]. Subsequently, in a 2019 single-center study of 2094 consecutive patients evaluated over a 17- year period at a tertiary HCM referral center, 527 patients were implanted with a primary prevention ICD based on clinical evaluation and the presence of one or more high-risk markers [61]. Cumulative five-year likelihood of appropriate ICD intervention was 10.5 percent, with 82 primary prevention ICD recipients (15.6 percent) experiencing VT or VF requiring ICD therapy, whereas only five patients (0.3 percent) without an ICD experienced SCD (including two patients in whom primary prevention ICD was declined by the patient). Data in low-risk patients are limited, but those meeting the following profile probably have an incidence of SCD of <0.5 percent per year [14,16,62]: None of the five major risk factors No or only mild symptoms of HF Left atrium 45 mm LV wall thickness <20 mm LV outflow gradient <50 mmHg Risk prediction model While the risk of SCD in patients with HCM can be estimated from large populations, individualized risk prediction offers the hope of the most accurate risk assessment and appropriate interventions. Given the complexity of SCD risk assessment in patients with HCM and the mixed data on the HCM Risk-SCD calculator, we feel that additional studies are warranted to further validate and refine this risk model in other HCM populations, along with the need for additional comparisons with the current United States guideline-based approach using a number of noninvasive risk markers [63,64]. As with risk prediction in any situation, the ability to discriminate patients with HCM at risk of SCD has been most successful in patients deemed at higher risk. In a retrospective cohort study involving 3675 patients from six European centers (2082 in the development cohort and 1593 in the validation cohort) with a median follow-up of 5.7 years, the primary outcome of SCD or appropriate ICD shock occurred in 198 patients (118 patients with SCD, 27 with aborted SCD, and 53 with appropriate ICD shock) [65]. Using the derived model (which incorporated parameters of age, maximal LV wall thickness, left atrial diameter, LVOT https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 14/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate gradient, family history of SCD, NSVT, and unexplained syncope), which can be accessed online, investigators predicted that for every 16 ICDs implanted, one patient would be saved from SCD every five years. Subsequent studies looking at validation of the HCM Risk-SCD calculator have reported widely varying results in terms of the accuracy of the score for predicting SCD [66-69]. In the largest reported validation cohort (International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy [EVIDENCE-HCM] cohort), which included 2147 patients with HCM and no prior history of SCD from 14 centers in the United States, Europe, the Middle East, and Asia, 44 patients experienced an SCD event (defined as SCD, successful resuscitation from SCA, or appropriate ICD intervention for VT/VF) over the five-year follow- up (0.5 percent per year) [70]. Among patients with high predicted risk ( 6 percent, n = 297), the five-year incidence of SCD was significantly higher (8.9 percent) compared with patients with intermediate (4 to 6 percent, n = 326) or low (<4 percent, n = 1524) predicted risk (five-year incidence 1.8 and 1.4 percent, respectively). In a cohort of 706 patients with HCM and no prior history of SCD who were seen at two European referral centers, 42 patients (5.9 percent) experienced an SCD event (defined as SCD, successful resuscitation from SCA, or appropriate ICD intervention for VT/VF) over the five-year follow-up (1.2 percent per year) [66]. Patients with an SCD event had significantly greater estimated five-year risk of SCD using the HCM Risk-SCD calculator (4.9 versus 2.8 percent in patients without SCD), with the calculator resulting in improved risk assessment compared with 2003 and 2011 society guidelines. The HCM Risk-SCD calculator has also been retrospectively applied to a cohort of 2094 patients with HCM seen at a large United States referral center [61]. The HCM Risk-SCD calculator accurately predicted patients at low risk without SCD events (92 percent specificity), but the sensitivity of a high-risk classification was only 34 percent for predicting SCD events, suggesting that the majority of patients at risk for SCD would have been missed using only the calculator to quantify risk. In contrast, the enhanced 2011 ACC/AHA guideline criteria had sensitivity and specificity of 87 and 78 percent, respectively, suggesting greater likelihood of preventing SCD with an ICD at the expense of slightly higher use of ICDs in patients without SCD events. The HCM Risk-SCD model and the conventional risk factors from the American College of Cardiology/American Heart Association (ACC/AHA) guidelines were compared in a cohort of 288 patients (mean age 52 years, 66 percent male, 25 percent with LVOT obstruction 30 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 15/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate mmHg) with HCM from a single referral center in the United Kingdom, among whom 14 patients experienced SCD or equivalent (resuscitation from cardiac arrest or appropriate ICD shock for VF or VT >200 beats per minute) over a mean follow-up of 5.6 years [71]. Compared with the conventional ACC/AHA risk factors, the HCM Risk-SCD model more accurately predicted low-risk patients who did not require an ICD (220 of 274 patients [82 percent] compared with 157 of 274 patients [57 percent]) but also failed to identify a significantly greater number of high-risk patients who experienced SCD or equivalent (6 of 14 patients [43 percent] compared with 1 of 14 patients [7 percent]). The presence of LGE identified on CMR may aid in further risk stratifying patients following calculation of the HCM Risk-SCD score. Among 354 patients with HCM and calculated HCM Risk SCD score suggesting low to intermediate five-year risk (<6 percent), patients with LGE extent 10 percent had much higher five-year rates of hard cardiac events including SCD, resuscitated cardiac arrest, appropriate ICD therapies, and sustained VT (23 versus 3 percent) [72]. (See 'Risk modifiers' above.) In a 2019 meta-analysis which included 7291 patients with HCM (including the original HCM Risk- SCD cohort and five subsequent cohorts), 70 percent of patients were identified as low risk, 15 percent as intermediate risk, and 15 percent as high risk [73]. In total, 184 SCD events occurred, with 68 percent occurring in the intermediate and high risk (prevalence of SCD events 1, 2.4, and 8.4 percent in low, intermediate, and high risk groups, respectively). The majority of patients with HCM are stratified as low risk for SCD, but the greatest number of appropriate ICD therapies occur in this low-risk group. Conversely, patients identified as being at high risk of SCD are more likely to receive an appropriate ICD shock, but overall this group receives the lowest number of appropriate ICD therapies. However, proportionally, since the denominator is much larger in low-risk patients, the percentage of patients with ICD shocks is greatest in the high-risk group. This essentially means that, similar to other risk prediction scenarios, the risk score discriminates best those patients with HCM at highest risk for sudden death, but may fail to identify a significant number of patients who have low-risk scores but who are at high risk for sudden death. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 16/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hypertrophic cardiomyopathy in adults (The Basics)") Beyond the Basics topic (see "Patient education: Hypertrophic cardiomyopathy (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Patients with hypertrophic cardiomyopathy (HCM) are prone to ventricular arrhythmias. Ventricular arrhythmias can range from isolated ventricular premature beats (VPBs) to nonsustained ventricular tachycardia (NSVT) to sustained VT and ventricular fibrillation (VF). While the frequency of ventricular arrhythmias is highly variable, the annual incidence of sudden cardiac death (SCD) in the clinically identified general HCM patient population is approximately 1 percent. (See 'Introduction' above and 'Epidemiology' above.) The presentation of ventricular arrhythmias in patients with HCM is highly variable, ranging from an absence of symptoms to palpitations to SCD. Most patients with VPBs or NSVT will be asymptomatic or have intermittent palpitations, while on rare occasions SCD can be the initial presentation of sustained VT or VF. (See 'Clinical manifestations' above.) Since the underlying abnormal myocardial substrate in HCM can evolve over time, all patients with known or suspected HCM should undergo serial evaluations for SCD risk stratification, including history and physical examination, interim family history, echocardiography, ambulatory electrocardiographic (ECG) monitoring, and exercise testing (on a case-by-case basis). With the emerging role of extensive late gadolinium https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 17/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate enhancement (LGE) informing risk assessment, contrast-enhanced cardiac magnetic resonance (CMR) should also be considered. It is reasonable to repeat SCD risk assessment every 12 to 24 months in patients who remain at risk and potentially eligible for an implantable cardioverter-defibrillator (ICD) for primary prevention of SCD. (See 'Evaluation' above.) Major risk factors and risk modifiers associated with an increased risk of SCD in patients with HCM include (see 'Risk stratification' above): Prior or sustained ventricular arrhythmias. Family history of close relative with SCD due to HCM. Syncope suspected to be arrhythmic in origin, particularly when occurring relatively recently to time of evaluation and in younger patients. Multiple bursts of NSVT on ambulatory ECG monitoring. Massive LV hypertrophy 30 mm anywhere in LV wall. LV apical aneurysm. End-stage HCM with LV ejection fraction <50 percent. The results of contrast-enhanced CMR with extensive LGE (ie, myocardial scarring) can be used to help arbitrate ICD decision-making if risk remains ambiguous or uncertain following conventional risk stratification assessment. Age at time of sudden death risk assessment ACKNOWLEDGMENT The editorial staff at UpToDate acknowledges Perry Elliott, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Adabag AS, Casey SA, Kuskowski MA, et al. Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy. J Am https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 18/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Coll Cardiol 2005; 45:697. 2. Elliott PM, Gimeno JR, Thaman R, et al. Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy. Heart 2006; 92:785. 3. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet 2004; 363:1881. 4. Maron BJ. Clinical Course and Management of Hypertrophic Cardiomyopathy. N Engl J Med 2018; 379:655. 5. Weissler-Snir A, Allan K, Cunningham K, et al. Hypertrophic Cardiomyopathy-Related Sudden Cardiac Death in Young People in Ontario. Circulation 2019; 140:1706. 6. Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol 2000; 36:2212. 7. Cecchi F, Olivotto I, Montereggi A, et al. Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in an unselected non-referral based patient population. Heart 1998; 79:331. 8. Monserrat L, Elliott PM, Gimeno JR, et al. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol 2003; 42:873. 9. Fananapazir L, Chang AC, Epstein SE, McAreavey D. Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic, and electrophysiological findings. Circulation 1992; 86:730. 10. Spirito P, Rapezzi C, Autore C, et al. Prognosis of asymptomatic patients with hypertrophic cardiomyopathy and nonsustained ventricular tachycardia. Circulation 1994; 90:2743. 11. Maron BJ, Savage DD, Wolfson JK, Epstein SE. Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study. Am J Cardiol 1981; 48:252. 12. McKenna WJ, England D, Doi YL, et al. Arrhythmia in hypertrophic cardiomyopathy. I: Influence on prognosis. Br Heart J 1981; 46:168. 13. Maron BJ, Rowin EJ, Casey SA, et al. Risk stratification and outcome of patients with hypertrophic cardiomyopathy >=60 years of age. Circulation 2013; 127:585. 14. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 124:e783. 15. Spirito P, Autore C. Management of hypertrophic cardiomyopathy. BMJ 2006; 332:1251. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 19/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate 16. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002; 287:1308. 17. Veselka J, Anavekar NS, Charron P. Hypertrophic obstructive cardiomyopathy. Lancet 2017; 389:1253. 18. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 19. Authors/Task Force members, Elliott PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014; 35:2733. 20. McKenna W, Deanfield J, Faruqui A, et al. Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemodynamic features. Am J Cardiol 1981; 47:532. 21. Maron BJ, Lipson LC, Roberts WC, et al. "Malignant" hypertrophic cardiomyopathy: identification of a subgroup of families with unusually frequent premature death. Am J Cardiol 1978; 41:1133. 22. McKenna WJ, Behr ER. Hypertrophic cardiomyopathy: management, risk stratification, and prevention of sudden death. Heart 2002; 87:169. 23. Priori SG, Aliot E, Blomstrom-Lundqvist C, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J 2001; 22:1374. 24. Spirito P, Bellone P, Harris KM, et al. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000; 342:1778. 25. Elliott PM, Gimeno Blanes JR, Mahon NG, et al. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet 2001; 357:420. 26. Sorajja P, Nishimura RA, Ommen SR, et al. Use of echocardiography in patients with hypertrophic cardiomyopathy: clinical implications of massive hypertrophy. J Am Soc Echocardiogr 2006; 19:788. 27. Olivotto I, Gistri R, Petrone P, et al. Maximum left ventricular thickness and risk of sudden death in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003; 41:315. 28. O'Mahony C, Jichi F, Monserrat L, et al. Inverted U-Shaped Relation Between the Risk of Sudden Cardiac Death and Maximal Left Ventricular Wall Thickness in Hypertrophic https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 20/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Cardiomyopathy. Circ Arrhythm Electrophysiol 2016; 9. 29. Tower-Rader A, Kramer CM, Neubauer S, et al. Multimodality Imaging in Hypertrophic Cardiomyopathy for Risk Stratification. Circ Cardiovasc Imaging 2020; 13:e009026. 30. Bois JP, Geske JB, Foley TA, et al. Comparison of Maximal Wall Thickness in Hypertrophic Cardiomyopathy Differs Between Magnetic Resonance Imaging and Transthoracic Echocardiography. Am J Cardiol 2017; 119:643. 31. Rowin EJ, Maron BJ, Romashko M, et al. Impact of Effective Management Strategies on Patients With the Most Extreme Phenotypic Expression of Hypertrophic Cardiomyopathy. Am J Cardiol 2019; 124:113. 32. Maron MS, Finley JJ, Bos JM, et al. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation 2008; 118:1541. 33. Rowin EJ, Maron BJ, Haas TS, et al. Hypertrophic Cardiomyopathy With Left Ventricular Apical Aneurysm: Implications for Risk Stratification and Management. J Am Coll Cardiol 2017; 69:761. 34. Rowin EJ, Maron BJ, Chokshi A, Maron MS. Left ventricular apical aneurysm in hypertrophic cardiomyopathy as a risk factor for sudden death at any age. Pacing Clin Electrophysiol 2018. 35. Maron BJ, Maron MS, Lesser JR, et al. Sudden cardiac arrest in hypertrophic cardiomyopathy in the absence of conventional criteria for high risk status. Am J Cardiol 2008; 101:544. 36. Weissler-Snir A, Hindieh W, Spears DA, et al. The relationship between the quantitative extent of late gadolinium enhancement and burden of nonsustained ventricular tachycardia in hypertrophic cardiomyopathy: A delayed contrast-enhanced magnetic resonance study. J Cardiovasc Electrophysiol 2019; 30:651. 37. Kramer CM, Neubauer S. Further Refining Risk in Hypertrophic Cardiomyopathy With Late Gadolinium Enhancement by CMR. J Am Coll Cardiol 2018; 72:871. 38. Moravsky G, Ofek E, Rakowski H, et al. Myocardial fibrosis in hypertrophic cardiomyopathy: accurate reflection of histopathological findings by CMR. JACC Cardiovasc Imaging 2013; 6:587. 39. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014; 130:484. 40. Mentias A, Raeisi-Giglou P, Smedira NG, et al. Late Gadolinium Enhancement in Patients With Hypertrophic Cardiomyopathy and Preserved Systolic Function. J Am Coll Cardiol 2018; 72:857. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 21/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate 41. Weng Z, Yao J, Chan RH, et al. Prognostic Value of LGE-CMR in HCM: A Meta-Analysis. JACC Cardiovasc Imaging 2016; 9:1392. 42. Briasoulis A, Mallikethi-Reddy S, Palla M, et al. Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis. Heart 2015; 101:1406. 43. Maron BJ, Ackerman MJ, Nishimura RA, et al. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol 2005; 45:1340. 44. McKenna WJ, Camm AJ. Sudden death in hypertrophic cardiomyopathy. Assessment of patients at high risk. Circulation 1989; 80:1489. 45. Yetman AT, Hamilton RM, Benson LN, McCrindle BW. Long-term outcome and prognostic determinants in children with hypertrophic cardiomyopathy. J Am Coll Cardiol 1998; 32:1943. 46. Cecchi F, Olivotto I, Montereggi A, et al. Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population. J Am Coll Cardiol 1995; 26:1529. 47. Spirito P, Chiarella F, Carratino L, et al. Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med 1989; 320:749. 48. Wang W, Lian Z, Rowin EJ, et al. Prognostic Implications of Nonsustained Ventricular Tachycardia in High-Risk Patients With Hypertrophic Cardiomyopathy. Circ Arrhythm Electrophysiol 2017; 10. 49. Dilsizian V, Bonow RO, Epstein SE, Fananapazir L. Myocardial ischemia detected by thallium scintigraphy is frequently related to cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1993; 22:796. 50. Yamada M, Elliott PM, Kaski JC, et al. Dipyridamole stress thallium-201 perfusion abnormalities in patients with hypertrophic cardiomyopathy. Relationship to clinical presentation and outcome. Eur Heart J 1998; 19:500. 51. Sorajja P, Ommen SR, Nishimura RA, et al. Adverse prognosis of patients with hypertrophic cardiomyopathy who have epicardial coronary artery disease. Circulation 2003; 108:2342. 52. Fananapazir L. Advances in molecular genetics and management of hypertrophic cardiomyopathy. JAMA 1999; 281:1746. 53. Maron BJ, Bonow RO, Cannon RO 3rd, et al. Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (1). N Engl J Med 1987; 316:780. 54. Elliott PM, Gimeno JR, Tom MT, et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006; 27:1933. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 22/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate 55. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003; 348:295. 56. Ommen SR, Maron BJ, Olivotto I, et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005; 46:470. 57. McLeod CJ, Ommen SR, Ackerman MJ, et al. Surgical septal myectomy decreases the risk for appropriate implantable cardioverter defibrillator discharge in obstructive hypertrophic cardiomyopathy. Eur Heart J 2007; 28:2583. 58. O'Mahony C, Tome-Esteban M, Lambiase PD, et al. A validation study of the 2003 American College of Cardiology/European Society of Cardiology and 2011 American College of Cardiology Foundation/American Heart Association risk stratification and treatment algorithms for sudden cardiac death in patients with hypertrophic cardiomyopathy. Heart 2013; 99:534. 59. Maron BJ, Shen WK, Link MS, et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000; 342:365. 60. Maron BJ, Spirito P, Shen WK, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007; 298:405. 61. Maron MS, Rowin EJ, Wessler BS, et al. Enhanced American College of Cardiology/American Heart Association Strategy for Prevention of Sudden Cardiac Death in High-Risk Patients With Hypertrophic Cardiomyopathy. JAMA Cardiol 2019; 4:644. 62. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med 1997; 336:775. 63. Grace A. Prophylactic implantable defibrillators for hypertrophic cardiomyopathy: disarray in the era of precision medicine. Circ Arrhythm Electrophysiol 2015; 8:763. 64. Weissler-Snir A, Adler A, Williams L, et al. Prevention of sudden death in hypertrophic cardiomyopathy: bridging the gaps in knowledge. Eur Heart J 2017; 38:1728. 65. O'Mahony C, Jichi F, Pavlou M, et al. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). Eur Heart J 2014; 35:2010. 66. Vriesendorp PA, Schinkel AF, Liebregts M, et al. Validation of the 2014 European Society of Cardiology guidelines risk prediction model for the primary prevention of sudden cardiac death in hypertrophic cardiomyopathy. Circ Arrhythm Electrophysiol 2015; 8:829. 67. Maron BJ, Casey SA, Chan RH, et al. Independent Assessment of the European Society of Cardiology Sudden Death Risk Model for Hypertrophic Cardiomyopathy. Am J Cardiol 2015; https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 23/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate 116:757. 68. Ruiz-Salas A, Garc a-Pinilla JM, Cabrera-Bueno F, et al. Comparison of the new risk prediction model (HCM Risk-SCD) and classic risk factors for sudden death in patients with hypertrophic cardiomyopathy and defibrillator. Europace 2016; 18:773. 69. Fern ndez A, Quiroga A, Ochoa JP, et al. Validation of the 2014 European Society of Cardiology Sudden Cardiac Death Risk Prediction Model in Hypertrophic Cardiomyopathy in a Reference Center in South America. Am J Cardiol 2016; 118:121. 70. O'Mahony C, Jichi F, Ommen SR, et al. International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (EVIDENCE-HCM). Circulation 2018; 137:1015. 71. Leong KMW, Chow JJ, Ng FS, et al. Comparison of the Prognostic Usefulness of the European Society of Cardiology and American Heart Association/American College of Cardiology Foundation Risk Stratification Systems for Patients With Hypertrophic Cardiomyopathy. Am J Cardiol 2018; 121:349. 72. Todiere G, Nugara C, Gentile G, et al. Prognostic Role of Late Gadolinium Enhancement in Patients With Hypertrophic Cardiomyopathy and Low-to-Intermediate Sudden Cardiac Death Risk Score. Am J Cardiol 2019; 124:1286. 73. O'Mahony C, Akhtar MM, Anastasiou Z, et al. Effectiveness of the 2014 European Society of Cardiology guideline on sudden cardiac death in hypertrophic cardiomyopathy: a systematic review and meta-analysis. Heart 2019; 105:623. Topic 4952 Version 37.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 24/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate GRAPHICS Morphologic variants of hypertrophic cardiomyopathy HCM typically presents with asymmetric or localized areas of LV hypertrophy, which are diagrammed in B to J. (A) Normal LV wall thickness. (B) ASH. (C) Sigmoid septum, which is more common in older adults. (D) Midcavity hypertrophy associated with midcavity obstruction. (E) Predominantly free wall hypertrophy, an unusual pattern in HCM. (F) LV wall thinning (associated with low LV ejection fraction) and biatrial enlargement. (G) Predominantly apical LV hypertrophy. (H) Severe concentric hypertrophy with cavity obliteration. (I) Biventricular hypertrophy. (J) Mild to moderate symmetric hypertrophy. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 25/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate HCM: hypertrophic cardiomyopathy; LV: left ventricular; ASH: asymmetrical septal hypertrophy. Graphic 58156 Version 6.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 26/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac Ordinary physical Patients can perform to disease but without activity, such as completion any activity requiring 7 metabolic equivalents (ie, can resulting limitations of physical activity. walking and climbing stairs, does not cause Ordinary physical activity does not cause angina. Angina with strenuous or rapid carry 24 lb up 8 steps; do outdoor work undue fatigue, palpitation, dyspnea, or prolonged exertion at work or recreation. [shovel snow, spade soil]; do recreational anginal pain. activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in Slight limitation of ordinary activity. Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse without stopping, garden, rake, weed, roller skate, dance foxtrot, walk at 4 mph slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal Walking or climbing stairs rapidly, walking uphill, walking or stair- climbing after meals, in cold, in wind, or when under emotional stress, or only during pain. the few hours after awakening. Walking more than 2 blocks on on level ground) but cannot and do not perform to completion activities requiring 7 metabolic equivalents. the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac disease resulting in Marked limitation of ordinary physical Patients can perform to completion any activity requiring 2 metabolic equivalents (eg, shower without stopping, strip marked limitation of activity. Walking 1 to 2 physical activity. They are comfortable at rest. blocks on the level and climbing 1 flight in Less-than-ordinary physical activity causes normal conditions. and make bed, clean windows, walk 2.5 fatigue, palpitation, mph, bowl, play golf, https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 27/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate dyspnea, or anginal dress without stopping) pain. but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac Inability to carry on any Patients cannot or do disease resulting in physical activity not perform to inability to carry on any physical activity without discomfort. Anginal syndrome may completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac be present at rest. equivalents. Cannot carry out activities insufficiency or of the anginal syndrome may listed above (specific activity scale III). be present even at rest. If any physical activity is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 28/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Myocyte disarray in hypertrophic cardiomyopathy Microscopic appearance of the myocardium in hypertrophic cardiomyopathy, stained with hematoxylin and eosin, shows myocyte disarray with an irregular arrangement of abnormal shaped myocytes that contain bizarre nuclei and surrounding areas of increased connective tissue. Courtesy of Professor Michael Davies, St. George's Hospital, London. Graphic 55914 Version 2.0 Normal endomyocardial biopsy Normal endomyocardial biopsy in longitudinal section. Courtesy of Helmut Rennke, MD. Graphic 61625 Version 2.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 29/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Pyramid profile of risk stratification model currently used to identify patients a sudden cardiac death (SCD) risk who may be candidates for an implantable card defibrillator (ICD) Major and minor risk markers appear in boxes at the left. At the right are the results of ICD therapy in 730 ch adolescents, and adults assembled from two registry studies.

model (HCM Risk-SCD) and classic risk factors for sudden death in patients with hypertrophic cardiomyopathy and defibrillator. Europace 2016; 18:773. 69. Fern ndez A, Quiroga A, Ochoa JP, et al. Validation of the 2014 European Society of Cardiology Sudden Cardiac Death Risk Prediction Model in Hypertrophic Cardiomyopathy in a Reference Center in South America. Am J Cardiol 2016; 118:121. 70. O'Mahony C, Jichi F, Ommen SR, et al. International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (EVIDENCE-HCM). Circulation 2018; 137:1015. 71. Leong KMW, Chow JJ, Ng FS, et al. Comparison of the Prognostic Usefulness of the European Society of Cardiology and American Heart Association/American College of Cardiology Foundation Risk Stratification Systems for Patients With Hypertrophic Cardiomyopathy. Am J Cardiol 2018; 121:349. 72. Todiere G, Nugara C, Gentile G, et al. Prognostic Role of Late Gadolinium Enhancement in Patients With Hypertrophic Cardiomyopathy and Low-to-Intermediate Sudden Cardiac Death Risk Score. Am J Cardiol 2019; 124:1286. 73. O'Mahony C, Akhtar MM, Anastasiou Z, et al. Effectiveness of the 2014 European Society of Cardiology guideline on sudden cardiac death in hypertrophic cardiomyopathy: a systematic review and meta-analysis. Heart 2019; 105:623. Topic 4952 Version 37.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 24/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate GRAPHICS Morphologic variants of hypertrophic cardiomyopathy HCM typically presents with asymmetric or localized areas of LV hypertrophy, which are diagrammed in B to J. (A) Normal LV wall thickness. (B) ASH. (C) Sigmoid septum, which is more common in older adults. (D) Midcavity hypertrophy associated with midcavity obstruction. (E) Predominantly free wall hypertrophy, an unusual pattern in HCM. (F) LV wall thinning (associated with low LV ejection fraction) and biatrial enlargement. (G) Predominantly apical LV hypertrophy. (H) Severe concentric hypertrophy with cavity obliteration. (I) Biventricular hypertrophy. (J) Mild to moderate symmetric hypertrophy. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 25/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate HCM: hypertrophic cardiomyopathy; LV: left ventricular; ASH: asymmetrical septal hypertrophy. Graphic 58156 Version 6.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 26/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac Ordinary physical Patients can perform to disease but without activity, such as completion any activity requiring 7 metabolic equivalents (ie, can resulting limitations of physical activity. walking and climbing stairs, does not cause Ordinary physical activity does not cause angina. Angina with strenuous or rapid carry 24 lb up 8 steps; do outdoor work undue fatigue, palpitation, dyspnea, or prolonged exertion at work or recreation. [shovel snow, spade soil]; do recreational anginal pain. activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in Slight limitation of ordinary activity. Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse without stopping, garden, rake, weed, roller skate, dance foxtrot, walk at 4 mph slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal Walking or climbing stairs rapidly, walking uphill, walking or stair- climbing after meals, in cold, in wind, or when under emotional stress, or only during pain. the few hours after awakening. Walking more than 2 blocks on on level ground) but cannot and do not perform to completion activities requiring 7 metabolic equivalents. the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac disease resulting in Marked limitation of ordinary physical Patients can perform to completion any activity requiring 2 metabolic equivalents (eg, shower without stopping, strip marked limitation of activity. Walking 1 to 2 physical activity. They are comfortable at rest. blocks on the level and climbing 1 flight in Less-than-ordinary physical activity causes normal conditions. and make bed, clean windows, walk 2.5 fatigue, palpitation, mph, bowl, play golf, https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 27/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate dyspnea, or anginal dress without stopping) pain. but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac Inability to carry on any Patients cannot or do disease resulting in physical activity not perform to inability to carry on any physical activity without discomfort. Anginal syndrome may completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac be present at rest. equivalents. Cannot carry out activities insufficiency or of the anginal syndrome may listed above (specific activity scale III). be present even at rest. If any physical activity is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 28/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Myocyte disarray in hypertrophic cardiomyopathy Microscopic appearance of the myocardium in hypertrophic cardiomyopathy, stained with hematoxylin and eosin, shows myocyte disarray with an irregular arrangement of abnormal shaped myocytes that contain bizarre nuclei and surrounding areas of increased connective tissue. Courtesy of Professor Michael Davies, St. George's Hospital, London. Graphic 55914 Version 2.0 Normal endomyocardial biopsy Normal endomyocardial biopsy in longitudinal section. Courtesy of Helmut Rennke, MD. Graphic 61625 Version 2.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 29/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Pyramid profile of risk stratification model currently used to identify patients a sudden cardiac death (SCD) risk who may be candidates for an implantable card defibrillator (ICD) Major and minor risk markers appear in boxes at the left. At the right are the results of ICD therapy in 730 ch adolescents, and adults assembled from two registry studies. BP: blood pressure; CAD: coronary artery disease; EF: ejection fraction; ICD: implantable cardioverter-defibril ventricular; LGE: late gadolinium enhancement; LVH: left ventricular hypertrophy; NSVT: nonsustained ventri tachycardia; SD: sudden death; VT/VF: ventricular tachycardia/ventricular fibrillation. Extensive LGE is a novel primary risk marker that can also be used as an arbitrator when conventional risk a ambiguous. SD events are uncommon after 60 years of age, even with conventional risk factors. Reproduced from: Maron B, Ommen S, Semsarian C. Hypertrophic cardiomyopathy: Present and future, with translation into contempo medicine. J Am Coll Cardiol 2014; 64:83. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 99534 Version 2.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 30/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate The recognized markers of risk in HCM and their sensitivity, specificity, and positive and negative predictive accuracy (PPA and NPA) Sensitivity, Specificity, PPA, NPA, Risk factor percent percent percent percent Abnormal blood pressure [1] response: <40 years old 75 66 15 97 [2] NSVT: adult <45 years old 69 80 22 97 [3] NSVT: 21 years old <10 89 <10 85 Inducible VT/VF: high risk [4] population 82 68 17 98 [5] Syncope: <45 years old* 35 82 25 86 Family history: at least one unexplained sudden death HCM* 42 79 28 88 [5] [6] LVH 3 cm 26 88 13 95 [7] Two or more risk factors 45 90 23 96 HCM: hypertrophic cardiomyopathy; LVH: left ventricular hypertrophy; ICD: implantable cardioverter- defibrillator; NPA: negative predictive accuracy; NSVT: nonsustained ventricular tachycardia; PPA: positive predictive accuracy; VF: ventricular fibrillation; VT: ventricular tachycardia. Figures provided are for the risk of death from all causes rather than sudden death only. Figures provided are for risk of sudden death and/or appropriate ICD discharge. In this data set from Elliott and colleagues, family history and syncope were combined in order to achieve statistical significance of relative risk. 1. McKenna WJ, Franklin RC, Nihoyannopoulos P, et al. Arrhythmia and prognosis in infants, children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 1988; 11:147. 2. Maron BJ, Savage DD, Wolfson JK, et al. Prognostic signi cance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study. Am J Cardiol 1981; 48:252. 3. McKenna WJ, Oakley CM, Krikler DM, et al. Improved survival with amiodarone in patients with hypertrophic cardiomyopathy and ventricular tachycardia. Br Heart J 1985; 53:412. 4. Fananapazir L, Chang AC, Epstein SE, McAreavey D. Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic, and electrophysiological ndings. Circulation 1992; 86:730. 5. McKenna W, Dean eld J, Faruqui A, et al. Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemodynamic features. Am J Cardiol 1981; 47:532. 6. Elliott PM, Gimeno BJ, Mahon NG, et al. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet 2001; 357:420. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 31/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate 7. Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identi cation of high risk patients. J Am Coll Cardiol 2000; 36:2212. Reproduced with permission from: McKenna, WJ, Behr, ER. Hypertrophic cardiomyopathy: management, risk strati cation, and prevention of sudden death. Heart 2002; 87:169. Copyright 2002 BMJ Publishing Group, Ltd. Graphic 80617 Version 3.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 32/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Established major risk markers and risk modifiers associated with increased risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) Risk factor Comment Major risk factors Family history of HCM- SCD due to HCM in a close relative, particularly if <40 years of age, related SCD should be considered evidence for increased risk of SCD in other related family members. Syncope Unexplained syncope that, based on clinical history, appears to be due to arrhythmia (and not neurally mediated) is associated with increased SCD risk, particularly in young patients and when the event occurred close to the time of evaluation (<6 months). Massive LV hypertrophy An increased risk of SCD in patients with HCM is seen in patients with echocardiographic evidence of 30 mm wall thickness anywhere in the LV chamber. If maximal wall thickness is not clearly defined using echocardiography, additional evaluation with CMR to clarify the extent of LV wall thickening may be warranted. LV apical aneurysm Uncommon subgroup with thin-walled dyskinetic LV apex with regional scarring. LV apical aneurysm is associated with increased risk for sustained monomorphic VT and warrants consideration for ICD. End-stage HCM (LVEF <50 percent) Higher incidence of life-threatening VT associated with this uncommon phase of HCM. These patients often develop advanced heart failure at a young age and therefore are often considered for ICD as a bridge to definitive therapy with heart transplant. Risk Modifiers Extensive LGE (ie, myocardial fibrosis) occupying 15 percent of LV mass is associated with markers of disease severity and adverse outcomes including increased risk for SCD and should be considered Extensive LGE by contrast-enhanced CMR an important arbitrator to resolving ICD decision-making when uncertain following assessment with established major risk markers. Age at time of SCD risk assessment Risk of SCD is greatest in young patients <30 years old and lessens through mid-life. In patients who have achieved advanced age ( 60 years), risk of SCD is low, even in the presence of other risk factors. Defined as 3 consecutive ventricular beats at >120 beats per minute, lasting less than 30 seconds. Multiple bursts identified on ambulatory NSVT on ambulatory monitoring monitoring are associated with increased risk, particularly in younger patients. Although the data relating characteristics of NSVT to SCD risk remain poorly defined, it would be reasonable to give greater weight to increased SCD risk in those patients with HCM with NSVT that is https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 33/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate frequent (>1 burst), of long duration (>7 beats), or particularly fast (>200 beats per minute). LVEF: left ventricular ejection fraction; CMR: cardiovascular magnetic resonance; NSVT: nonsustained ventricular tachycardia; BP: blood pressure; ICD: implantable cardioverter-defibrillator; LGE: late gadolinium enhancement; LVOT: left ventricular outflow tract obstruction. Graphic 102357 Version 9.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 34/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Left ventricular wall thickness predicts sudden death in HCM In a study of 480 patients with an HCM, the incidence of sudden death during a 6.5-year follow-up was directly related to maximal wall thickness. The incidence of sudden death almost doubled for each 5 mm increase in wall thickness. HCM: hypertrophic cardiomyopathy. Data from Spirito P, Bellone P, Harris KM, et al. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000; 342:1778. Graphic 75913 Version 4.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 35/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Sudden cardiac death and risk factors in hypertrophic cardiomyopathy Kaplan-Meier estimates of the proportions of patients surviving from sudden cardiac death, appropriate ICD discharge, or resuscitated ventricular fibrillation in relation to number of risk factors in patients with obstruction. ICD: implantable cardioverter-defibrillator. Reproduced with permission from: Elliott PM, Gimeno JR, Tome MT, et al. Left ventricular out ow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006; 27:1933. Copyright 2006 Oxford University Press. Graphic 65115 Version 2.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 36/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Risk of sudden death in HCM A set of four predictors of sudden death were analyzed to develop a risk stratification algorithm in a study of 368 patients with HCM. The predictors included a history of syncope and/or a family history of sudden death, a left ventricular wall thickness 30 mm, nonsustained ventricular tachycardia on ambulatory monitoring, and an abnormal blood pressure response to exercise (refer to text). This bar graph shows the percentage of each risk factor group (zero, one, two, and three risk factors) in which patients died during follow-up (black bars = sudden death; hatched bars = congestive cardiac failure or transplant; white = all deaths). The majority of deaths were sudden, and the greatest proportion occurred in patients with multiple risk factors. HCM: hypertrophic cardiomyopathy. Data from Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identi cation of high risk patients. J Am Coll Cardiol 2000; 36:2212. Graphic 75731 Version 3.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 37/38 7/6/23, 3:34 PM Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death - UpToDate Contributor Disclosures Martin S Maron, MD Grant/Research/Clinical Trial Support: iRhythm [Hypertrophic cardiomyopathy]. Consultant/Advisory Boards: Cytokinetics [Steering committee, REDWOOD-HCM]; Edgewise Pharmaceuticals [Myosin inhibitor for treatment of symptomatic hypertrophic cardiomyopathy]; Imbria Pharmaceuticals [Hypertrophic cardiomyopathy]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. William J McKenna, MD Consultant/Advisory Boards: Bristol Meyers Squibb [Novel pharmacological treatments for HCM]; Cytokinetics [Novel pharmacological treatments for HCM]; Health in Code [Genetic testing in inherited cardiac disease]; Tenaya Therapeutics [Gene therapy in cardiomyopathy]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-risk-stratification-for-sudden-cardiac-death/print 38/38

7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Left ventricular hypertrophy and arrhythmia : Philip J Podrid, MD, FACC : George L Bakris, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 09, 2022. INTRODUCTION Left ventricular hypertrophy (LVH) is a common finding in patients with cardiovascular disease (CVD) and CVD risk factors and is diagnosed either by electrocardiogram (ECG) or imaging (eg, echocardiography, cardiovascular computed tomography, cardiovascular magnetic resonance [CMR] imaging) [1]. (See "Left ventricular hypertrophy: Clinical findings and ECG diagnosis".) LVH has been associated with both ventricular and supraventricular arrhythmias [2]. Data, primarily from the Framingham Heart Study, have identified electrocardiographic LVH as a blood pressure-independent risk for sudden cardiac death (SCD) [3,4], acute myocardial infarction [5], and other cardiovascular morbidity and mortality [6]. (See "Left ventricular hypertrophy: Clinical findings and ECG diagnosis" and "Left ventricular hypertrophy: Clinical findings and ECG diagnosis", section on 'Prognosis'.) This topic will review the association between LVH and arrhythmias (both ventricular and supraventricular) as well as sudden cardiac death. DEFINITION AND ETIOLOGIES OF LVH LVH is defined as an increase in the mass of the left ventricle, which can be secondary to an increase in wall thickness or muscle mass. This increase in mass predominantly results from a chronic increase in LV afterload or a primary disease of the myocardium (eg, hypertrophic cardiomyopathy) (see "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation" and "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing"). In https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 1/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate addition to the increased muscle mass, myocardial fibrosis is often present and may contribute to the arrhythmias seen with LVH. In addition, LVH may result in diastolic dysfunction and diastolic heart failure (ie, heart failure with preserved ejection fraction). (See "Pathophysiology of heart failure with preserved ejection fraction".) LV mass can be estimated using various imaging techniques, including echocardiography and CMR imaging ( table 1). LVH can also be defined electrocardiographically, with the most common findings including increased QRS voltage, increased QRS duration, physiologic left axis deviation (between 0 to -30 degrees), repolarization abnormalities, and left atrial abnormalities. The electrocardiographic diagnosis of LVH is discussed in detail separately. (See "Left ventricular hypertrophy: Clinical findings and ECG diagnosis".) LVH occurs as a physiologic adaptation to increased myocardial wall stress. Typically, LVH results from increases in LV pressures due to increased afterload, most commonly from hypertension or aortic stenosis, although less common causes of increased afterload (eg, coarctation of the aorta, supraaortic or subaortic membranes) may also result in LVH. LVH resulting from pressure overload most commonly results in thickening of the LV walls with normal or reduced LV cavity size. In addition to pressure overload conditions, increased LV mass can result from chronic volume overload conditions (eg, aortic regurgitation, mitral regurgitation, dilated cardiomyopathy), although these conditions typically result in normal to thicker than normal LV walls with increased LV cavity size. Asymmetric LVH (eg, hypertrophy more prominent in the ventricular septum or apex) may also result from hypertrophic cardiomyopathy, a genetically determined heart muscle disease caused by mutations in one of several sarcomere genes that encode components of the contractile apparatus, with variable phenotypic expressions and clinical manifestations. The unique risks associated with hypertrophic cardiomyopathy are discussed separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death" and "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation".) LVH frequently occurs as a normal physiologic response to extreme and frequent exercise, such as in highly-trained athletes, and often must be distinguished from pathologic LVH due to other conditions (most commonly hypertrophic cardiomyopathy). LVH in athletes is typically concentric with isometric exercise and eccentric with endurance sports [7-9]. Myocardial fibrosis is generally not present. The mechanisms accounting for LVH in these situations and the consequences of LVH are quite different from those in LVH due to hypertension or valvular heart disease [10,11]. https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 2/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate Both systolic and diastolic function are generally maintained in LVH occurring in athletes [8]. The arrhythmias that are seen in athletes who do not have associated cardiac abnormalities are similar in type and frequency to those that occur in the general population [12]. Moreover, in athletes, there is no relationship between arrhythmia and the degree of physiologic LVH [13]. Some of the arrhythmias, such as sinus bradycardia and sinus arrhythmia, are the result of enhanced vagal tone. (See "Athletes: Overview of sudden cardiac death risk and sport participation" and "Athletes with arrhythmias: Treatment and returning to athletic participation".) MAKING THE DIAGNOSIS OF LVH LVH can be diagnosed from a 12-lead ECG or by cardiac imaging, traditionally using echocardiography, but newer imaging modalities such as CMR imaging are also highly effective for calculating cardiac mass. In general, echocardiography and CMR are both more sensitive and more specific than ECG for the diagnosis of LVH, but ECG is more readily available, easy to perform and interpret, and is much less expensive. Imaging the myocardium can also identify specific pathologic features, particularly an eccentric or concentric pattern of LVH. The specific details regarding the diagnosis of LVH with both ECG and imaging modalities are presented separately. (See "Left ventricular hypertrophy: Clinical findings and ECG diagnosis" and "Transthoracic echocardiography: Normal cardiac anatomy and tomographic views".) LVH AND VENTRICULAR ARRHYTHMIAS Patients with evidence of LVH, both electrocardiographic and echocardiographic, are more like to have ventricular ectopy and ventricular tachyarrhythmias compared with normotensive patients or hypertensive patients without LVH [14-22]. Regardless of the method for diagnosing LVH, the presence of LVH is associated with an increased risk for sudden cardiac arrest [23]. In a meta-analysis of 10 studies involving 27,141 patients, the occurrence of ventricular tachycardia or fibrillation was significantly greater in the presence of LVH (odds ratio 2.8 compared with no LVH; 95% CI 1.8-4.5) [2]. The frequency and complexity of ventricular premature beats (VPBs) is related to the severity of LVH as well as chamber volume and indices of left ventricular contractility [18,19]. For every 1 mm increase in wall thickness, there was a two to threefold increase in the occurrence and complexity of VPBs [18]. In addition, several studies have suggested that complex ventricular ectopy, especially nonsustained ventricular tachycardia, is predictive of an increased risk of all- cause mortality [24-26]. https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 3/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate LVH AND SUPRAVENTRICULAR ARRHYTHMIAS Patients with LVH have an increased risk of supraventricular arrhythmias, primarily atrial fibrillation (AF). This is generally due to an increase in left atrial size and/or an increase in left atrial pressure with stretch on the left atrial myocardium. In addition, there is an increase in left atrial muscle mass (hypertrophy) with fibrosis. This results from the thickness and rigidity of the left ventricular myocardium with the occurrence of diastolic dysfunction and the increase in left atrial pressure in order to maintain left ventricular filling during diastole. In a meta-analysis of 10 studies involving 27,141 patients, the occurrence of supraventricular arrhythmias was significantly greater in patients with LVH (odds ratio 3.4 compared with no LVH; 95% CI 1.6-7.3), although there was significant heterogeneity among the baseline covariates in the included studies [2]. The relationship between LVH and AF is well established. The importance of LVH in the development AF was illustrated in a study of 2482 subjects with primary hypertension (formerly called "essential" hypertension) followed for up to 16 years [27]. During follow-up, in which 61 patients developed AF (0.46 per 100 person years), advancing age and increased LV mass were the only independent predictors of developing AF. For every one standard deviation increase on left ventricular mass, the risk of AF increased by 20 percent. LVH identified by cardiac magnetic resonance imaging has also been shown to be associated with AF. In a cohort of 4942 patients followed for a median of 6.9 years, the risk of AF was significantly greater in patients with LVH identified by either magnetic resonance imaging or electrocardiogram (ECG)-derived voltage measurements of LVH [28]. Additionally, there appears to be an increased risk of sudden cardiac death (SCD) in patients with ECG evidence of LVH who develop AF [29]. (See 'LVH and risk of sudden cardiac death' below.) LVH AND RISK OF SUDDEN CARDIAC DEATH LVH is a risk factor for SCD as well as overall cardiovascular mortality, as shown in the following examples: In a nationwide study of SCD occurring in persons aged 15 to 35 years in Ireland between 2005 and 2007, 10 percent (12 of 116 autopsy-adjudicated cases) had evidence of LVH that did not meet the criteria for another diagnosis (eg, hypertrophic cardiomyopathy) [30]. Among 3661 subjects over the age of 40 from the Framingham Heart Study in whom the relationship between left ventricular mass and hypertrophy and SCD was investigated, the https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 4/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate prevalence of LVH was 22 percent [31]. Over an average follow-up of 14 years, patients with LVH had a significantly greater risk of SCD (adjusted hazard ratio 2.2 compared with no 2 LVH; 95% CI 1.2-3.8), with a 50 percent increase in SCD risk for each 50 g/m increase in left ventricular mass. Among a cohort of 8831 hypertensive patients with baseline sinus rhythm and ECG evidence of LVH who were followed for an average of 4.7 years, 701 (7.9 percent) patients developed atrial fibrillation (AF), and 151 patients (1.7 percent) experienced SCD [29]. Multivariate analysis revealed a greater than threefold increased risk of SCD among patients who developed AF (hazard ratio 3.1 compared with those who remained in sinus rhythm, 95% CI 1.9-5.2). MECHANISMS OF ARRHYTHMIAS IN LVH Little is known about the physiologic mechanisms accounting for ventricular arrhythmia in LVH. Several theories have been proposed, although it seems likely that the arrhythmogenicity of LVH is multifactorial in origin. Ischemia LVH and hypertension without LVH are commonly associated with myocardial ischemia, particularly chronic subendocardial ischemia, accounting for the presence of ST-T wave changes that are often seen with LVH; in addition, microvascular angina can occur in patients with hypertension even in the absence of LVH [32-36]. Several factors can contribute to the development of myocardial ischemia: A reduction in subendocardial blood flow due to the increase in left ventricular end- diastolic blood pressure. The repolarization changes seen with LVH reflect this reduction in subendocardial blood flow. (See "Left ventricular hypertrophy: Clinical findings and ECG diagnosis", section on 'Electrocardiographic findings: General'.) Increased peripheral vascular resistance and an overall reduction in coronary artery blood flow resulting from augmented vasoconstrictor tone and the increased wall/lumen ratio. Failure of the coronary arteries to grow at a rate sufficient to compensate for the muscular hypertrophy, resulting in decreased coronary reserve and chronic ischemia, a well- recognized stimulus for arrhythmias of all type [36]. Increased oxygen demand due to the rise in wall tension and the increase in myocardial wall thickness, resulting in a reduction in oxygen supply, particularly to the subendocardial layer. https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 5/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate Electrophysiologic abnormalities The irregular hypertrophy pattern and local areas of fibrosis in LVH can impede the homogeneous propagation of the electric impulse throughout the myocardium and its subsequent recovery [37-40]. Fibrosis is one of the deleterious anatomic abnormalities associated with LVH and may be the main substrate for the development of ventricular arrhythmias, particularly reentrant arrhythmias [21]. Other proposed mechanisms of arrhythmias include lengthening of the action potential duration, reduced action potential upstroke velocity, slower membrane repolarization, the generation of early and delayed afterdepolarizations, and beat-to-beat changes in repolarization [41,42]. In an animal model, the presence of LVH is associated with an increase in transmural repolarization dispersion and the occurrence of early afterdepolarization, which increase the potential for ventricular tachyarrhythmias [43]. (See "T wave (repolarization) alternans: Overview of technical aspects and clinical applications".) Abnormalities of the hypertrophied myocardial cell The hypertrophied cardiac myocyte is electrophysiologically different from and more arrhythmogenic than the normal myocyte [38,44]. A number of structural changes that occur in hypertrophy have been related to the susceptibility of the hypertrophied myocardium to arrhythmias. Whether these structural changes correlate with the above electrophysiologic abnormalities is not known. Increased sympathetic activity Increased activity of the sympathetic nervous system and the renin-angiotensin system has been implicated in the pathogenesis of primary hypertension (formerly called "essential" hypertension). One study found that abnormal circadian blood pressure variations, as assessed by 24-hour blood pressure monitoring, correlated with the presence of echocardiographic LVH [45]. Thus, at any given level of blood pressure, sympathetic/parasympathetic imbalance may influence the development of LVH and the occurrence of atrial and ventricular arrhythmias. In addition, sympathetic stimulation exerts a direct proarrhythmic effect by enhancing automaticity [46,47]. (See "Enhanced cardiac automaticity".) REGRESSION OF LVH In general, lowering blood pressure with antihypertensive agents, weight loss, or dietary sodium restriction decreases cardiac mass in patients with LVH. However, fibrosis, if present, is not reversible. The degree of hypertrophy in patients with hypertension can be reduced by specific antihypertensive therapy, although not all antihypertensive drugs are equipotent in this regard. Regression of LVH diminishes LVH-associated arrhythmias and appears to reduce the risk of sudden cardiac death (SCD). The effect of various blood pressure lowering agents on the incidence of atrial fibrillation (AF) is, however, less certain. https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 6/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate Effect on atrial fibrillation Data strongly suggest that regression of LVH results in a reduction in the frequency of paroxysmal AF, perhaps mechanistically due to a reduction in left atrial pressure and diameter [48]. There is also a reduction in the likelihood of new onset AF [49]. The effect of various blood pressure lowering agents on the incidence of AF is, however, less certain. In a meta-analysis of 56,308 patients the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) was associated with a significant 28 percent reduction in the relative risk of AF. Reduction in AF was similar between the two classes of drugs (ACEI 28 percent, ARB 29 percent) and was greatest in patients with heart failure [50]. However, there was no significant reduction in AF in patients with hypertension. Effect on ventricular arrhythmias Regression of LVH appears to be associated with a reduction in ventricular arrhythmia. In animal models, regression of hypertrophy normalized action potential duration and dispersion of refractoriness and decreased vulnerability to inducible polymorphic ventricular tachycardia (VT) and ventricular fibrillation [51,52]. In trials of various antihypertensive agents, improved blood pressure control was generally associated with regression of LVH and reduction in ventricular ectopy and tachyarrhythmias, although the effect was not consistent among all classes of drugs (notably thiazide diuretics, which were less efficacious) [53-56]. In a trial of 46 hypertensive patients randomly assigned to therapy with enalapril, hydrochlorothiazide, atenolol, or verapamil, in which all drugs significantly lowered blood pressure, LV mass index and ventricular ectopy were reduced by enalapril, atenolol, and verapamil but not hydrochlorothiazide [54]. Similar lack of efficacy with hydrochlorothiazide was previously reported [53]. In a randomized trial of captopril compared with placebo in 27 hypertensive patients with LVH, captopril was associated with a marked reduction in LVH and a marked reduction in ventricular ectopy, whereas the placebo group showed progression of LVH without change in ventricular ectopy [55]. In a randomized trial of 45 hypertensive patients, isradipine (a calcium channel blocker), spirapril (an ACE inhibitor), and the combination produced an equivalent degree of LVH regression and reduction in ventricular ectopy [56]. Based upon the combination of animal and human data, it seems likely that the decrease in ventricular ectopy associated with regression of LVH is not related to a direct antiarrhythmic effect of antihypertensive therapy but to its effects on hemodynamics and perhaps neurohormonal activation. https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 7/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate Effect on sudden cardiac death Studies of the effects of the regression of LVH on cardiovascular morbidity and mortality are limited; they generally support but do not prove an improvement in outcome beyond that associated with the reduction in blood pressure alone [37,57,58]. Reports from the Framingham Heart Study showed that regression of LVH, as assessed by electrocardiographic criteria, was associated with reductions in the risk of SCD, acute myocardial infarction, and congestive heart failure [59]. Further support for the benefit of LVH regression on SCD comes from a post hoc analysis of the LIFE trial, which enrolled 9193 patients with hypertension and ECG evidence of LVH and randomly assigned them to treatment with atenolol or losartan [60,61]. Over a mean follow-up of 4.8 years, absence of ECG evidence of LVH while on treatment was associated with a significant reduction in the risk of SCD, independent of treatment modality, blood pressure reduction, and other cardiovascular risk factors [60]. SUMMARY Definition Left ventricular hypertrophy (LVH), defined as an increase in the mass of the left ventricle, is a common finding in patients with cardiovascular disease (CVD) and CVD risk factors, and it can be diagnosed either by ECG or by echocardiography. (See 'Introduction' above and 'Definition and etiologies of LVH' above.) Diagnosis LVH can be diagnosed from a 12-lead ECG or by cardiac imaging, traditionally using echocardiography, but newer imaging modalities such as cardiovascular magnetic resonance (CMR) imaging are also highly effective for calculating cardiac mass. In general, echocardiography and CMR are both more sensitive and more specific than ECG for the diagnosis of LVH, but ECG is more readily available, easy to perform and interpret, and is much less expensive. (See 'Making the diagnosis of LVH' above and "Left ventricular hypertrophy: Clinical findings and ECG diagnosis" and "Transthoracic echocardiography: Normal cardiac anatomy and tomographic views".) Arrhythmias Patients with LVH are more likely to have ventricular ectopy, ventricular tachyarrhythmias, and sudden cardiac arrest compared with normotensive patients or hypertensive patients without LVH. Patients with LVH also have an increased risk of supraventricular arrhythmias, primarily atrial fibrillation. (See 'LVH and ventricular arrhythmias' above and 'LVH and supraventricular arrhythmias' above.) Mechanisms of arrhythmias in LVH Little is known about the physiologic mechanisms accounting for ventricular arrhythmia in LVH. Several theories have been proposed, https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 8/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate although it seems likely that the arrhythmogenicity of LVH is multifactorial in origin. (See 'Mechanisms of arrhythmias in LVH' above.) Regression of LVH In general, lowering blood pressure with antihypertensive agents, weight loss, or dietary sodium restriction decreases cardiac mass in patients with LVH. The degree of hypertrophy in patients with hypertension can be reduced by specific antihypertensive therapy, although not all antihypertensive drugs are equipotent in this regard. (See 'Regression of LVH' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Elias MF, Sullivan LM, Elias PK, et al. Left ventricular mass, blood pressure, and lowered cognitive performance in the Framingham offspring. Hypertension 2007; 49:439. 2. Chatterjee S, Bavishi C, Sardar P, et al. Meta-analysis of left ventricular hypertrophy and sustained arrhythmias. Am J Cardiol 2014; 114:1049. 3. Kannel WB, Gordon T, Offutt D. Left ventricular hypertrophy by electrocardiogram. Prevalence, incidence, and mortality in the Framingham study. Ann Intern Med 1969; 71:89. 4. Kannel WB, Doyle JT, McNamara PM, et al. Precursors of sudden coronary death. Factors related to the incidence of sudden death. Circulation 1975; 51:606. 5. Kannel WB, Gordon T, Castelli WP, Margolis JR. Electrocardiographic left ventricular hypertrophy and risk of coronary heart disease. The Framingham study. Ann Intern Med 1970; 72:813. 6. Kannel WB, Castelli WP, McNamara PM, et al. Role of blood pressure in the development of congestive heart failure. The Framingham study. N Engl J Med 1972; 287:781. 7. Fagard RH. Impact of different sports and training on cardiac structure and function. Cardiol Clin 1997; 15:397. 8. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE. The athlete's heart. A meta- analysis of cardiac structure and function. Circulation 2000; 101:336. 9. Abernethy WB, Choo JK, Hutter AM Jr. Echocardiographic characteristics of professional football players. J Am Coll Cardiol 2003; 41:280. 10. Cuspidi C, Lonati L, Sampieri L, et al. Similarities and differences in structural and functional changes of left ventricle and carotid arteries in young borderline hypertensives and in athletes. J Hypertens 1996; 14:759. https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 9/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate 11. Di Bello V, Pedrinelli R, Giorgi D, et al. Ultrasonic videodensitometric analysis of two different models of left ventricular hypertrophy. Athlete's heart and hypertension. Hypertension 1997; 29:937. 12. Zehender M, Meinertz T, Keul J, Just H. ECG variants and cardiac arrhythmias in athletes: clinical relevance and prognostic importance. Am Heart J 1990; 119:1378. 13. Biffi A, Maron BJ, Di Giacinto B, et al. Relation between training-induced left ventricular hypertrophy and risk for ventricular tachyarrhythmias in elite athletes. Am J Cardiol 2008; 101:1792. 14. McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med 1987; 317:787. 15. Levy D, Anderson KM, Savage DD, et al. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol 1987; 60:560. 16. Siegel D, Cheitlin MD, Black DM, et al. Risk of ventricular arrhythmias in hypertensive men with left ventricular hypertrophy. Am J Cardiol 1990; 65:742. 17. Vester EG, Kuhls S, Ochiulet-Vester J, et al. Electrophysiological and therapeutic implications of cardiac arrhythmias in hypertension. Eur Heart J 1992; 13 Suppl D:70. 18. Ghali JK, Kadakia S, Cooper RS, Liao YL. Impact of left ventricular hypertrophy on ventricular arrhythmias in the absence of coronary artery disease. J Am Coll Cardiol 1991; 17:1277. 19. Schmieder RE, Messerli FH. Determinants of ventricular ectopy in hypertensive cardiac hypertrophy. Am Heart J 1992; 123:89. 20. Novo S, Barbagallo M, Abrignani MG, et al. Increased prevalence of cardiac arrhythmias and transient episodes of myocardial ischemia in hypertensives with left ventricular hypertrophy but without clinical history of coronary heart disease. Am J Hypertens 1997; 10:843. 21. Mammarella A, Paradiso M, Basili S, et al. Morphologic left ventricular patterns and prevalence of high-grade ventricular arrhythmias in the normotensive and hypertensive elderly. Adv Ther 2000; 17:222. 22. Palmiero P, Maiello M. Ventricular arrhythmias and left ventricular hypertrophy in essential hypertension. Minerva Cardioangiol 2000; 48:427. 23. Narayanan K, Reinier K, Teodorescu C, et al. Electrocardiographic versus echocardiographic left ventricular hypertrophy and sudden cardiac arrest in the community. Heart Rhythm 2014; 11:1040. 24. Bikkina M, Larson MG, Levy D. Asymptomatic ventricular arrhythmias and mortality risk in subjects with left ventricular hypertrophy. J Am Coll Cardiol 1993; 22:1111. https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 10/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate 25. Aronow WS, Epstein S, Koenigsberg M, Schwartz KS. Usefulness of echocardiographic left ventricular hypertrophy, ventricular tachycardia and complex ventricular arrhythmias in predicting ventricular fibrillation or sudden cardiac death in elderly patients. Am J Cardiol 1988; 62:1124. 26. Saadehm Anm Joes, JV . Predictors of sudden cardiac death in never previously treated patients with essential hypertension: long-term follow up. J Hum Hypertens 2001; 15:667. 27. Verdecchia P, Reboldi G, Gattobigio R, et al. Atrial fibrillation in hypertension: predictors and outcome. Hypertension 2003; 41:218. 28. Chrispin J, Jain A, Soliman EZ, et al. Association of electrocardiographic and imaging surrogates of left ventricular hypertrophy with incident atrial fibrillation: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2014; 63:2007. 29. Okin PM, Bang CN, Wachtell K, et al. Relationship of sudden cardiac death to new-onset atrial fibrillation in hypertensive patients with left ventricular hypertrophy. Circ Arrhythm Electrophysiol 2013; 6:243. 30. Margey R, Roy A, Tobin S, et al. Sudden cardiac death in 14- to 35-year olds in Ireland from 2005 to 2007: a retrospective registry. Europace 2011; 13:1411. 31. Haider AW, Larson MG, Benjamin EJ, Levy D. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol 1998; 32:1454. 32. O'Gorman DJ, Sheridan DJ. Abnormalities of the coronary circulation associated with left ventricular hypertrophy. Clin Sci (Lond) 1991; 81:703. 33. Houghton JL, Prisant LM, Carr AA, et al. Relationship of left ventricular mass to impairment of coronary vasodilator reserve in hypertensive heart disease. Am Heart J 1991; 121:1107. 34. Lucarini AR, Picano E, Salvetti A. Coronary microvascular disease in hypertensives. Clin Exp Hypertens A 1992; 14:55. 35. Houghton JL, Carr AA, Prisant LM, et al. Morphologic, hemodynamic and coronary perfusion characteristics in severe left ventricular hypertrophy secondary to systemic hypertension and evidence for nonatherosclerotic myocardial ischemia. Am J Cardiol 1992; 69:219. 36. Harrison DG, Marcus ML, Dellsperger KC, et al. Pathophysiology of myocardial perfusion in hypertension. Circulation 1991; 83:III14. 37. Koren MJ, Devereux RB, Casale PN, et al. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114:345. https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 11/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate 38. Swynghedauw B, Chevalier B, Charlemagne D, et al. Cardiac hypertrophy, arrhythmogenicity and the new myocardial phenotype. II. The cellular adaptational process. Cardiovasc Res 1997; 35:6. 39. Levy D, Anderson KM, Plehn J, et al. Echocardiographically determined left ventricular structural and functional correlates of complex or frequent ventricular arrhythmias on one- hour ambulatory electrocardiographic monitoring. Am J Cardiol 1987; 59:836. 40. McLenachan JM, Dargie HJ. Ventricular arrhythmias in hypertensive left ventricular hypertrophy. Relationship to coronary artery disease, left ventricular dysfunction, and myocardial fibrosis. Am J Hypertens 1990; 3:735. 41. Gillis AM, Mathison HJ, Kulisz E, Lester WM. Dispersion of ventricular repolarization and ventricular fibrillation in left ventricular hypertrophy: influence of selective potassium channel blockers. J Pharmacol Exp Ther 2000; 292:381. 42. Hennersdorf MG, Niebch V, Perings C, Strauer BE. T wave alternans and ventricular arrhythmias in arterial hypertension. Hypertension 2001; 37:199. 43. Yan GX, Rials SJ, Wu Y, et al. Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization. Am J Physiol Heart Circ Physiol 2001; 281:H1968. 44. Toyoshima H, Park YD, Ishikawa Y, et al. Effect of ventricular hypertrophy on conduction velocity of activation front in the ventricular myocardium. Am J Cardiol 1982; 49:1938. 45. Verdecchia P, Schillaci G, Guerrieri M, et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990; 81:528. 46. Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation 1992; 85:I77. 47. Anderson JL, Rodier HE, Green LS. Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold. Am J Cardiol 1983; 51:1196. 48. Hennersdorf MG, Schueller PO, Steiner S, Strauer BE. Prevalence of paroxysmal atrial fibrillation depending on the regression of left ventricular hypertrophy in arterial hypertension. Hypertens Res 2007; 30:535. 49. Okin PM, Wachtell K, Devereux RB, et al. Regression of electrocardiographic left ventricular hypertrophy and decreased incidence of new-onset atrial fibrillation in patients with hypertension. JAMA 2006; 296:1242. 50. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin- converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 12/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate Cardiol 2005; 45:1832. 51. Rials SJ, Wu Y, Ford N, et al. Effect of left ventricular hypertrophy and its regression on ventricular electrophysiology and vulnerability to inducible arrhythmia in the feline heart. Circulation 1995; 91:426. 52. Rials SJ, Wu Y, Xu X, et al. Regression of left ventricular hypertrophy with captopril restores normal ventricular action potential duration, dispersion of refractoriness, and vulnerability to inducible ventricular fibrillation. Circulation 1997; 96:1330. 53. Messerli FH, Nunez BD, Nunez MM, et al. Hypertension and sudden death. Disparate effects of calcium entry blocker and diuretic therapy on cardiac dysrhythmias. Arch Intern Med 1989; 149:1263. 54. Novo S, Abrignani MG, Novo G, et al. Effects of drug therapy on cardiac arrhythmias and ischemia in hypertensives with LVH. Am J Hypertens 2001; 14:637. 55. Gonz lez-Fern ndez RA, Rivera M, Rodr guez PJ, et al. Prevalence of ectopic ventricular activity after left ventricular mass regression. Am J Hypertens 1993; 6:308. 56. Manolis AJ, Beldekos D, Handanis S, et al. Comparison of spirapril, isradipine, or combination in hypertensive patients with left ventricular hypertrophy: effects on LVH regression and arrhythmogenic propensity. Am J Hypertens 1998; 11:640. 57. Koren MJ, Devereux RB. Mechanism, effects, and reversal of left ventricular hypertrophy in hypertension. Curr Opin Nephrol Hypertens 1993; 2:87. 58. Yurenev AP, Dyakonova HG, Novikov ID, et al. Management of essential hypertension in patients with different degrees of left ventricular hypertrophy. Multicenter trial. Am J Hypertens 1992; 5:182S. 59. Levy D, Salomon M, D'Agostino RB, et al. Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy. Circulation 1994; 90:1786. 60. Wachtell K, Okin PM, Olsen MH, et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death: the LIFE Study. Circulation 2007; 116:700. 61. Dahl f B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359:995. Topic 966 Version 24.0 https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 13/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate GRAPHICS Normal adult echocardiographic dimensions Aorta M: 4 cm; F: 3.6 cm Sinus level M: 3.8 cm; F: 3.5 cm Ascending 3.0 cm Transverse 2.5 cm Descending Left atrium Anteroposterior dimension (parasternal long M: 3-4 cm; F: 2.7-3.8 cm axis) Indexed volume 16-34 mL/m2 Left ventricle Septum 6-11 mm Posterior wall 6-11 mm End-diastolic dimension M: 4.2-5.8 cm; F: 3.8-5.2 cm Pulmonary artery 3.0 cm Main Inferior vena cava 2.1 cm 1-2 cm from right atrial junction Coronary sinus 1 cm M: male; F: female. Graphic 52100 Version 4.0 https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 14/15 7/6/23, 3:34 PM Left ventricular hypertrophy and arrhythmia - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. George L Bakris, MD Grant/Research/Clinical Trial Support: Bayer [Diabetic nephropathy]; KBP Biosciences [Resistant hypertension]; Novo Nordisk [Diabetic kidney disease]. Consultant/Advisory Boards: Alnylam [Resistant hypertension]; AstraZeneca [Diabetic nephropathy]; Bayer [Nephropathy]; Ionis [Resistant hypertension]; KBP BioSciences [Resistant hypertension]; Vifor [Hyperkalemia]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/left-ventricular-hypertrophy-and-arrhythmia/print 15/15

7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Left ventricular thrombus after acute myocardial infarction : Gregory YH Lip, MD, FRCPE, FESC, FACC, Nikolaus Sarafoff, MD : Warren J Manning, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 08, 2022. INTRODUCTION Left ventricular (LV) thrombus may develop after acute myocardial infarction (MI) and occurs most often with a large, anterior ST-elevation MI (STEMI). However, the use of reperfusion therapies, including percutaneous coronary intervention and fibrinolysis, has significantly reduced the risk. LV thrombus can lead to arterial embolic complications such as stroke. Patients with LV thrombus or those at high risk for development of this complication should receive anticoagulation for at least three months. This topic will discuss LV thrombus in detail. Other potential causes of arterial emboli originating in the heart are presented elsewhere: (See "Clinical features and diagnosis of acute lower extremity ischemia", section on 'Arterial embolism'.) (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Cardiogenic embolism'.) PATHOPHYSIOLOGY LV thrombus is most often seen in patients with large, anterior ST-elevation MI with anteroapical aneurysm. In most cases, these infarcts occur in the distribution of the left anterior descending coronary artery [1]. These anteroapical infarcts have large areas of poorly contracting LV muscle; https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 1/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate adjacent intracavitary blood movement is sluggish (stasis) compared with normal areas. This relative stasis of blood is thought to increase the risk of thrombus formation. Many, but not all, of these patients will have an LV apical aneurysm with akinesis or dyskinesis. In most cases, thrombus is located within or adjacent to the LV apex [1] but can also occur with large basal inferolateral infarctions/aneurysms. Contact of blood with the fibrous tissue in the aneurysm rather than normal endocardium is also thought to trigger clot formation. AT-RISK PATIENTS Patients with one or more of the following are at risk for the development of LV thrombus. However, we do not routinely anticoagulate patients at risk in the absence of documented LV thrombus. Anterior ST-elevation MI by electrocardiographic criteria. (See "Electrocardiogram in the diagnosis of myocardial ischemia and infarction", section on 'Anterior, lateral, and apical MI'.) Left anterior descending coronary artery infarct (especially proximal left anterior descending coronary artery infarct). Large infarction defined as a LV ejection fraction (LVEF) <30 percent. Many, but not all, of these patients will have an LV aneurysm. (See "Left ventricular aneurysm and pseudoaneurysm following acute myocardial infarction", section on 'Left ventricular aneurysm'.) Long delay between onset of symptoms and reperfusion (more than four to six hours) due to the increased risk for an LV aneurysm due to more extensive infarction/systolic dysfunction. INCIDENCE Over the past 30 years, the incidence of LV thrombus has decreased as the frequency of early reperfusion therapies has increased. The likely mechanism is that early reperfusion, compared with no or late reperfusion, leads to smaller infarction [1-12]. Its impact may be greatest in patients with anterior infarctions, which tend to be larger than infarcts at other locations. (See 'Pathophysiology' above.) The incidence of LV thrombi in the prereperfusion era was reported to be as high as 40 percent in patients with anterior infarction [4,7]. Most thrombi developed within the first two weeks https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 2/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate (median five to six days) after MI [3,4,7,10,11]. In a series of 30 patients with LV thrombus after an acute anterior MI, 27 percent were present at less than 24 hours, 57 percent at 48 to 72 hours, 75 percent at one week, and 96 percent at two weeks [5]. Data are more limited on the incidence of LV thrombus in the reperfusion era. In two series of ST-elevation MI (STEMI) patients treated with primary percutaneous coronary intervention, the incidence of LV thrombus was about 4 percent [13,14]. However, the true incidence of LV thrombus in the current reperfusion era may be higher than in the above studies, as reported incidence depends on the sensitivity of the diagnostic test used. Cardiovascular magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE) has been shown to be considerably more sensitive than transthoracic echocardiography (TTE) with or without an intravenous endocardial border definition contrast agent. In a study of 201 STEMI patients, of whom 199 were treated with reperfusion, who were evaluated with LGE-CMR, the incidence of LV thrombus was 8 percent [1]. Finally, some of these studies may have underestimated the true incidence, as patients at high risk for LV thrombus (severe heart failure and systolic blood pressure below 100 mmHg) were excluded. (See 'Diagnosis' below.) DIAGNOSIS Most patients with acute ST-elevation MI (STEMI) should undergo (noncontrast) TTE to assess LV systolic function before discharge with specific evaluation of anteroapical systolic function, aneurysm, and the presence of an LV thrombus ( algorithm 1). In most patients, the diagnosis of an LV thrombus will be made using TTE ( image 1 and movie 1). (See 'At-risk patients' above.) TTE performed very early after an anteroapical infarction may show an LVEF <30 percent; however, repeat TTE 48 hours after reperfusion may show significant improvement in LV systolic function. (See 'Incidence' above.) When the sonographer is screening for LV thrombus, particular attention should be paid to the LV apex (or for any aneurysm or dyskinetic segment). In addition to reporting the presence of an aneurysm and wall motion in that region, the presence or absence of thrombus should be noted in the report. TTE characteristics of LV thrombus include a mural or pedunculated echodensity often of similar acoustic properties to myocardium ( movie 2A-B). (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism", section on 'Left ventricular thrombi'.) https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 3/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate TTE image quality may be suboptimal due to conditions such as chronic pulmonary disease or obesity. Distinguishing thrombus from normal trabeculations may also be difficult. Near-field artifact may also give the appearance of apical thrombus. The sonographer should use an intravenous endocardial border definition contrast agent whenever an apical aneurysm is identified [15,16]. With contrast injection, LV thrombus appears as a filling defect within the ventricular cavity. (See "Contrast echocardiography: Clinical applications", section on 'Rest echocardiography'.) In patients where there remains uncertainty regarding the presence or absence of thrombus, CMR with gadolinium contrast using a long inversion time should be considered. We consider transesophageal echocardiography (TEE) inferior to long inversion time late gadolinium enhancement (LGE) CMR for the diagnosis of LV thrombus since the apex is often not well visualized by the former test, but may be considered when CMR is not available. Contrast- enhanced cardiac computed tomography is another option. CMR is considered the gold standard for the noninvasive diagnosis of LV thrombus. Long inversion time LGE-CMR has a greater sensitivity than TTE and a similarly high specificity for the detection of LV thrombus in an ischemic cardiomyopathy population [17-19]. However, it is not used to screen for LV thrombus in all patients with an anteroapical aneurysm due to issues of cost and availability. (See "Clinical utility of cardiovascular magnetic resonance imaging".) In a retrospective study of 160 patients with a remote prior MI who had surgical and/or pathological confirmation of the presence (48 patients [30 percent]) or absence of LV thrombus, all patients underwent nonsimultaneous preoperative LGE-CMR, TTE, and intraoperative TEE [17]. CMR was significantly more sensitive (88 versus 23 and 40 percent with TTE and TEE, respectively). All imaging modalities had specificities of 96 percent or greater. In another study, 201 patients were evaluated with noncontrast and contrast TTE, cine-CMR, and LGE-CMR 7 to 30 days after STEMI [1]. Using LGE-CMR as the gold standard for determining the presence of absence of LV thrombus, the following findings were noted: LV thrombus was present in 17 patients (8 percent). The sensitivity of noncontrast and contrast TTE was only 35 and 64 percent, respectively. The specificity of noncontrast and contrast TTE was 98 and 99 percent, respectively. Only 12 percent of patients with thrombus had a LVEF 30 percent, and LV aneurysm was present in only 24 percent. https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 4/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate On both noncontrast and contrast TTE, a high apical wall motion score, as measure of apical dysfunction, was strongly correlated with the presence of LV thrombus. Differential diagnosis In addition to MI, true LV thrombus may occur in other conditions such as stress cardiomyopathy or myocarditis. However, in a patient with documented acute STEMI, the odds are in favor of the infarct being causative. Incidentally discovered LV thrombus An uncommon patient may present with incidentally discovered LV thrombus during a cardiac imaging study done for other reasons. We treat with oral anticoagulant (OAC) for three months and then reevaluate the thrombus. If there is evidence of thrombus resolution, we stop OAC and reevaluate with echocardiography in another three months. OUTCOMES Newly diagnosed LV thrombi may undergo complete resolution, partial resolution, or endothelialization. Prior to one of these end points, embolization may occur. The risk of embolization in patients with a documented LV thrombus who are not treated with anticoagulant therapy has been reported to be 10 to 15 percent. In a series of 85 patients with LV thrombus (most of whom had a recent MI) followed for almost two years, an embolic event occurred in 11 (13 percent) of those with thrombi compared with only 2 of 91 (2 percent) in a matched control group [20]. In another study of patients with an anterior MI, the presence of an LV mural thrombus identified by noncontrast TTE increased the incidence of an embolic event (odds ratio 5.5, 95% CI 3.0-9.8) [21]. Most embolic events occur within the first three to four months [2,5,6,20-23], although some occur later [20]. Two major echocardiographic risk factors for embolization have been identified: thrombus mobility and thrombus protrusion [2,6,20,24]. In one report, embolization occurred in 22 percent of 119 patients with an LV thrombus after acute MI [2]. Free mobility of the thrombus was present in 58 percent of patients with embolization compared with 3 percent without embolization; among the 18 patients with free thrombus mobility, embolization occurred in 15 (83 percent compared with 11 percent without mobility). Protrusion of the thrombus into the LV cavity was present in 88 percent of those patients with clinical thromboembolism compared with 18 percent without; among the 40 patients with thrombus protrusion, embolization occurred in 23 (58 percent compared with 4 percent without protrusion). An observational study of 159 patients with a confirmed LV thrombus, most of whom were anticoagulated, found the following at a median follow-up of 103 days [25]: https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 5/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate A reduction of the thrombus area from baseline was observed in 76 percent, with total regression in 62 percent. During a median follow-up of 632 days, death occurred in 18 percent, stroke in 13 percent, and major bleeding in 13 percent. A LVEF 35 percent and anticoagulation therapy >3 months were independently associated with lower rates of major adverse cardiovascular outcomes. PREVENTION OF EMBOLIC EVENTS The following is our approach to the prevention of stroke and systemic embolic events in at-risk patients: In all patients being considered for anticoagulant therapy, the benefit must be weighed against the risk of bleeding. This is particularly important since many patients will be receiving treatment with one or two oral antiplatelet agents for some period of time. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Discharge to 12 months'.) We anticoagulate most MI patients with documented LV thrombus [26]. (See 'Diagnosis' above.) Some of our contributors will consider anticoagulation in the absence of LV thrombus if apical or basal inferior akinesis/dyskinesis with aneurysm is present. This is a particularly high-risk group for the development of LV thrombus. (See 'At-risk patients' above.) There are no large prospective or direct comparison data of direct-acting oral anticoagulants (DOAC; also referred to as non-vitamin K antagonist oral anticoagulants [NOAC]) versus warfarin for prophylaxis for LV thrombus. We consider using DOAC rather than warfarin due to convenience and achievement of therapeutic anticoagulation so long as there is no specific indication for warfarin (eg, prosthetic heart valve). For patients in whom warfarin is chosen rather than DOAC, we recommend starting parenteral anticoagulation with unfractionated heparin or a low molecular weight heparin as soon as LV thrombus after acute MI is identified. The goal activated partial thromboplastin time is two to three times the control value. Parenteral anticoagulation should be continued until effective anticoagulation with warfarin (target international normalized ratio [INR] 2 to 3) has been achieved. This recommendation may need to be modified based on the specific antithrombotic requirements of patients treated with https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 6/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate primary percutaneous coronary intervention or fibrinolytic therapy. (See "Acute ST- elevation myocardial infarction: Management of anticoagulation", section on 'Summary and recommendations'.) There are no studies that have evaluated the optimal timing of parenteral anticoagulation. We believe it is reasonable to start therapy as soon as an at-risk patient is identified and to discontinue parenteral therapy when effective anticoagulation with warfarin has been achieved (INR of 2 to 3) or the diagnosis has been excluded. Early studies of patients treated with warfarin found that anticoagulation with heparin, if started early and continued for more than 48 hours, lowers the risk of thrombus formation [21]. Other studies suggested benefit from parenteral anticoagulation for up to 14 days [27-29]. However, we do not recommend prolonged parenteral therapy, as early initiation of oral warfarin therapy in appropriate patients is likely to be as effective and is more practical. If indicated, oral anticoagulant therapy should be started early after MI and continued for at least three months, as most embolic events occur within the first three to four months. (See 'Outcomes' above.) In patients who do not have a specific indication for warfarin (eg, mechanical heart valve), we often prefer a DOAC due to convenience in dosing and more rapid achievement of therapeutic anticoagulation. Concomitant antiplatelet therapy is indicated in all these patients, as they have sustained an MI. The use of combined anticoagulant and antiplatelet therapy is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Discharge to 12 months'.) Our approach to the use of antiplatelet therapy after termination of anticoagulation is presented separately. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Duration of dual antiplatelet therapy'.) Evidence for anticoagulation The approach to prevention of stroke and systemic emboli in high-risk acute MI patients is based on limited evidence: Older, observational studies provide support for a recommendation to anticoagulate reperfused patients with documented LV thrombus after MI to reduce the risk of embolization [7,21-23]. There are no randomized trials evaluating the efficacy of prolonged oral anticoagulation, compared with no anticoagulation, in the present reperfusion era. There are no studies that have compared anticoagulation with no anticoagulation in MI at- risk patients without LV thrombus. (See 'At-risk patients' above.) https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 7/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate There are no randomized studies that have compared warfarin to DOAC for the prevention of thrombus formation in patients at high risk or for the treatment of LV thrombus. However, in case series of DOAC use in patients with documented LV thrombi, some with recent ST-elevation MI, DOAC use was associated with thrombus resolution [30-34] and was more effective than warfarin [35]. One retrospective cohort study of 514 patients with echocardiographically detected LV thrombi included 300 who received warfarin and 185 who received a DOAC [36]. After a median follow-up of nearly one year, anticoagulation with DOAC was associated with a higher risk of stroke or systemic embolism on multivariable analysis (hazard ratio 2.64, 95% CI 1.28-5.43). Based on this one study, we consider performing a follow-up TTE with an endocardial border definition agent after two to four weeks of DOAC to assess thrombus resolution. If there is no resolution, we consider switching to warfarin. Concomitant antiplatelet therapy All decisions regarding the prolonged use of anticoagulant therapy in these patients must take into account the concurrent risk of bleeding. Bleeding is a particularly important issue, as most of these patients have an indication for intense dual antiplatelet therapy (in addition to anticoagulant therapy) due to the placement of an intracoronary stent after an acute coronary syndrome. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Summary and recommendations' and "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration and Type of Antiplatelet Treatment' and "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy".) While it is biologically plausible that intense antiplatelet therapy could protect against the formation and embolization of LV thrombus, this has not been studied, and we do not recommend it as a substitute for oral anticoagulation to prevent embolization of LV thrombus. Finally, there are no high-quality studies that address the issue of the optimal antithrombotic regimen in these patients with LV thrombus who are not stented. Specifically, the role of P2Y 12 receptor blockers has not been evaluated in randomized trials. ROLE OF FOLLOW-UP IMAGING TTE with contrast or long inversion time late gadolinium enhancement CMR imaging can be used to monitor resolution of thrombus with anticoagulation [2,4,6,7,12]. Most patients are followed by TTE, with CMR reserved only for situations in which TTE is technically suboptimal. https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 8/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate Based on a limited amount of evidence, we believe it is reasonable to get a follow-up TTE (if the thrombus was previously visualized on TTE) to determine if the thrombus identified on the first TTE has resolved or organized or to assess the degree of left ventricular (LV) remodeling. We obtain this follow-up TTE between two and three months after initial thrombus identification. The findings of persistent pedunculation of the thrombus may reasonably lead to a decision to prolong anticoagulation beyond the recommended time; the finding of significant improvement of the LVEF and resolution of the apical wall motion abnormality may reasonably lead to a decision to shorten the duration of anticoagulation. In three series in which serial TTE was performed, thrombus resolution was seen in 14 of 29 patients (47 percent) at six months, 24 of 51 (47 percent) at one year, and 16 of 21 (76 percent) at two-year follow-up [4,6,12]. As noted below, only a small number of late persistent thrombi are associated with embolic events, as most embolic events occur within the first four months. (See 'Prevention of embolic events' above.) The predictors of LV thrombus resolution are not well defined. In one report, the only independent predictor of thrombus resolution was the absence of apical dyskinesis at six weeks after MI [12]. This observation is consistent with apical dyskinesis or akinesis being a risk factor for thrombus formation [3]. Although warfarin therapy appears to reduce the rate of embolization, it may not increase the rate of thrombus resolution [7]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: ST-elevation myocardial infarction (STEMI)" and "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)".) SUMMARY AND RECOMMENDATIONS Pathophysiology Left ventricular (LV) thrombus is a major cause of embolic stroke after acute myocardial infarction (MI). Patients with large anterior MI are at the highest risk for the development of LV thrombi; these patients usually have an LV ejection fraction (LVEF) less than 30 percent and a severe anteroapical or basal inferolateral wall motion abnormality with aneurysm on an imaging study. (See 'Pathophysiology' above.) https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 9/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate Diagnosis For patients at risk of LV thrombus, we obtain a transthoracic echocardiogram with echo contrast to screen for LV thrombus in those with an aneurysm. (See 'Diagnosis' above.) Treatment Our recommendations for the use of anticoagulation are as follows: Documented thrombus For patients with MI and documented LV thrombus, we recommend anticoagulation (Grade 1B). Most of our contributors prefer direct-acting oral anticoagulants (DOAC; also referred to as non-vitamin K antagonist oral anticoagulants) to warfarin for prophylaxis for LV thrombus. (See 'Prevention of embolic events' above.) In patients treated with warfarin, parenteral anticoagulation with unfractionated heparin or low molecular weight heparin should be started as soon as possible and continued until effective oral anticoagulation has been achieved. Warfarin should be started soon after initiation of parenteral anticoagulation; the goal of therapy is an international normalized ratio of 2 to 3. Low left ventricular ejection fraction For patients with MI and no clear thrombus but an LVEF less than 30 with anteroapical or basal inferior/inferolateral wall akinesis/dyskinesis and aneurysm, we suggest prophylactic anticoagulation (Grade 2C). (See 'Prevention of embolic events' above.) For patients with MI and an LVEF between 30 and 40 percent with a severe anteroapical hypokinesis on imaging but no dyskinesis or aneurysm or thrombus on imaging, we suggest not treating with prophylactic anticoagulation (Grade 2C). The relative benefits and risks of anticoagulation need to be weighed carefully in these two groups. For those prescribed anticoagulation with warfarin or DOAC, we suggest continuing anticoagulation for three months rather than a longer duration (Grade 2C). We consider longer duration if there is residual thrombus after three months. ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Scott Solomon, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 10/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate REFERENCES 1. Weinsaft JW, Kim J, Medicherla CB, et al. Echocardiographic Algorithm for Post-Myocardial Infarction LV Thrombus: A Gatekeeper for Thrombus Evaluation by Delayed Enhancement CMR. JACC Cardiovasc Imaging 2016; 9:505. 2. Visser CA, Kan G, Meltzer RS, et al. Embolic potential of left ventricular thrombus after myocardial infarction: a two-dimensional echocardiographic study of 119 patients. J Am Coll Cardiol 1985; 5:1276. 3. Asinger RW, Mikell FL, Elsperger J, Hodges M. Incidence of left-ventricular thrombosis after acute transmural myocardial infarction. Serial evaluation by two-dimensional echocardiography. N Engl J Med 1981; 305:297. 4. Nihoyannopoulos P, Smith GC, Maseri A, Foale RA. The natural history of left ventricular thrombus in myocardial infarction: a rationale in support of masterly inactivity. J Am Coll Cardiol 1989; 14:903. 5. K pper AJ, Verheugt FW, Peels CH, et al. Left ventricular thrombus incidence and behavior studied by serial two-dimensional echocardiography in acute anterior myocardial infarction: left ventricular wall motion, systemic embolism and oral anticoagulation. J Am Coll Cardiol 1989; 13:1514. 6. Keren A, Goldberg S, Gottlieb S, et al. Natural history of left ventricular thrombi: their appearance and resolution in the posthospitalization period of acute myocardial infarction. J Am Coll Cardiol 1990; 15:790. 7. Weinreich DJ, Burke JF, Pauletto FJ. Left ventricular mural thrombi complicating acute myocardial infarction. Long-term follow-up with serial echocardiography. Ann Intern Med 1984; 100:789. 8. Vecchio C, Chiarella F, Lupi G, et al. Left ventricular thrombus in anterior acute myocardial infarction after thrombolysis. A GISSI-2 connected study. Circulation 1991; 84:512. 9. Chiarella F, Santoro E, Domenicucci S, et al. Predischarge two-dimensional echocardiographic evaluation of left ventricular thrombosis after acute myocardial infarction in the GISSI-3 study. Am J Cardiol 1998; 81:822. 10. Greaves SC, Zhi G, Lee RT, et al. Incidence and natural history of left ventricular thrombus following anterior wall acute myocardial infarction. Am J Cardiol 1997; 80:442. 11. Nayak D, Aronow WS, Sukhija R, et al. Comparison of frequency of left ventricular thrombi in patients with anterior wall versus non-anterior wall acute myocardial infarction treated with antithrombotic and antiplatelet therapy with or without coronary revascularization. Am J Cardiol 2004; 93:1529. https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 11/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate 12. Neskovi AN, Marinkovi J, Boji M, Popovi AD. Predictors of left ventricular thrombus formation and disappearance after anterior wall myocardial infarction. Eur Heart J 1998; 19:908. 13. Rehan A, Kanwar M, Rosman H, et al. Incidence of post myocardial infarction left ventricular thrombus formation in the era of primary percutaneous intervention and glycoprotein IIb/IIIa inhibitors. A prospective observational study. Cardiovasc Ultrasound 2006; 4:20. 14. Gianstefani S, Douiri A, Delithanasis I, et al. Incidence and predictors of early left ventricular thrombus after ST-elevation myocardial infarction in the contemporary era of primary percutaneous coronary intervention. Am J Cardiol 2014; 113:1111. 15. Mansencal N, Nasr IA, Pilli re R, et al. Usefulness of contrast echocardiography for assessment of left ventricular thrombus after acute myocardial infarction. Am J Cardiol 2007; 99:1667. 16. Weinsaft JW, Kim RJ, Ross M, et al. Contrast-enhanced anatomic imaging as compared to contrast-enhanced tissue characterization for detection of left ventricular thrombus. JACC Cardiovasc Imaging 2009; 2:969. 17. Srichai MB, Junor C, Rodriguez LL, et al. Clinical, imaging, and pathological characteristics of left ventricular thrombus: a comparison of contrast-enhanced magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography with surgical or pathological validation. Am Heart J 2006; 152:75. 18. Mollet NR, Dymarkowski S, Volders W, et al. Visualization of ventricular thrombi with contrast-enhanced magnetic resonance imaging in patients with ischemic heart disease. Circulation 2002; 106:2873. 19. Barkhausen J, Hunold P, Eggebrecht H, et al. Detection and characterization of intracardiac thrombi on MR imaging. AJR Am J Roentgenol 2002; 179:1539. 20. Stratton JR, Resnick AD. Increased embolic risk in patients with left ventricular thrombi. Circulation 1987; 75:1004. 21. Vaitkus PT, Barnathan ES. Embolic potential, prevention and management of mural thrombus complicating anterior myocardial infarction: a meta-analysis. J Am Coll Cardiol 1993; 22:1004. 22. Keating EC, Gross SA, Schlamowitz RA, et al. Mural thrombi in myocardial infarctions. Prospective evaluation by two-dimensional echocardiography. Am J Med 1983; 74:989. 23. Cregler LL. Antithrombotic therapy in left ventricular thrombosis and systemic embolism. Am Heart J 1992; 123:1110. https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 12/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate 24. Meltzer RS, Visser CA, Fuster V. Intracardiac thrombi and systemic embolization. Ann Intern Med 1986; 104:689. 25. Lattuca B, Bouziri N, Kerneis M, et al. Antithrombotic Therapy for Patients With Left Ventricular Mural Thrombus. J Am Coll Cardiol 2020; 75:1676. 26. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127:e362. 27. Turpie AG, Robinson JG, Doyle DJ, et al. Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction. N Engl J Med 1989; 320:352. 28. Kontny F, Dale J, Abildgaard U, Pedersen TR. Randomized trial of low molecular weight heparin (dalteparin) in prevention of left ventricular thrombus formation and arterial embolism after acute anterior myocardial infarction: the Fragmin in Acute Myocardial Infarction (FRAMI) Study. J Am Coll Cardiol 1997; 30:962. 29. Heik SC, Kupper W, Hamm C, et al. Efficacy of high dose intravenous heparin for treatment of left ventricular thrombi with high embolic risk. J Am Coll Cardiol 1994; 24:1305. 30. Cheong KI, Chuang WP, Wu YW, Huang SH. Successful Resolution of Left Ventricular Thrombus after ST-Elevation Myocardial Infarction by Edoxaban in a Patient with High Bleeding Risk. Acta Cardiol Sin 2019; 35:85. 31. Shokr M, Ahmed A, Abubakar H, et al. Use of direct oral anticoagulants in the treatment of left ventricular thrombi: A tertiary center experience and review of the literature. Clin Case Rep 2019; 7:135. 32. Bhatnagar UB, Rezkalla J, Sethi P, Stys A. Successful Resolution of a Large Left Ventricular Thrombus with Rivaroxaban Therapy after Acute Myocardial Infarction. S D Med 2018; 71:62. 33. Bahmaid RA, Ammar S, Al-Subaie S, et al. Efficacy of direct oral anticoagulants on the resolution of left ventricular thrombus-A case series and literature review. JRSM Cardiovasc Dis 2019; 8:2048004019839548. 34. Fleddermann A, Eckert R, Muskala P, et al. Efficacy of Direct Acting Oral Anticoagulant Drugs in Treatment of Left Atrial Appendage Thrombus in Patients With Atrial Fibrillation. Am J Cardiol 2019; 123:57. 35. Jones DA, Wright P, Alizadeh MA, et al. The use of novel oral anticoagulants compared to vitamin K antagonists (warfarin) in patients with left ventricular thrombus after acute myocardial infarction. Eur Heart J Cardiovasc Pharmacother 2021; 7:398. https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 13/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate 36. Robinson AA, Trankle CR, Eubanks G, et al. Off-label Use of Direct Oral Anticoagulants Compared With Warfarin for Left Ventricular Thrombi. JAMA Cardiol 2020; 5:685. Topic 90 Version 41.0 https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 14/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate GRAPHICS Evaluation of the need for anticoagulation in patients at risk for left ventricular thrombus after myocardial infarction LV: left ventricular; MI: myocardial infarction; long T1 LGE-CMR: long inversion time late gadolinum enhancement cardiovascular magnetic resonance; TEE: transesophageal echocardiography. Long LGE-CMR is preferred. Transesophageal echocardiogram or coronary computed tomographic angiography if LGE-CMR is not available. Refer to relevant UpToDate topic reviews for more information. Clinicians making the decision to anticoagulate should carefully weigh benefits and risks as well as patient preference. Graphic 116123 Version 4.0 https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 15/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate Apical left ventricular thrombus Graphic 109717 Version 1.0 https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 16/17 7/6/23, 3:35 PM Left ventricular thrombus after acute myocardial infarction - UpToDate Contributor Disclosures Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Nikolaus Sarafoff, MD Consultant/Advisory Boards: Boehringer Ingelheim [Heart failure]. Speaker's Bureau: Denk Pharma GmbH & Co KG [Oral anticoagulation]. All of the relevant financial relationships listed have been mitigated. Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/left-ventricular-thrombus-after-acute-myocardial-infarction/print 17/17

7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Premature ventricular complexes: Clinical presentation and diagnostic evaluation : Antonis S Manolis, MD : Hugh Calkins, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 28, 2022. INTRODUCTION Premature ventricular complexes/contractions (PVCs; also referred to as premature ventricular beats, premature ventricular depolarizations, or ventricular extrasystoles) are triggered from the ventricular myocardium in a variety of situations. PVCs are common and occur in a broad spectrum of the population. This includes patients without structural heart disease and those with any form of cardiac disease, independent of severity. The prevalence, mechanisms, clinical presentation, and approach to diagnostic testing for patients with known or suspected PVCs will be presented here. Discussion of the treatment and prognosis related to PVCs, as well as review of supraventricular premature beats, are presented separately. (See "Premature ventricular complexes: Treatment and prognosis" and "Supraventricular premature beats".) PREVALENCE The prevalence of PVCs is directly related to the study population, the detection method, and the duration of observation. PVCs are more likely to be detected in older patients, patients with more comorbidities, and patients who are monitored for longer durations of time [1]. In patients with no known heart disease, PVCs have been seen in approximately 1 percent of routine 12-lead electrocardiograms (ECG) of 30 to 60 seconds duration and up to 6 percent of https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 1/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate ECGs of two minutes duration [2-4]. By comparison, when 24-hour ambulatory monitoring is used, up to 80 percent of apparently healthy people have occasional PVCs [5,6]. The occurrence of frequent PVCs accounting for more than 20 percent of overall heart beats is rare, seen in less than 2 percent of patients [7]. There is an age-related increase in the prevalence of PVCs in normal individuals and those with underlying heart disease [2,4,6,8]. The prevalence of PVCs increase with age and in the presence of other factors, such as faster sinus rate, hypokalemia, hypomagnesemia, and hypertension [4]. It is generally considered that a "normal number" of PVCs in an adult is <500 per 24 hours [9]. MECHANISMS FOR PVCS Since invasive testing is rarely performed in patients with only simple PVCs, there is little information about the mechanisms of PVCs in humans. Mechanisms by which PVCs are generated include [1]: Reentry Reentry is one potential mechanism for PVCs, particularly in patients with structural heart disease such as in the post-myocardial infarction (MI) setting. Reentrant PVCs occur with conduction delay and unidirectional block, settings that are characteristically seen in patients with a healed MI or evidence of myocardial fibrosis of any etiology. A wave front may then perpetuate under the correct set of circumstances, such as the administration of a drug that prolongs conduction. (See "Reentry and the development of cardiac arrhythmias".) Abnormal automaticity Abnormal automaticity is most probable with electrolyte abnormalities or acute ischemia and is enhanced by catecholamines. These conditions tend to lower the diastolic transmembrane voltage, resulting in premature depolarization. The principal site of PVC development due to abnormal automaticity is the Purkinje fiber layer. (See "Enhanced cardiac automaticity".) Triggered activity Early (phase 3 of the action potential) or late (phase 4) afterdepolarizations may occur in Purkinje cells or in the ventricular myocardium; such electrical activity may arise because of a number of conditions, including hypokalemia, ischemia, infarction, cardiomyopathy, excess calcium, and drug toxicity (such as digoxin or agents that prolong repolarization or the QT interval). If repetitive firing allows these afterdepolarizations to reach threshold potential, PVCs will be generated and may perpetuate if the proper conditions are present. https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 2/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate CLASSIFICATION PVCs can be classified in a variety of manners: The absence (idiopathic) or presence of underlying structural heart disease (SHD) Clinical presentation (symptomatic or asymptomatic) ECG morphology (LBBB) ( waveform 1) or RBBB ( waveform 2); unifocal with single morphology or multifocal with >1 morphologies; interpolated when interposed within two sinus beats without a compensatory pause) ( waveform 3) Relationship (or not) to exercise (ie, exercise-induced or not) Frequency of occurrence (PVC burden) Prognosis (potentially "malignant," eg, frequent PVCs in patients with SHD, or short- coupled "idiopathic" PVCs) Idiopathic PVCs most commonly originate from the right ventricular outflow tract, the left ventricular outflow tract, and the paravalvular aortic cusps. (See 'Electrocardiography' below.) CLINICAL PRESENTATION AND ECG FINDINGS The presence of PVCs is associated with several characteristic findings on history, physical examination, and ECG. The identification of PVCs in an otherwise healthy person is usually a benign and incidental finding, but PVCs may also be seen in a variety of inherited and acquired forms of heart disease. Symptoms The vast majority of patients with PVCs experience no symptoms. When patients experience symptoms, palpitations are the most frequent symptom, with dizziness occurring infrequently. PVCs rarely cause true hemodynamic compromise, except when they occur frequently in a patient with severely depressed left ventricular (LV) function or when they are associated with an underlying bradycardia. Though less commonly seen, associated symptoms of syncope, (especially with no prodrome, preceded by palpitations), chest pain, or dyspnea could signal associated underlying cardiac structural or electrical conduction system disease. The most common symptoms resulting from PVCs are palpitations. Palpitations result from the hypercontractility of a post-PVC beat or a feeling that the heart has stopped secondary to a post- PVC pause. Less often, frequent PVCs can result in a pounding sensation in the neck, lightheadedness, or near syncope. There is great variability as to when the symptoms are most prominent, although a quiet environment, such as at night while lying in bed, may make patients more aware of their ectopy. https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 3/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate They are more frequently appreciated when subjects are lying on their left side and the heart is closer to the chest wall. Correctable causes or triggers should be sought by clinical history (inquiring about possible underlying cardiovascular diseases, but also about use of alcohol or caffeine-containing beverages, or illicit drugs, etc) and/or laboratory testing (electrolyte levels, thyroid stimulating hormone [TSH]). (See 'Laboratory studies' below.) Physical examination Unless the patient is actively experiencing PVCs at the time of evaluation, there are no sensitive or specific findings from the physical examination. When PVCs are actively occurring, the following may be seen: Irregular pulse The most characteristic finding on physical exam is the presence of an irregular pulse resulting from the presence of PVCs during the examination. Atrioventricular dissociation If present, this will result in variable intensity of the first heart sound (secondary to a changing PR interval) and in cannon "A" waves (due to almost simultaneous retrograde atrial and antegrade ventricular activation and subsequent contraction). The splitting of the second heart sound (S2) This will also vary, depending upon whether the PVC has a right or left bundle branch morphology; a widely split S2 due to a delayed P2 may be appreciated if a right bundle branch block PVC occurs. (See "Auscultation of heart sounds".) Compensatory pause An auscultated fully compensatory pause is present with most PVCs and is identified by the prolonged pause following the premature beat. Electrocardiography An ECG should be part of the standard evaluation for any patient with suspected PVCs ( waveform 4) [1]. PVCs have the following ECG characteristics (see "ECG tutorial: Ventricular arrhythmias"): QRS duration A PVC has a duration of more than 120 milliseconds. QRS morphology A PVC morphology is different from usual aberration (ie, a typical right bundle branch block [RBBB] or left bundle branch block [LBBB]), although RBBB-like and LBBB-like morphologies may also be seen. T wave In a PVC this is in the opposite direction from the main QRS vector. A fully compensatory pause This is defined as a PP interval surrounding the PVC that is twice the sinus PP interval; less frequently, the PVC is interpolated and does not alter the https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 4/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate baseline sinus interval (ie, the PP interval surrounding the PVC is equal to the sinus PP interval). The pause results from retrograde block in the atrioventricular (AV) node and hence an inability of the ventricular impulse to penetrate the atrium and affect the sinus node. The sinus node fires on time, but the impulse it generates is unable to conduct to the ventricle. Multifocal PVCs These may originate from various sites, from one site with multiple exit points into the ventricular myocardium, or from changes in the pattern or direction of myocardial activation due to variables in ventricular electrophysiologic properties. Specific PVC pattern Several specific PVC patterns have been described. One pattern, ventricular bigeminy, refers to a persistent alternation of normal and premature beats (ie, every other QRS complex is a PVC) ( waveform 5). Ventricular trigeminy (two normal beats followed by a PVC) and quadrigeminy (three normal beats followed by a PVC) have also been described ( waveform 6). They rarely cause severe symptoms and have no known independent prognostic importance. There are notable exceptions to these characteristic findings, including: A less wide QRS complex This can result from a PVC originating from the contralateral ventricle in a patient with a preexisting bundle branch block. A relatively narrow QRS complex (<130 milliseconds) with an RBBB morphology This is seen in fascicular PVCs displaying a left axis deviation (left anterior fascicular block) when originating in the left posterior fascicle or a right axis deviation (left posterior fascicular block) when originating in the anterior fascicle of the left bundle [10]. Very rarely, a PVC may originate from the left bundle branch itself and resemble a sinus beat, indistinguishable from an PAC on surface ECG [11]. A pseudonormalized T wave This is seen in PVCs in a patient with a prior myocardial infarction. Noncompensatory pause A PVC that resets the sinus node and thereby creates a noncompensatory pause. An interpolated PVC This is interposed between two sinus beats without a compensatory pause ( waveform 3). Interpolated PVCs have also been reported to be associated with PVC-induced cardiomyopathy [12]. (See "ECG tutorial: Ventricular arrhythmias", section on 'Premature ventricular contractions'.) https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 5/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Classically, unifocal PVCs have fixed coupling intervals with the preceding beat since the most frequent mechanism is localized reentry. By comparison, unifocal PVCs with variable coupling suggests a parasystolic focus due to ectopic tissue that exhibits autonomy. Ventricular parasystole represents an independent ectopic ventricular rhythm that competes with the sinus rhythm. It appears on the ECG as unifocal PVCs with a variable coupling interval (the interval between the prior sinus beat and the premature beat varies) ( waveform 7). There is entrance block into this focus, and thus it continues to fire at its own rate. There is also exit block from this focus (ie, it will result in ventricular depolarization and a ventricular complex only when the ventricular myocardium is capable of being stimulated). (See "ECG tutorial: Ventricular arrhythmias", section on 'Ventricular parasystole'.) R-on-T phenomenon The term "R-on-T phenomenon" (ie, when the PVC occurs at or near the T wave apex, otherwise known as the vulnerable period), has little prognostic importance in most clinical situations [13-15]. During the performance of an electrophysiology study, PVCs are applied at the vulnerable period of the cardiac cycle, without producing malignant ventricular arrhythmias in normal hearts. However, the R-on-T phenomenon may be of importance in subsets of patients at risk for polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF), such as those with acute myocardial ischemia, the Brugada syndrome, the malignant form of early repolarization, and idiopathic VF [16-18]. (See "Early repolarization" and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) Associated conditions While PVCs can and do occur sporadically at some point in nearly all persons, certain conditions, both cardiac and non-cardiac, are associated with more frequent PVCs. Examples of cardiac conditions in which PVCs are frequently seen include [19-26]: Hypertension with LV hypertrophy (the presence of LVH has been associated with a higher prevalence of PVCs in patients with hypertension; LVH has been linked to higher morbidity and mortality) [27]. Acute MI HF Myocarditis Arrhythmogenic right ventricular cardiomyopathy Hypertrophic cardiomyopathy Congenital heart disease https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 6/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Idiopathic ventricular tachycardia Non-cardiac conditions in which PVCs may arise include [28-31]: Chronic obstructive pulmonary disease Sleep apnea syndromes Pulmonary hypertension Endocrinopathies (thyroid, adrenal, or gonadal abnormalities) can all be associated with PVCs Nicotine, alcohol, or stimulants use, including sympathomimetic medications (eg, beta- agonists, decongestants, antihistamines) or illicit drugs (eg, cocaine, amphetamines) Although there is a widespread belief that caffeine, particularly at high doses, is associated with palpitations and a number of arrhythmias, there is no evidence that it is proarrhythmic [32-34]. In a study of 1388 participants in the Cardiovascular Health Study, in which caffeine consumption was self-reported and patients underwent 24-hour ambulatory monitoring, there was no significant differences in the frequency of PVCs between users and non-users of caffeine [35]. Additionally, more frequent consumption of caffeine in this study was not associated with more ectopy. Nevertheless, there are patients who may be more sensitive to caffeine and note a relationship of palpitations to caffeine intake. A greater discussion of the relevance of PVCs in various clinical conditions can be found in the specific topics. PVC-induced cardiomyopathy Frequent PVCs are associated with a reversible cardiomyopathy, even in the absence of sustained ventricular arrhythmias or symptoms [36]. Risk factors for PVC-induced cardiomyopathy are a greater PVC burden and epicardial origin of PVCs [37], as well as longer PVC QRS duration [38], superiorly directed PVC axis (odds ratio [OR] 2.7), high PVC burden of 10 to 20 percent (OR 3.5) or >20 percent (OR 4.4), PVC coupling interval >500 ms (OR 4.7), nonsustained ventricular tachycardia (OR 5.3) [39], duration of ectopic (PVC) activity, male sex, lack of diurnal variation, and interpolated PVCs [40]. PVC burden has been found to be the most consistent parameter for the risk of development of PVC cardiomyopathy [41]. Data on the time course of PVC cardiomyopathy are limited. Some studies suggest PVC cardiomyopathy develops slowly and may take as long as four years, even in persons with a high PVC (>20 percent) burden [42]. However, animal studies have suggested that left ventricular https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 7/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate dysfunction may develop as early as two to four weeks, dependent on pattern (eg, bigeminal), coupling interval, PVC burden, degree of asynchrony, and individual-related characteristics [42]. Elimination of PVCs using catheter ablation or medications often leads to normalization of cardiac function. This is discussed in more detail separately. (See "Arrhythmia-induced cardiomyopathy", section on 'Frequent ventricular ectopy'.) PVC-related cardiomyopathy should be suspected in individuals who present with an unexplained cardiomyopathy and very frequent unifocal PVCs (typically >15 percent of all beats). It should be noted that some patients with high PVC burdens can maintain normal cardiac function, and PVC-induced cardiomyopathy has also been reported in patients with PVC burdens as low as 4 to 5 percent. One large population study suggested that PVC-induced cardiomyopathy may be underdiagnosed or mistaken for idiopathic cardiomyopathy. In this database study of 16.8 million patients, those with PVCs were more likely to develop systolic heart failure compared with those who did not have VCs (62.8 versus 6.1 per 1000 patient-years; hazard ratio [HR] 1.8, 95% CI 1.8-1.9) [24]. The effect of PVCs on the incidence of systolic heart failure is even greater in younger patients (<65 years of age) without comorbidities, suggesting that PVCs may be an important cause of "idiopathic" HF (HR 6.5, 95% CI 5.5-7.7). ADDITIONAL TESTING Once PVCs are suspected or definitively identified, the need for additional testing is based on the suspected presence or absence of associated cardiac disease and possibly if PVCs with high-risk features are present. This is discussed separately. (See "Premature ventricular complexes: Treatment and prognosis", section on 'Underlying or associated cardiac disease' and "Premature ventricular complexes: Treatment and prognosis", section on 'Risk assessment'.) Laboratory studies Although there is no routine approach to laboratory testing in patients with PVCs, patient history and physical examination can guide appropriate testing for PVC triggers ( table 1). Ambulatory monitoring Ambulatory ECG monitoring should be performed for diagnostic or prognostic purposes in many and/or most patients with PVCs. Ambulatory monitoring is especially valuable in the following settings: Unclear etiology Patients with palpitations of unclear etiology with significant symptoms, in whom therapeutic decisions will differ depending upon the etiology of https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 8/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate palpitations Management decisions Patients in whom PVCs have been identified when therapeutic or prognostic decisions may vary based on the quantity and morphology of PVCs. Examples include patients with cardiomyopathy that may be PVC related in whom catheter ablation is being considered, underlying heart disease in whom PVCs may contribute to prognosis and therapeutic decisions (eg, for an implantable cardioverter-defibrillator in patients with hypertrophic cardiomyopathy, etc) or any patient with arrhythmogenic right ventricular cardiomyopathy. When ambulatory ECG monitoring is indicated, a monitoring period of 24 to 48 hours is typically sufficient to identify PVCs and quantify the overall PVC burden. A variety of ambulatory ECG monitoring techniques are available, but for most patients Holter monitoring or patch monitoring will be the preferred approach. (See "Ambulatory ECG monitoring".) Echocardiogram An echocardiogram should be performed if there are high-risk symptoms, frequent PVCs, or if there is any suspicion of underlying or new structural heart disease (including PVC cardiomyopathy) and/or high-risk information from other risk assessments such as abnormal 12-lead ECG or family history of heart disease and especially of sudden cardiac death. Most commonly, transthoracic echocardiography is the initial test (and test of choice) for the evaluation of underlying cardiac structure, function, and noninvasive hemodynamic measurements. Further testing in selected patients In selected patients with PVCs, exercise testing, cardiac magnetic resonance imaging, and electrophysiologic testing are indicated. These tests and their indications are described separately. (See "Premature ventricular complexes: Treatment and prognosis", section on 'Further testing in selected patients'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ventricular arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 9/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Ventricular premature beats (The Basics)") SUMMARY AND RECOMMENDATIONS Background Premature ventricular complexes/contractions (PVCs; also referred to as premature ventricular beats, premature ventricular depolarizations, or ventricular extrasystoles) are common and occur in a broad spectrum of the population, including patients with and without structural heart disease. (See 'Introduction' above.) Prevalence The prevalence of PVCs is directly related to the study population, the detection method, and the duration of observation. PVCs are more likely to be detected in older patients, patients with more comorbidities, and patients who are monitored for longer durations of time. (See 'Prevalence' above.) Clinical presentation The vast majority of patients with PVCs experience no symptoms. When patients experience symptoms, palpitations are the most frequent symptom, and dizziness is less common. PVCs rarely cause true hemodynamic compromise, except when they occur frequently in a patient with severely depressed left ventricular (LV) function or when they are associated with an underlying bradycardia. (See 'Symptoms' above.) PVC-induced cardiomyopathy Frequent PVCs have been associated with a reversible cardiomyopathy, even in the absence of sustained ventricular arrhythmias or symptoms. (See 'PVC-induced cardiomyopathy' above and "Arrhythmia-induced cardiomyopathy", section on 'Frequent ventricular ectopy'.) Diagnostic evaluation Electrocardiogram This should be part of the standard evaluation for any patient with suspected PVCs. Typical electrocardiographic (ECG) findings of PVCs include QRS https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 10/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate duration >120 milliseconds, QRS morphology that is different from usual aberration, T wave in the opposite direction from the main QRS vector, and a fully compensatory pause (ie, the PP interval surrounding the PVC is twice the sinus PP interval). (See 'Electrocardiography' above.) Laboratory studies Although there is no routine approach to laboratory testing in patients with PVCs, patient history and physical examination can guide appropriate testing for PVC triggers ( table 1). (See 'Laboratory studies' above.) Ambulatory monitoring Ambulatory ECG monitoring is performed for diagnostic or prognostic purposes in many and/or most patients with PVCs. (See 'Ambulatory monitoring' above.) Echocardiogram This should be performed if there are high-risk symptoms, frequent PVCs, suspicion of underlying or new structural heart disease, and/or high-risk information from other risk assessments; these include abnormal 12-lead ECG, family history of sudden cardiac death, or other cardiac disease. (See 'Echocardiogram' above.) Further testing In selected patients with PVCs, exercise testing, cardiac magnetic resonance imaging, and electrophysiologic testing are indicated. (See "Premature ventricular complexes: Treatment and prognosis", section on 'Further testing in selected patients'.) ACKNOWLEDGMENT The authors and UpToDate thank Dr. Philip Podrid, Dr. Brian Olshansky, and Dr. Bernard Gersh, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Marcus GM. Evaluation and Management of Premature Ventricular Complexes. Circulation 2020; 141:1404. 2. HISS RG, LAMB LE. Electrocardiographic findings in 122,043 individuals. Circulation 1962; 25:947. 3. Jouven X, Zureik M, Desnos M, et al. Long-term outcome in asymptomatic men with exercise-induced premature ventricular depolarizations. N Engl J Med 2000; 343:826. https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 11/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate 4. Simpson RJ Jr, Cascio WE, Schreiner PJ, et al. Prevalence of premature ventricular contractions in a population of African American and white men and women: the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J 2002; 143:535. 5. Sobotka PA, Mayer JH, Bauernfeind RA, et al. Arrhythmias documented by 24-hour continuous ambulatory electrocardiographic monitoring in young women without apparent heart disease. Am Heart J 1981; 101:753. 6. Brodsky M, Wu D, Denes P, et al. Arrhythmias documented by 24 hour continuous electrocardiographic monitoring in 50 male medical students without apparent heart disease. Am J Cardiol 1977; 39:390. 7. Yang J, Dudum R, Mandyam MC, Marcus GM. Characteristics of unselected high-burden premature ventricular contraction patients. Pacing Clin Electrophysiol 2014; 37:1671. 8. Glasser SP, Clark PI, Applebaum HJ. Occurrence of frequent complex arrhythmias detected by ambulatory monitoring: findings in an apparently healthy asymptomatic elderly population. Chest 1979; 75:565. 9. Kostis JB, McCrone K, Moreyra AE, et al. Premature ventricular complexes in the absence of identifiable heart disease. Circulation 1981; 63:1351. 10. Zhang J, Tang C, Zhang Y, Su X. Catheter ablation of premature ventricular complexes arising from the left fascicular system. Heart Rhythm 2019; 16:527. 11. Pathak RK, Betensky BP, Santangeli P, Dixit S. Distinct Electrocardiographic Form of Idiopathic Ventricular Arrhythmia Originating From the Left Bundle Branch. J Cardiovasc Electrophysiol 2017; 28:115. 12. Olgun H, Yokokawa M, Baman T, et al. The role of interpolation in PVC-induced cardiomyopathy. Heart Rhythm 2011; 8:1046. 13. Wolff GA, Veith F, Lown B. A vulnerable period for ventricular tachycardia following myocardial infarction. Cardiovasc Res 1968; 2:111. 14. de Soyza N, Bissett JK, Kane JJ, et al. Ectopic ventricular prematurity and its relationship to ventricular tachycardia in acute myocardial infarction in man. Circulation 1974; 50:529. 15. Roberts R, Ambos HD, Loh CW, Sobel BE. Initiation of repetitive ventricular depolarizations by relatively late premature complexes in patients with acute myocardial infarction. Am J Cardiol 1978; 41:678. 16. Nam GB, Ko KH, Kim J, et al. Mode of onset of ventricular fibrillation in patients with early repolarization pattern vs. Brugada syndrome. Eur Heart J 2010; 31:330. 17. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 1999; 100:1660. https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 12/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate 18. Viskin S, Lesh MD, Eldar M, et al. Mode of onset of malignant ventricular arrhythmias in idiopathic ventricular fibrillation. J Cardiovasc Electrophysiol 1997; 8:1115. 19. McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med 1987; 317:787. 20. Eldar M, Sievner Z, Goldbourt U, et al. Primary ventricular tachycardia in acute myocardial infarction: clinical characteristics and mortality. The SPRINT Study Group. Ann Intern Med 1992; 117:31. 21. Heidb chel H, Tack J, Vanneste L, et al. Significance of arrhythmias during the first 24 hours of acute myocardial infarction treated with alteplase and effect of early administration of a beta-blocker or a bradycardiac agent on their incidence. Circulation 1994; 89:1051. 22. Teerlink JR, Jalaluddin M, Anderson S, et al. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. PROMISE (Prospective Randomized Milrinone Survival Evaluation) Investigators. Circulation 2000; 101:40. 23. Le VV, Mitiku T, Hadley D, et al. Rest premature ventricular contractions on routine ECG and prognosis in heart failure patients. Ann Noninvasive Electrocardiol 2010; 15:56. 24. Agarwal V, Vittinghoff E, Whitman IR, et al. Relation Between Ventricular Premature Complexes and Incident Heart Failure. Am J Cardiol 2017; 119:1238. 25. Jeserich M, Merkely B, Olschewski M, et al. Patients with exercise-associated ventricular ectopy present evidence of myocarditis. J Cardiovasc Magn Reson 2015; 17:100. 26. Adabag AS, Casey SA, Kuskowski MA, et al. Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy. J Am Coll Cardiol 2005; 45:697. 27. Almendral J, Villacastin JP, Arenal A, et al. Evidence favoring the hypothesis that ventricular arrhythmias have prognostic significance in left ventricular hypertrophy secondary to systemic hypertension. Am J Cardiol 1995; 76:60D. 28. Almeneessier AS, Alasousi N, Sharif MM, et al. Prevalence and Predictors of Arrhythmia in Patients with Obstructive Sleep Apnea. Sleep Sci 2017; 10:142. 29. Zuchinali P, Ribeiro PA, Pimentel M, et al. Effect of caffeine on ventricular arrhythmia: a systematic review and meta-analysis of experimental and clinical studies. Europace 2016; 18:257. 30. Kerola T, Dewland TA, Vittinghoff E, et al. Modifiable Predictors of Ventricular Ectopy in the Community. J Am Heart Assoc 2018; 7:e010078. https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 13/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate 31. Sekizuka H, Miyake H. The Relationship Between Premature Ventricular Contractions and Lifestyle-Related Habits among the Japanese Working Population (FUJITSU Cardiovascular and Respiratory Observational Study-1; FACT-1). J Nippon Med Sch 2018; 85:337. 32. Enriquez A, Frankel DS. Arrhythmogenic effects of energy drinks. J Cardiovasc Electrophysiol 2017; 28:711. 33. Engstrom G, Hedblad B, Juul-Moller S, et al. Cardiac arrhythmias and stroke: increased risk in men with high frequency of atrial ectopic beats. Stroke 2001; 31:2925. 34. Manolis AA, Manolis TA, Apostolopoulos EJ, et al. The Cardiovascular Benefits of Caffeinated Beverages: Real or Surreal? "Metron Ariston - All in Moderation". Curr Med Chem 2022; 29:2235. 35. Dixit S, Stein PK, Dewland TA, et al. Consumption of Caffeinated Products and Cardiac Ectopy. J Am Heart Assoc 2016; 5. 36. Tran CT, Calkins H. Premature ventricular contraction-induced cardiomyopathy: an emerging entity. Expert Rev Cardiovasc Ther 2016; 14:1227. 37. Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart Rhythm 2012; 9:1460. 38. Park KM, Im SI, Lee SH, et al. Left Ventricular Dysfunction in Outpatients with Frequent Ventricular Premature Complexes. Tex Heart Inst J 2022; 49. 39. Voskoboinik A, Hadjis A, Alhede C, et al. Predictors of adverse outcome in patients with frequent premature ventricular complexes: The ABC-VT risk score. Heart Rhythm 2020; 17:1066. 40. Latchamsetty R, Bogun F. Premature Ventricular Complex-Induced Cardiomyopathy. JACC Clin Electrophysiol 2019; 5:537. 41. Huizar JF, Tan AY, Kaszala K, Ellenbogen KA. Clinical and translational insights on premature ventricular contractions and PVC-induced cardiomyopathy. Prog Cardiovasc Dis 2021; 66:17. 42. Cojocaru C, Penela D, Berruezo A, Vatasescu R. Mechanisms, time course and predictability of premature ventricular contractions cardiomyopathy-an update on its development and resolution. Heart Fail Rev 2022; 27:1639. Topic 994 Version 58.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 14/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate GRAPHICS Left ventricular outflow tract premature ventricular complexes Courtesy of Antonis Manolis, MD. Graphic 139343 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 15/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Right ventricular outflow tract premature ventricular complexes Courtesy of Antonis Manolis, MD. Graphic 139349 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 16/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Single lead electrocardiogram (ECG) showing an interpolated ventricular premature beat (VPB) The third beat is a ventricular premature beat (VPB). It is called an interpolated VPB since it does not alter the underlying sinus RR interval. Graphic 72768 Version 3.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 17/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Single-lead electrocardiogram showing a ventricular premature beat The fourth beat is a ventricular premature beat (VPB). It has a wide, bizarre morphology, with a duration >0.16 seconds. Graphic 57511 Version 4.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 18/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Electrocardiogram showing ventricular bigeminy A ventricular premature beat follows each sinus beat, and the coupling interval between the ventricular premature beat and the previous sinus QRS complex is constant (fixed coupling interval). The resulting pattern is referred to as ventricular bigeminy. Graphic 51529 Version 5.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 19/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Single-lead electrocardiogram showing ventricular trigeminy Every third beat is a ventricular premature beat. The coupling interval between the ventricular premature beat and the previous sinus QRS complex is constant (fixed coupling interval). The resulting pattern is referred to as ventricular trigeminy. Graphic 64181 Version 4.0

24. Agarwal V, Vittinghoff E, Whitman IR, et al. Relation Between Ventricular Premature Complexes and Incident Heart Failure. Am J Cardiol 2017; 119:1238. 25. Jeserich M, Merkely B, Olschewski M, et al. Patients with exercise-associated ventricular ectopy present evidence of myocarditis. J Cardiovasc Magn Reson 2015; 17:100. 26. Adabag AS, Casey SA, Kuskowski MA, et al. Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy. J Am Coll Cardiol 2005; 45:697. 27. Almendral J, Villacastin JP, Arenal A, et al. Evidence favoring the hypothesis that ventricular arrhythmias have prognostic significance in left ventricular hypertrophy secondary to systemic hypertension. Am J Cardiol 1995; 76:60D. 28. Almeneessier AS, Alasousi N, Sharif MM, et al. Prevalence and Predictors of Arrhythmia in Patients with Obstructive Sleep Apnea. Sleep Sci 2017; 10:142. 29. Zuchinali P, Ribeiro PA, Pimentel M, et al. Effect of caffeine on ventricular arrhythmia: a systematic review and meta-analysis of experimental and clinical studies. Europace 2016; 18:257. 30. Kerola T, Dewland TA, Vittinghoff E, et al. Modifiable Predictors of Ventricular Ectopy in the Community. J Am Heart Assoc 2018; 7:e010078. https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 13/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate 31. Sekizuka H, Miyake H. The Relationship Between Premature Ventricular Contractions and Lifestyle-Related Habits among the Japanese Working Population (FUJITSU Cardiovascular and Respiratory Observational Study-1; FACT-1). J Nippon Med Sch 2018; 85:337. 32. Enriquez A, Frankel DS. Arrhythmogenic effects of energy drinks. J Cardiovasc Electrophysiol 2017; 28:711. 33. Engstrom G, Hedblad B, Juul-Moller S, et al. Cardiac arrhythmias and stroke: increased risk in men with high frequency of atrial ectopic beats. Stroke 2001; 31:2925. 34. Manolis AA, Manolis TA, Apostolopoulos EJ, et al. The Cardiovascular Benefits of Caffeinated Beverages: Real or Surreal? "Metron Ariston - All in Moderation". Curr Med Chem 2022; 29:2235. 35. Dixit S, Stein PK, Dewland TA, et al. Consumption of Caffeinated Products and Cardiac Ectopy. J Am Heart Assoc 2016; 5. 36. Tran CT, Calkins H. Premature ventricular contraction-induced cardiomyopathy: an emerging entity. Expert Rev Cardiovasc Ther 2016; 14:1227. 37. Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart Rhythm 2012; 9:1460. 38. Park KM, Im SI, Lee SH, et al. Left Ventricular Dysfunction in Outpatients with Frequent Ventricular Premature Complexes. Tex Heart Inst J 2022; 49. 39. Voskoboinik A, Hadjis A, Alhede C, et al. Predictors of adverse outcome in patients with frequent premature ventricular complexes: The ABC-VT risk score. Heart Rhythm 2020; 17:1066. 40. Latchamsetty R, Bogun F. Premature Ventricular Complex-Induced Cardiomyopathy. JACC Clin Electrophysiol 2019; 5:537. 41. Huizar JF, Tan AY, Kaszala K, Ellenbogen KA. Clinical and translational insights on premature ventricular contractions and PVC-induced cardiomyopathy. Prog Cardiovasc Dis 2021; 66:17. 42. Cojocaru C, Penela D, Berruezo A, Vatasescu R. Mechanisms, time course and predictability of premature ventricular contractions cardiomyopathy-an update on its development and resolution. Heart Fail Rev 2022; 27:1639. Topic 994 Version 58.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 14/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate GRAPHICS Left ventricular outflow tract premature ventricular complexes Courtesy of Antonis Manolis, MD. Graphic 139343 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 15/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Right ventricular outflow tract premature ventricular complexes Courtesy of Antonis Manolis, MD. Graphic 139349 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 16/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Single lead electrocardiogram (ECG) showing an interpolated ventricular premature beat (VPB) The third beat is a ventricular premature beat (VPB). It is called an interpolated VPB since it does not alter the underlying sinus RR interval. Graphic 72768 Version 3.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 17/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Single-lead electrocardiogram showing a ventricular premature beat The fourth beat is a ventricular premature beat (VPB). It has a wide, bizarre morphology, with a duration >0.16 seconds. Graphic 57511 Version 4.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 18/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Electrocardiogram showing ventricular bigeminy A ventricular premature beat follows each sinus beat, and the coupling interval between the ventricular premature beat and the previous sinus QRS complex is constant (fixed coupling interval). The resulting pattern is referred to as ventricular bigeminy. Graphic 51529 Version 5.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 19/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Single-lead electrocardiogram showing ventricular trigeminy Every third beat is a ventricular premature beat. The coupling interval between the ventricular premature beat and the previous sinus QRS complex is constant (fixed coupling interval). The resulting pattern is referred to as ventricular trigeminy. Graphic 64181 Version 4.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 20/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Electrocardiogram (ECG) showing ventricular parasystole Unifocal parasystolic ventricular premature beats (VPBs) occur at a rate which is slower than the underlying sinus rhythm and manifest different coupling intervals (ie, the distance between the VPB and the prior QRS complex). The ectopic focus does not always activate the ventricular myocardium (and therefore does not produce a VPB on the ECG) since it may arrive at a time when the ventricle is refractory due to activation from the normal conduction pathway. However, the interval between two successive VPBs is always some integer of the underlying rate of the ectopic focus (the interectopic intervals have a common denominator) since the ectopic focus is undisturbed and continues to fire at its own intrinsic rate. Graphic 70928 Version 5.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 21/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Triggers for premature ventricular contractions Trigger Patient group Test Alcohol Patients reporting alcohol use, Alcohol screen, urine toxicology physical examination signs of alcohol use Caffeine (eg, coffee or tea Patients reporting caffeine use intake) Recreational/stimulating drugs Patients in whom stimulant drug use is suspected Drug screen (eg, for cocaine, amphetamines) Electrolyte abnormalities (eg, potassium or magnesium) Patients with suspected metabolic derangements (eg, vomiting, diarrhea, diuretic use, Serum electrolytes etc) Hypoxia Patients with COPD or other Pulse oximetry, arterial blood chronic lung disease gas Uncontrolled hypertension Patients with a history of hypertension or risk factors for hypertension Blood pressure measurement Hyper/hypothyroidism Patients with symptoms/signs of hyper- or hypothyroidism TSH High digoxin level Patients taking the drug Digoxin level Heart failure exacerbation Patients with heart failure symptoms or physical examination signs of volume overload Brain-type natriuretic peptide Anemia Patients with symptoms/signs of anemia Complete blood count Psychological stress/anxiety Patients reporting increase in life stressors, anxiety Menopausal transition Females in the perimenopause period COPD: chronic obstructive pulmonary disease; TSH: thyroid-stimulating hormone. Graphic 138370 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 22/23 7/6/23, 3:34 PM Premature ventricular complexes: Clinical presentation and diagnostic evaluation - UpToDate Contributor Disclosures Antonis S Manolis, MD No relevant financial relationship(s) with ineligible companies to disclose. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/premature-ventricular-complexes-clinical-presentation-and-diagnostic-evaluation/print 23/23

7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Premature ventricular complexes: Treatment and prognosis : Antonis S Manolis, MD : Hugh Calkins, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 07, 2022. INTRODUCTION Premature ventricular complexes/contractions (PVCs; also referred to premature ventricular beats, premature ventricular depolarizations, or ventricular extrasystoles) are common and occur in a broad spectrum of the population. This includes patients without apparent structural heart disease as well as those with any form of cardiac disease, independent of severity. The approach to risk assessment and treatment of PVCs along with information on prognosis will be presented here. Discussion of the prevalence, mechanisms, clinical presentation, and approach to diagnostic testing for patients with known or suspected PVCs, as well as review of supraventricular premature beats, are presented separately: (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation".) (See "Supraventricular premature beats".) RISK ASSESSMENT The management of the patient with PVCs depends on whether the initial evaluation indicates that the patient is at high versus low risk of complications including cardiomyopathy, heart failure exacerbation, and ventricular tachyarrhythmias. High-risk features will indicate more intensive treatment and monitoring. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 1/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Our approach, outlined below, is in general agreement with the published recommendations of multiple professional societies [1-3]. Symptoms Most patients with PVCs have no symptoms; only a minority describe bothersome symptoms (usually palpitations). These PVC-related symptoms are described separately. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Symptoms'.) Patients with no or mild PVC symptoms and none of the other risk factors described below can typically be reassured by their providers that PVCs are usually self-limiting, rarely life- threatening, and in most cases do not require treatment. (See 'Asymptomatic patients with low premature ventricular complex burden' below.) Patients with significant and/or persistent PVC-related symptoms should be treated to reduce the PVC burden; the treatment approach will depend upon the presence or absence of other risk factors. (See 'Patient with symptoms and/or high premature ventricular complex burden' below and 'Premature ventricular complex burden' below.) Symptoms of syncope (especially with no prodrome or preceded by palpitations), chest pain, or dyspnea are uncommonly reported in patients with PVCs and signal underlying cardiac structural or electrical conduction system disease. These symptoms may identify a higher-risk patient and require specific evaluation. (See 'Underlying or associated cardiac disease' below.) Family history A detailed family history should be taken regarding coronary heart disease, sudden death, or arrythmia and cardiomyopathy. A family history of sudden cardiac death or arrest or an inherited arrythmia syndrome identifies the patient to be at higher risk for electrical or structural heart disease, which in turn requires a more specific evaluation. (See 'Further testing in selected patients' below.) Premature ventricular complex burden In all patients, it is important to assess and then continue to monitor for reduction in PVC burden throughout treatment. High PVC burden is a predictor of PVC-induced cardiomyopathy, heart failure, and mortality, and therefore requires more aggressive therapy [4]. Monitoring can usually be done with 24- to 48-hour continuous electrocardiographic monitoring. (See "Ambulatory ECG monitoring", section on 'Continuous ambulatory ECG (Holter) monitor'.) PVC burden is classified as: https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 2/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Low: <1 percent or 1000 PVCs/day Intermediate burden: >1 to <15 percent PVCs/ day High: >15 percent or 15,000 PVCs/day Premature ventricular complex characteristics PVC characteristics such as origin and morphology can be considered when determining whether a patient is at high or low risk for cardiomyopathy or malignant arrythmia. Even when the PVCs seem to be idiopathic in a patient with a previously normal heart, some PVCs can still be potentially malignant (ie, cause cardiomyopathy, or trigger sudden death) [5-7]. PVC morphology is also of value as it can predict the ablation target and response to PVC catheter ablation. (See 'Catheter ablation' below.) Characteristics associated with higher risk include increased QRS duration [8,9] (these are often of epicardial origin [10-12]) ( waveform 1), interpolated PVCs [13] ( waveform 2), PVCs involving the Purkinje system (these can trigger ventricular fibrillation and have a short coupling interval figure [14-16]), and polymorphic PVCs [17] ( waveform 3). PVCs with highly variable coupling interval (>60 ms) have been identified as originating in unusual areas (aortic sinuses of Valsalva, great cardiac vein) and have been associated with a higher risk for cardiac events [18]. In the same context, greater PVC coupling interval heterogeneity has been associated with both reduced LV function and an increased risk of developing heart failure [19]. Right and left ventricular outflow tract PVCs morphologies have also been associated with malignant ventricular arrhythmias [5,20,21] ( waveform 4 and waveform 5). In patients without apparent heart disease, frequent, complex, and polymorphic PVCs have been associated with worse prognosis [22-24]. Older studies suggested these PVCs were associated with a twofold increase in myocardial infarction or death in males [22,24]. A newer study in a Taiwanese population suggested a smaller magnitude of effect; multiform PVCs were associated with a 20 percent increased risk of mortality and 10 percent increased risk for hospitalization [17]. Underlying or associated cardiac disease PVCs can be the first manifestation of cardiac disease, including coronary artery disease, cardiomyopathy, and inherited arrhythmia syndromes (eg, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy). In addition, patients with a high PVC burden can develop a cardiomyopathy. In some people with inherited arrythmia syndromes, PVCs can trigger ventricular tachyarrhythmia. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Triggered activity' and "Brugada syndrome: Epidemiology and pathogenesis", section on 'Ventricular arrhythmias and phase 2 reentry' and "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'R-on-T phenomenon'.) https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 3/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate If a patient has a left ventricular ejection fraction (LVEF) <50 percent (regardless of symptoms) and a high PVC burden, the LVEF reduction is assumed to be related to frequent PVCs (also called PVC-induced cardiomyopathy [25,26]). In one series of 245 patients with PVC-induced cardiomyopathy, independent predictors for development of PVC-induced cardiomyopathy were male sex, high PVC burden, lack of symptoms, and epicardial PVC origin [27]. (See 'Premature ventricular complex cardiomyopathy' below.) Evaluation in most patients In order to assess PVC burden and the presence of structural heart disease, all patients should undergo: A 12-lead electrocardiogram (ECG). Twenty-four-hour Holter monitoring. An echocardiogram should be performed if there are high-risk symptoms, frequent PVCs, or if there is any suspicion of underlying or new structural heart disease (including PVC cardiomyopathy) and/or high-risk information from other risk assessments such as abnormal 12-lead ECG or family history of heart disease and especially of sudden cardiac death. (See 'Symptoms' above and 'Family history' above and 'Premature ventricular complex burden' above and 'Premature ventricular complex characteristics' above.) When ambulatory ECG monitoring is indicated, a monitoring period of 24 to 48 hours is typically sufficient to identify PVCs and quantify the overall PVC burden. A variety of ambulatory ECG monitoring techniques are available, but for most patients Holter monitoring or patch monitoring will be the preferred approach. (See "Ambulatory ECG monitoring".) Further testing in selected patients Specific symptoms and/or high-risk features are reasons to get further cardiac testing. If obstructive coronary disease is suspected (on the basis of symptoms or risk factors), or the PVCs are effort related, the patient should also undergo: Exercise stress testing Among patients with effort-related symptoms and who are suspected to have obstructive coronary disease, exercise stress testing can evaluate ischemia [28] and provide useful prognostic information. (See "Prognostic features of stress testing in patients with known or suspected coronary disease".) PVCs occurring during exercise may be secondary to underlying ischemia or could represent adrenergic or catecholamine-sensitive arrhythmias (eg, inherited channelopathies) [29]. For patients whose PVCs are induced by exercise, exercise testing in https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 4/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate conjunction with ambulatory monitoring can be used to assess the effectiveness of antiarrhythmic drug treatment. For patients with exercise-related PVCs, further cardiac testing for underlying cardiovascular disease should be undertaken that may include additional cardiac tests, such as stress testing with imaging, cardiac magnetic resonance imaging (CMR), and electrophysiology testing [30-32]. More commonly, however, PVCs are suppressed during exercise and reemerge in the ensuing recovery period. Cardiac magnetic resonance imaging Selected patients (ie, those with high-risk PVC features, a family history of sudden death or cardiomyopathy, and/or cardiomyopathy of uncertain etiology) may require CMR [33]. CMR can be particularly useful in diagnosing hypertrophic cardiomyopathy, cardiac sarcoid, arrhythmogenic right ventricular cardiomyopathy, and amyloid cardiomyopathy. CMR is generally obtained if these conditions are suspected based on baseline ECG and/or echocardiogram characteristics, family history, and exercise history. We do not routinely use CMR imaging for all patients with frequent PVCs due to limited availability of this test, high cost, lack of expertise in cardiac MRI imaging, and the lack of prospective randomized trials demonstrating that a CMR-based strategy improves outcomes, including mortality. CMR is used selectively and can be center dependent, based on local availability and expertise. Screening with CMR may be useful before further invasive electrophysiology assessment and therapeutic decision-making are undertaken. For instance, CMR may play a role in evaluating need for implantable cardioverter-defibrillator (ICD) in patients with PVC cardiomyopathy. (See 'Implantable cardioverter-defibrillator' below.) Observational studies in patients with frequent PVCs have shown that myocardial abnormalities on CMR are commonly seen (ie, in 15 to 35 percent of such patients) and are associated with adverse cardiac outcomes [34-36]. Among an international cohort of 518 patients (mean age 44 years) with frequent (>1000/24 hours) PVCs and otherwise negative diagnostic work-up, myocardial abnormalities were found in 85 patients (16 percent) [34]. In a single-center observational study, 255 patients with frequent PVCs (>5 percent per 24 hours) who had a contrast-enhanced CMR for work-up of PVCs were followed for the composite outcome (mortality, ventricular fibrillation, sustained ventricular tachycardia, or reduction in left ventricular ejection fraction of 10 percent) [35]. Thirty-five percent of patients had a myocardial abnormality on CMR, and the composite outcome occurred in 5.9 percent. After a median follow-up of 36 months, the incidence of the composite https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 5/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate outcome was higher among patients with myocardial abnormalities versus a normal CMR (20 versus 3.6 percent; hazard ratio 4.35, 95% CI 1.34-14.15). Electrophysiology testing Electrophysiology testing is used only in selected patients with higher-risk PVC features as a risk stratification tool to guide therapy or in patients undergoing catheter ablation procedure (ie, as treatment for frequent symptomatic PVCs refractory to medical therapy or in whom the PVCs have resulted in cardiomyopathy). (See "Invasive diagnostic cardiac electrophysiology studies" and 'Implantable cardioverter- defibrillator' below.) MANAGE TRIGGERS AND RISK FACTORS Prior to initiating therapy, correctable causes or triggers should be identified and, where possible, corrected ( table 1). Patients with hypertension often have PVCs, and if there is left ventricular hypertrophy, outcomes are often worse. These patients should have their blood pressure controlled, preferably with a beta blocker and/or an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, and receive treatment for concurrent left ventricular dysfunction/heart failure if present. Efforts should be made to avoid hypokalemia, which can result from the diuretic class of antihypertensive agents [37]. (See "Choice of drug therapy in primary (essential) hypertension" and "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Associated conditions'.) MANAGEMENT OF HIGH-RISK PATIENTS High-risk patients have any of the following conditions: high (>10 to 15 percent) PVC burden, PVC-induced cardiomyopathy, preexisting cardiac structural or electrical conduction system disease, history of syncope, and abnormalities on cardiac magnetic resonance (CMR) imaging even in the presence of a normal LVEF [34,38,39]. Management in these patients is required to reverse or reduce the risk of developing a cardiomyopathy and to reduce the risk of ventricular arrhythmias and sudden cardiac death ( algorithm 1). Premature ventricular complex cardiomyopathy If a patient has an LVEF <50 percent (regardless of symptoms), and a high PVC burden, the LVEF reduction is assumed to be related to frequent PVCs, and the diagnosis is PVC-induced cardiomyopathy [25,26]. (See "Premature https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 6/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'PVC-induced cardiomyopathy' and 'Underlying or associated cardiac disease' above and 'Premature ventricular complex burden' above.) In such patients, treatment is aimed towards reducing PVC burden, which can in turn avert or reverse the cardiomyopathy. Even patients who already have an implantable cardioverter- defibrillator (ICD) benefit from PVC reduction and ablation. Some patients with PVC-induced cardiomyopathy will exhibit signs and symptoms of heart failure that may require treatment with heart failure medications. However, the definitive treatment is to suppress or ablate the PVCs. (See "Arrhythmia-induced cardiomyopathy", section on 'Frequent ventricular ectopy' and "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'PVC-induced cardiomyopathy'.) Calcium channel blockers should generally be avoided in patients with cardiomyopathy. (See "Drugs that should be avoided or used with caution in patients with heart failure", section on 'Calcium channel blockers'.) Beta blockers The first-line therapy to reduce PVC burden is beta blockers. An exception may be those with heart failure who may proceed directly to catheter ablation. Commonly used beta blockers to treat PVCs include metoprolol and carvedilol. Typical starting doses, alternatives, and maximum dosages for PVC treatment are given in a table ( table 2). Once given, the patient should be monitored for a reduction in symptoms that correspond with a reduction in PVCs, titrating the medication as necessary. Repeat ambulatory ECG monitoring is typically obtained after three months of treatment to determine if the patient has responded to beta blockers. If symptoms and PVC burden have been reduced and are not high, the beta blocker should be continued. If after one month of maximal beta blocker therapy there is no symptom relief or decrease in PVC burden, a catheter ablation is usually considered (especially if PVCs are monomorphic, making them more amenable to ablation). Alternatively, some patients are treated with antiarrhythmic drugs. Efficacy of beta blockers Beta blockers are effective at reducing PVC symptoms. This is because beta blockers reduce the post-extrasystolic potentiation via the Starling mechanism (increased inotropy related to the increased stroke volume) associated with the PVC. Beta blockers can also prevent PVC recurrence. However, it should be recognized that they have no direct effects on the ventricular myocardium. Therefore, beta blockers are https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 7/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate most likely to suppress PVCs that result from excess sympathetic stimulation or are catecholamine sensitive. In an observational study, beta blockers were reported to reduce PVC burden in one-third of patients taking them [40]. Similar findings (a 21 to 36 percent PVC reduction) were reported by other studies [41,42]. Weaning Sometimes, a patient will prefer to stop the beta blocker after symptom relief is achieved. In this case, one can try to wean the beta blocker after 6 to 12 months of medication treatment. The dose can be gradually reduced and a 24-hour Holter recording can be repeated periodically. It is preferable to keep the patient on at least a low-dose beta blocker if they are willing, as this may prevent PVC reoccurrence. (See 'Premature ventricular complex burden' above.) Catheter ablation Catheter ablation is an effective option ( algorithm 2) to reduce or eliminate PVCs in patients who do not respond to beta blocker therapy [41,43-49] and may be first-line treatment in those with heart failure. In a multicenter study of 1185 patients undergoing PVC ablation, 85 percent did not require the use of antiarrhythmic medications at two years following ablation [27]. In patients with PVC-induced cardiomyopathy, PVC ablation can lead to left ventricular function recovery. In a multicenter study of 245 patients with PVC-induced cardiomyopathy who underwent ablation, the LVEF increased from 38 to 50 percent after ablation [27]. The decision to recommend radiofrequency catheter ablation versus antiarrhythmic therapy in a particular patient will depend on clinical factors (ie, predictors of procedural success) and on patient preference. Some patients will not want to undergo an invasive catheter ablation procedure. Not all centers have catheter ablation expertise. Reasonable attempts should be made to refer appropriate patients to centers with catheter ablation expertise. Predictors of procedural success Clinical variables that identify patients most likely to respond to catheter ablation and/or less likely to experience complications include [37]: Unifocal PVCs. High PVC burden. (See 'Premature ventricular complex burden' above.) Right ventricular outflow tract (RVOT) origin. PVCs of right ventricular origin (left bundle branch block inferior axis) will have left bundle branch inferior axis morphology on 12- lead ECG ( waveform 5). For such patients, we have a lower threshold to do catheter ablation, as ablation of PVCs in the right ventricle requires only venous access. In https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 8/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate contrast, PVCs arising in the LV outflow tract or LV require retrograde aortic or transeptal access and have a higher associated procedural risk. In a 2014 meta-analysis of small nonrandomized studies of patients with idiopathic PVCs originating from the RVOT, catheter ablation was associated with a reduction in PVC burden (97 percent mean reduction) along with an improvement in LVEF (mean increase 10 percent) [50]. Heterogeneity across studies limited the certainty of these effect estimates. The majority of patients with PVC-induced LV dysfunction have a recovery of LV function within four months. In some patients, recovery of LV function may take longer; an epicardial origin of PVCs and/or a significantly longer PVC-QRS width are more often present in patients with delayed recovery of LV function than in patients with early recovery of LV function. In a study of 75 patients with frequent idiopathic PVCs and PVC-induced cardiomyopathy submitted to successful PVC ablation, the majority (68 percent) had a recovery of LV function within four months [48]. Patients with delayed recovery of LV function were more likely to have epicardial origin of PVCs (54 versus 4 percent) and longer PVC-QRS width (170 21 versus 159 16 ms) compared with those with an earlier recovery. Similarly, in a study of 114 patients, mean PVC- QRS was 173 ms for those with irreversible LV dysfunction versus 158 ms for those with reversible LV dysfunction (odds ratio 5) [51]. Predictors of ablation failure include multiple PVC morphologies, epicardial or papillary muscle origins, and decreased/short earliest local activation time [27,52]. PVC ablation complications Regardless of whether venous or arterial access is needed, vascular complications are a potential risk of the procedure. Ablation of PVCs originating in the LV require arterial access, and therefore, circulatory complications of stroke, myocardial infarction, and mitral or aortic valve damage can occur. Myocardial perforation and cardiac tamponade or coronary artery injury are potentially lethal complications [53,54]. In a study of 1185 patients undergoing catheter ablation for PVCs, the major complication rate was 2.4 percent, with the most common complications related to vascular access [27]. Nine patients (0.8 percent) had pericardial tamponade requiring pericardiocentesis, and a single patient experienced permanent atrioventricular block. No patients died or experienced stroke. In another study, among 1231 patients undergoing PVC ablation, the overall complication rate was 2.7 percent, with cardiac tamponade being the most common complication (27 percent of all complications or an overall rate of 0.7 percent) [54]. Two ablation-related deaths occurred; one patient died from coronary artery injury during the procedure, and the other died from infectious endocarditis. Location (LV and epicardium) was the main predictor of complications, with RVOT predicting fewer complications. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 9/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Potential risks of catheter ablation are discussed separately. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) Expected timeframe for recovery of LVEF Repeat cardiac monitoring should be performed post-procedure at approximately three months to assess PVC burden. Also, a repeat echocardiogram should be performed three months after the PVC ablation to assess for LV function recovery. Most patients experience complete LVEF recovery after three to six months post-ablation [55]. In about one-third of patients, recovery is delayed and can take up to three to four years [48]. Predictors of delayed recovery included epicardial-origin PVCs [27] and increased intrinsic QRS duration [56]. Antiarrhythmic therapy If a patient is not an optimal candidate for, or prefers not to have, an invasive ablation procedure, an antiarrhythmic agent can be tried. In patients with structural heart disease, including those with PVC cardiomyopathy, there are limited safe and efficacious antiarrhythmic drugs [37,50]. Preferred agents for patients with underlying heart disease are amiodarone and ranolazine: Amiodarone Amiodarone is the least proarrhythmic agent in patients with structural heart disease, although there are substantial risks of organ toxicities with long-term use. Trials of amiodarone use in patients with PVCs and prior myocardial infarction or heart failure have demonstrated a reduction in PVCs and in arrhythmic mortality (6.9 versus 4.5 percent; relative risk 0.49; 95% CI 0.05-0.72) but not overall mortality ( figure 1) [57]. However, routine amiodarone therapy in asymptomatic patients is not recommended because of the limited benefit and potential side effects [57-59]. Oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used. The usual maintenance dose should be the lowest effective dose; this is usually 200 mg daily but can be as low as 100 mg daily. (See "Amiodarone: Clinical uses", section on 'Amiodarone for ventricular arrhythmias'.) Ranolazine Ranolazine, an oral antianginal medication that has I and IKr-blocking Na properties, is approved for patients with chronic stable angina. Observational studies [60] and case reports/series [61-63] suggest that ranolazine may be a safe and effective treatment for PVCs; however, no randomized trials have been performed to confirm these results. In one cohort of 59 patients with ventricular ectopy with or without cardiac disease, ranolazine reduced PVCs by 71 percent (from 13,329 to 3837 per day) [60]. Ventricular https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 10/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate bigeminy and couplets were each reduced by 80 percent, and ventricular tachycardia was reduced by 90 percent. Safety and efficacy of ranolazine for ventricular tachycardia were studied in the MERLIN- TIMI 36 trial (ventricular tachycardia lasting 3 beats, 52 versus 61 percent; relative risk 0.86, 95% CI 0.82-0.90) [64] without causing significant proarrhythmia [65]. Starting dose is 500 mg orally twice daily; maximum daily dose 1000 mg twice daily. Class IC drugs may be proarrhythmic in patients with coronary artery disease and/or significant myocardial dysfunction; therefore, they should not be used in these patients [66,67]. In patients with a prior myocardial infarction, the use of flecainide and other class IC antiarrhythmic drugs ( table 3) for PVCs has been associated with increased mortality due to proarrhythmia ( figure 2 and figure 3) [66,67]. Flecainide and propafenone (class IC antiarrhythmic drugs ( table 3)) have been successfully used in patients with suspected PVC-induced cardiomyopathy who have failed previous catheter ablation attempts [68], but they should not be generally used in this setting due to safety concerns. The use of these drugs in lower-risk patients is discussed below. (See 'Subsequent therapy' below.) Implantable cardioverter-defibrillator In patients with PVC-induced cardiomyopathy and very low LVEF (<35 percent) that would otherwise meet primary prevention criteria for an ICD, elimination of the PVCs can generally restore LV function and obviate the need for ICD implantation [69]. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Primary prevention'.) However, when the etiology of nonischemic cardiomyopathy is not clear, which can be the case before PVCs are eliminated and the LVEF normalizes, there remains a concern about the risk of sudden cardiac death. Thus, preprocedural CMR followed by an electrophysiology study with programmed ventricular stimulation, particularly in CMR-positive patients, may be considered [30]. In the absence of CMR-defined myocardial fibrosis/scarring and/or inducible ventricular tachycardia during an electrophysiology study, one can wait for improvement in LVEF following PVC elimination, withholding the ICD and reevaluating the patient within six months of ablation. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Cardiovascular magnetic resonance' and "Premature ventricular complexes: Clinical presentation and diagnostic evaluation" and "Invasive diagnostic cardiac electrophysiology studies".) Preexisting cardiac disease Patients with coronary artery disease, cardiomyopathy, or electrical conduction system disease who have PVCs are considered high risk. High-risk PVC https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 11/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate characteristics, including morphology and origin, are discussed above. (See 'Premature ventricular complex characteristics' above.) For patients with underlying structural heart disease, it is important to reduce the PVC burden if it is high (ie, >15 percent or 15,000 PVCs/day) in order to lower the risk of developing PVC- induced cardiomyopathy. The first-line therapy for these patients is to reduce PVC burden with beta blockers. If after two to four weeks of beta blocker therapy, there is no decrease in PVC burden and/or there is a persistent reduction in LVEF, catheter ablation is usually considered next [27,37,41,43-50]. (See 'Catheter ablation' above.) Generally, treating the underlying condition often improves and can reduce PVC burden. For an inherited cardiomyopathy or arrythmia syndrome, referral to a genetic counselor is also appropriate. Heart failure Patients with dilated cardiomyopathy or heart failure have a reported 70 to 95 percent prevalence of PVCs [70]. The evaluation and management of PVCs in such patients are discussed separately. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".) Coronary artery disease The management of PVCs differs in patients with acute and chronic coronary syndrome. Acute coronary syndrome For persons with PVCs in the setting of acute coronary syndromes, the best antiarrhythmic approach is the use of antiischemic therapies (reperfusion/revascularization) combined with a beta blocker. As mentioned, treatment with ranolazine may significantly lower the incidence of ventricular arrhythmias in patients with a non-ST-elevation acute coronary syndrome, as shown in MERLIN-TIMI 36 trial [64]. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Management' and "Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment", section on 'Ventricular premature beats'.) Chronic coronary syndrome In patients who have had past myocardial infarctions, PVCs, particularly if frequent (more than 10 per hour) or complex (ie, repetitive forms, primarily nonsustained ventricular tachycardia), appear to be associated with a worse prognosis. Most patients with a prior myocardial infarction will be taking a beta blocker as part of standard therapy for their underlying disease, which may be associated with a https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 12/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate reduction in PVCs [71,72]. (See "Beta blockers in the management of chronic coronary syndrome" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction".) Amiodarone is the preferred antiarrhythmic drug in patients with symptomatic PVCs despite beta blocker therapy. Attempted suppression of PVCs with class IC antiarrhythmic drugs in patients with coronary artery disease has been associated with increased mortality ( figure 2). (See 'Antiarrhythmic therapy' above and "Amiodarone: Clinical uses", section on 'Amiodarone for ventricular arrhythmias'.) In cases of complex and/or symptomatic ventricular arrhythmia, an electrophysiology study with programmed ventricular stimulation may better guide therapy. In patients with inducible sustained ventricular tachycardia, an ICD will be needed [73]. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Secondary prevention'.) Patients with cardiac resynchronization therapy (CRT) Patients with a CRT device need to have effective biventricular pacing greater than 98 percent of all ventricular beats in order to have a mortality reduction [74]. Frequent PVCs compromise effective biventricular pacing and diminish clinical response to CRT [75]. Hence, a more aggressive approach to suppress PVCs is recommended in these patients. (See "Implantable cardioverter- defibrillators: Overview of indications, components, and functions".) Hypertension This is discussed elsewhere. (See 'Manage triggers and risk factors' above.) Long QT syndrome This is discussed elsewhere. (See "Congenital long QT syndrome: Treatment".) Brugada syndrome This is discussed elsewhere. (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) Hypertrophic cardiomyopathy This is discussed elsewhere. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".) Arrhythmogenic right ventricular cardiomyopathy This is discussed elsewhere. (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis".) Cardiac sarcoidosis This is discussed elsewhere. (See "Management and prognosis of cardiac sarcoidosis".) https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 13/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Amyloid cardiomyopathy This is discussed elsewhere. (See "Amyloid cardiomyopathy: Treatment and prognosis".) MANAGEMENT OF LOW-RISK PATIENTS Low-risk patients are those in whom cardiomyopathy and/or inherited arrythmia syndrome has been reasonably excluded. Our approach to treatment in low-risk patients differs according to whether there are significant PVC-related symptoms. Specific PVC-related symptoms are discussed elsewhere. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Symptoms'.) Asymptomatic patients with low premature ventricular complex burden For patients with a low burden of PVCs (<1 percent or 1000 PVCs/day), no underlying apparent structural heart disease, and no symptoms, neither medical therapy nor catheter ablation are required; observation and reassurance along with eliminating possible triggers are appropriate ( algorithm 2 and algorithm 3) [49]. While PVCs have been associated with increased risk of cardiovascular death and other adverse outcomes, there is no clear evidence that PVC suppression or elimination with beta blockers, non-dihydropyridine calcium channel blockers, antiarrhythmic drugs, or catheter ablation improves overall survival in patients who have no symptoms, no heart disease, and no sustained ventricular arrhythmias. Patient with symptoms and/or high premature ventricular complex burden Most low-risk patients with significant symptoms from their PVCs will require medical therapy or ablation in an effort to reduce or eliminate symptoms ( algorithm 2 and algorithm 3). Patients with high PVC burden (>15 percent or 15,000 PVCs/day) also benefit from treatment even in the absence of bothersome symptoms to lower their risk of PVC-induced cardiomyopathy. PVC-induced cardiomyopathy typically takes several months or a few years to develop. In a study of 240 patients referred for PVC ablation, symptom duration of 30 to 60 months, as well as symptom duration >60 months, independently predicted impaired LV function (odds ratio 4.0, 95% CI 1.1-14.4 and 20.1, 95% CI 6.3-64.1, respectively) [76]. In a low-risk patient who has more noticeable symptoms in a quiet environment, such as at night while lying in bed, counseling them to move around and increase their heart rate may alleviate symptoms and provide reassurance to the patient. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 14/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate The decision to recommend antiarrhythmic medication or radiofrequency catheter ablation in a particular patient will depend on many clinical factors and also on patient preference. Some patients will not want to undergo an invasive catheter ablation procedure. Potential risks of the catheter ablation are discussed elsewhere. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) Initial therapy Prior to initiating therapy, correctable causes or triggers should be identified and corrected ( table 1). Beta blockers For low-risk patients with symptomatic and/or a high burden of PVCs, we suggest first-line therapy with a beta blocker. (See 'Beta blockers' above.) Non-dihydropyridine calcium channel blockers In patients without a reduced LVEF, a non-dihydropyridine calcium channel blocker can be substituted if beta blockers are not tolerated or are not successful in reducing symptoms. A table lists specific agents with dosages ( table 2). Non-dihydropyridine calcium channel blockers may be particularly effective in patients without apparent structural heart disease when PVCs are often due to triggered activity of calcium-dependent mechanisms. One example of this is PVCs of fascicular origin (relatively narrow QRS, right bundle branch block-like, left axis deviation) ( waveform 6). Calcium channel blockers may also be preferred to beta blockers if hypertension treatment is needed. Patients should be evaluated for PVCs burden with periodic examinations and continuous ECG monitoring, usually for 24 to 48 hours. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Ambulatory monitoring'.) If symptoms and PVC burden have been reduced and are not high, treatment should be continued. If a patient prefers to stop or reduce their medications, a trial of weaning and/or stopping may be done after 6 to 12 months. (See 'Premature ventricular complex burden' above and 'Beta blockers' above.)

syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Management' and "Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment", section on 'Ventricular premature beats'.) Chronic coronary syndrome In patients who have had past myocardial infarctions, PVCs, particularly if frequent (more than 10 per hour) or complex (ie, repetitive forms, primarily nonsustained ventricular tachycardia), appear to be associated with a worse prognosis. Most patients with a prior myocardial infarction will be taking a beta blocker as part of standard therapy for their underlying disease, which may be associated with a https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 12/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate reduction in PVCs [71,72]. (See "Beta blockers in the management of chronic coronary syndrome" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction".) Amiodarone is the preferred antiarrhythmic drug in patients with symptomatic PVCs despite beta blocker therapy. Attempted suppression of PVCs with class IC antiarrhythmic drugs in patients with coronary artery disease has been associated with increased mortality ( figure 2). (See 'Antiarrhythmic therapy' above and "Amiodarone: Clinical uses", section on 'Amiodarone for ventricular arrhythmias'.) In cases of complex and/or symptomatic ventricular arrhythmia, an electrophysiology study with programmed ventricular stimulation may better guide therapy. In patients with inducible sustained ventricular tachycardia, an ICD will be needed [73]. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Secondary prevention'.) Patients with cardiac resynchronization therapy (CRT) Patients with a CRT device need to have effective biventricular pacing greater than 98 percent of all ventricular beats in order to have a mortality reduction [74]. Frequent PVCs compromise effective biventricular pacing and diminish clinical response to CRT [75]. Hence, a more aggressive approach to suppress PVCs is recommended in these patients. (See "Implantable cardioverter- defibrillators: Overview of indications, components, and functions".) Hypertension This is discussed elsewhere. (See 'Manage triggers and risk factors' above.) Long QT syndrome This is discussed elsewhere. (See "Congenital long QT syndrome: Treatment".) Brugada syndrome This is discussed elsewhere. (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) Hypertrophic cardiomyopathy This is discussed elsewhere. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".) Arrhythmogenic right ventricular cardiomyopathy This is discussed elsewhere. (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis".) Cardiac sarcoidosis This is discussed elsewhere. (See "Management and prognosis of cardiac sarcoidosis".) https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 13/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Amyloid cardiomyopathy This is discussed elsewhere. (See "Amyloid cardiomyopathy: Treatment and prognosis".) MANAGEMENT OF LOW-RISK PATIENTS Low-risk patients are those in whom cardiomyopathy and/or inherited arrythmia syndrome has been reasonably excluded. Our approach to treatment in low-risk patients differs according to whether there are significant PVC-related symptoms. Specific PVC-related symptoms are discussed elsewhere. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Symptoms'.) Asymptomatic patients with low premature ventricular complex burden For patients with a low burden of PVCs (<1 percent or 1000 PVCs/day), no underlying apparent structural heart disease, and no symptoms, neither medical therapy nor catheter ablation are required; observation and reassurance along with eliminating possible triggers are appropriate ( algorithm 2 and algorithm 3) [49]. While PVCs have been associated with increased risk of cardiovascular death and other adverse outcomes, there is no clear evidence that PVC suppression or elimination with beta blockers, non-dihydropyridine calcium channel blockers, antiarrhythmic drugs, or catheter ablation improves overall survival in patients who have no symptoms, no heart disease, and no sustained ventricular arrhythmias. Patient with symptoms and/or high premature ventricular complex burden Most low-risk patients with significant symptoms from their PVCs will require medical therapy or ablation in an effort to reduce or eliminate symptoms ( algorithm 2 and algorithm 3). Patients with high PVC burden (>15 percent or 15,000 PVCs/day) also benefit from treatment even in the absence of bothersome symptoms to lower their risk of PVC-induced cardiomyopathy. PVC-induced cardiomyopathy typically takes several months or a few years to develop. In a study of 240 patients referred for PVC ablation, symptom duration of 30 to 60 months, as well as symptom duration >60 months, independently predicted impaired LV function (odds ratio 4.0, 95% CI 1.1-14.4 and 20.1, 95% CI 6.3-64.1, respectively) [76]. In a low-risk patient who has more noticeable symptoms in a quiet environment, such as at night while lying in bed, counseling them to move around and increase their heart rate may alleviate symptoms and provide reassurance to the patient. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 14/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate The decision to recommend antiarrhythmic medication or radiofrequency catheter ablation in a particular patient will depend on many clinical factors and also on patient preference. Some patients will not want to undergo an invasive catheter ablation procedure. Potential risks of the catheter ablation are discussed elsewhere. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) Initial therapy Prior to initiating therapy, correctable causes or triggers should be identified and corrected ( table 1). Beta blockers For low-risk patients with symptomatic and/or a high burden of PVCs, we suggest first-line therapy with a beta blocker. (See 'Beta blockers' above.) Non-dihydropyridine calcium channel blockers In patients without a reduced LVEF, a non-dihydropyridine calcium channel blocker can be substituted if beta blockers are not tolerated or are not successful in reducing symptoms. A table lists specific agents with dosages ( table 2). Non-dihydropyridine calcium channel blockers may be particularly effective in patients without apparent structural heart disease when PVCs are often due to triggered activity of calcium-dependent mechanisms. One example of this is PVCs of fascicular origin (relatively narrow QRS, right bundle branch block-like, left axis deviation) ( waveform 6). Calcium channel blockers may also be preferred to beta blockers if hypertension treatment is needed. Patients should be evaluated for PVCs burden with periodic examinations and continuous ECG monitoring, usually for 24 to 48 hours. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Ambulatory monitoring'.) If symptoms and PVC burden have been reduced and are not high, treatment should be continued. If a patient prefers to stop or reduce their medications, a trial of weaning and/or stopping may be done after 6 to 12 months. (See 'Premature ventricular complex burden' above and 'Beta blockers' above.) A prospective cohort study of 100 untreated adult patients (mean age 51.8 years, 57 percent female) with a median PVC burden of 18.4 percent showed that reduction to <1 percent of PVCs occurred in 44 percent at a median follow-up of 15.4 months. Recurrence was uncommon (9.1 percent) [77]. Hence, the authors suggested that a strategy of active surveillance may be appropriate for the majority of patients with frequent idiopathic PVCs in association with preserved LVEF. One may extrapolate from these studies that in certain patients who respond to https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 15/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate medical treatment, one may trial them off antiarrhythmic drug therapy, possibly at one to two years, and closely observe for arrhythmia recurrences. Subsequent therapy For patients with ongoing PVC-related symptoms and/or high burden following initial medical therapy with beta blockers and/or non-dihydropyridine calcium channel blockers, or for those who do not tolerate medical therapy due to adverse effects, antiarrhythmic medications or catheter ablation are each reasonable next steps. In patients without structural heart disease or coronary artery disease, it is reasonable to start a class 1C antiarrhythmic rather than to pursue catheter ablation if one or more of the following are present: Multiple PVC morphologies. A low frequency of PVCs (<3 percent or 500 PVCs/day). Patients are deemed to be high-risk candidates for catheter ablation, such as those with challenging PVC foci locations that might limit a successful procedure (eg, epicardium, LV summit, intramural site, papillary muscles, and a para-Hisian location) [78]. A strong patient preference to avoid catheter ablation. The use of antiarrhythmic drugs (eg, flecainide and other class IC antiarrhythmic drugs) ( table 3) for PVCs is an off-label use. Whereas proarrhythmia with these drugs is of concern in patients with structural heart disease, there is little to no concern in patients without underlying heart disease [79]. Importantly, class IC antiarrhythmic agents should not be used to treat patients with PVC-induced cardiomyopathy and LV dysfunction due to grave concerns for proarrhythmia [66,80]. Nevertheless, IC agents have been used in such patients with favorable results. However, these agents should only be prescribed in patients who have ICDs to treat life-threatening ventricular arrythmias [68]. Typical antiarrhythmic options among patients without apparent structural heart disease include: Flecainide, starting dose 50 to 100 mg orally twice daily; maximum daily dose 150 mg twice daily (although doses higher than 100 mg twice daily are rarely used). Propafenone 150 mg three times daily; maximum daily dose 300 mg three times daily. In one observational study of 120 patients with frequent PVCs without structural heart disease, antiarrhythmic medications had superior effectiveness in PVC reduction as https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 16/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate compared with beta blockers and calcium channel blockers and conservative therapy [40]. Median initial PVC burden ranged from 16 to 21 percent. The median relative reduction of PVCs in the conservative therapy, beta blockers/calcium channel blockers, and antiarrhythmic medication cohorts was 33, 31, and 81 percent, respectively. PVC reduction to <1 percent was similar across these groups at 35, 17, 33 percent, respectively. Four patients (3 percent) developed LV dysfunction: One patient was on conservative therapy, two were on a bisoprolol, and one was on flecainide. Rates of adverse drug reactions and medication discontinuation were similar between groups, with no serious adverse events noted. If a patient remains symptomatic and/or has a high PVC burden, catheter ablation should be pursued next. PROGNOSIS The presence of PVCs should alert the clinician to potential coexistent cardiac disease, which may require additional clinical assessment or therapy. In patients without a history of cardiac disease, PVCs are associated with increased mortality. However, prophylactic treatment of asymptomatic PVCs in patients without cardiomyopathy has not been shown to improve mortality. An important caveat pertains to patients with potentially problematic PVCs. (See 'Premature ventricular complex characteristics' above.) No apparent heart disease Mortality Data are mixed as to whether the presence of PVCs in patients with apparently normal hearts is associated with increased mortality. In a meta-analysis of five prospective cohort studies (3629 persons) without apparent heart disease, the presence of PVCs was not associated with all-cause mortality (odds ratio 1.34, 95% CI 0.85-2.12) [81]. However, only one study used advanced testing (ie, echocardiography or stress testing) to exclude underlying structural heart disease. In a Taiwanese cohort of 5778 persons, PVC frequency >12 beats per day was associated with mortality (hazard ratio 1.4, 95% CI 1.28-1.59) [82]. Regarding PVC morphology, an observational study indicated that among 3351 individuals with apparently normal hearts, those with multiform PVCs had an increased incidence of mortality (HR 1.6, 95% CI 1.32-2.03) over a mean follow-up period of 10 years [17]. Reduction in LVEF and heart failure A greater frequency of PVCs has been associated with reduced LVEF and heart failure. Among 1139 patients without known heart disease in the Cardiovascular Health Study, the upper quartile of PVCs on 24-hour Holter monitoring https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 17/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate (>0.12 percent of total heart beats) was associated with reduced LVEF (odds ratio 3.1, 95% CI 1.4-6.8) or heart failure (odds ratio 1.5, 95% CI 1.1-2.0) over the next 10 years [4]. Stroke PVCs are associated with increased risk of stroke. In a prospective evaluation of 14,783 participants in the ARIC observational cohort, 6.1 percent had PVCs on a two-minute ECG, and 729 (4.9 percent) had incident stroke [83]. Incident strokes in individuals with any PVC was 6.6 percent compared with 4.1 percent in those without PVCs (HR 1.7, 95% CI 1.3- 2.2). Similar findings were reported by the REGARDS study [84]. Whether this association relates to increased tendency toward formation of thrombi or embolization through cardiac remodeling or possibly atrial fibrillation or other reason, remains unknown. Heart failure or cardiomyopathy Heart failure In a Danish study of 850 patients with nonischemic systolic heart failure (LVEF <35 percent), 350 patients with high-burden PVCs ( 30 PVCs in a 24-hour Holter monitor, 352 patients) had increased mortality (HR 1.38; 95% CI 1.00-1.90) and cardiovascular disease (HR 1.78, CI 1.19-2.66). However, they did not have a survival benefit from ICD implantation [85]. Patients requiring resynchronization therapy According to a MADIT-CRT substudy, among 698 patients with cardiac resynchronization therapy (CRT)-defibrillator (with ischemic and nonischemic cardiomyopathy), those with >10 PVCs per hour, had significantly higher three-year risk of heart failure/death (25 versus 7 percent) and ventricular tachycardia/ventricular fibrillation (24 versus 8 percent) compared with those with a lower burden of ectopy [86]. Patients with >10 PVCs-per-hour burden had approximately threefold increased risk of both heart failure/death (HR 2.8) and ventricular tachycardia/ventricular fibrillation (HR 2.8). Other cardiomyopathy In patients with hypertrophic cardiomyopathy, PVCs are common, but unlike nonsustained ventricular tachycardia, PVCs have not been associated with an increased risk of sudden cardiac death. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".) In patients with arrhythmogenic right ventricular dysplasia, frequent PVCs and/or the presence of nonsustained ventricular tachycardia are markers of increased arrhythmic risk [87]. (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis", section on 'Prognosis'.) In patients with cardiac sarcoidosis, PVCs can help identify patients in whom an electrophysiologic study would be helpful in decision-making for implantable cardioverter- https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 18/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate defibrillator placement/sudden cardiac death prevention. (See "Management and prognosis of cardiac sarcoidosis".) Exercise-induced premature ventricular complexes The prognostic significance of exercise- induced PVCs is discussed separately. (See "Prognostic features of stress testing in patients with known or suspected coronary disease", section on 'Premature ventricular complexes'.) PREGNANCY PVCs occurring during pregnancy constitute a special situation, where antiarrhythmic agents should be avoided if at all possible, especially during the first trimester, due to the risks posed for the embryo [88]. Triggers Some experts counsel patients with palpitations to discontinue potential precipitant factors such as smoking, coffee intake, alcohol intake, and other stimulants [89]. However, the role of caffeine restriction has not been established. Moderate caffeine exposure has not been demonstrated to increase PVCs in patients with or without structural heart disease [90,91], and caffeine restriction was not found to improve symptoms or reduce the frequency of PVCs in a small trial [92]. However, frequent and/or symptomatic PVCs may need treatment, mainly with the use of beta blockers (eg, metoprolol or bisoprolol). Ablation, if at all needed, should be postponed until the postpartum period. It is reasonable to check electrolytes (eg, potassium, magnesium) in pregnant patients with symptomatic and frequent PVCs, as these are not part of the routine prenatal laboratory measurements, and abnormal levels can be treated. The presence of PVCs in pregnancy has not been shown to cause a worse prognosis. Among a cohort of 49 pregnant women with a structurally normal heart and "high" PVC burden (median PVC burden approximately 9 percent), overall maternal outcomes were favorable [93]. Although 11 percent of pregnancies were complicated by a cardiac event, all were successfully managed with medical therapy, mostly with beta blockers. With the exception of one patient requiring ventricular tachycardia ablation postpartum, no further therapy was required in the postpartum period, and PVC burden was found to decrease. The rate of adverse obstetric and fetal/neonatal outcomes in the PVC group was comparable to the normal pregnant population. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 19/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Catheter ablation of arrhythmias" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Ventricular premature beats (The Basics)") SUMMARY AND RECOMMENDATIONS Introduction Premature ventricular complexes/contractions (PVCs; also referred to as premature ventricular beats, premature ventricular depolarizations, or ventricular extrasystoles) are common and can occur in patients with and without apparent structural heart disease. (See 'Introduction' above.) Risk stratification Risk stratification is important to determine treatment and is based on symptoms, family history, high PVC burden (>15 percent or 10,000 PVCs in 24 hours) and key PVC characteristics. (See 'Risk assessment' above.) All patients should have triggers identified and eliminated ( table 1). Our treatment approach is summarized in an algorithm ( algorithm 2). Patients with PVC-induced cardiomyopathy Management of patients with reduced left ventricular ejection fraction (LVEF; <50 percent) thought to be related to frequent PVCs is as follows (See 'Premature ventricular complex cardiomyopathy' above.): https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 20/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate For patients with PVC-induced cardiomyopathy, we suggest initial therapy with a beta blocker (Grade 2C). There is low threshold to proceeding with catheter ablation if the PVC burden remains high or the LVEF does not improve. (See 'Beta blockers' above.) For patients with signs and symptoms of heart failure due to suspected PVC-induced cardiomyopathy, we suggest initial treatment with catheter ablation (Grade 2C). Heart failure treatment and beta blocker therapy are also appropriate. (See 'Catheter ablation' above.) Patients with cardiac disease For patients in whom underlying structural or electrical heart disease is identified, management focuses on providing appropriate therapy tailored to the specific underlying condition. Components of this therapy (eg, beta blockers) can contribute to a reduction in PVCs. Calcium channel blockers should be avoided in patients with cardiomyopathy and/or heart failure. (See 'Preexisting cardiac disease' above and "Primary pharmacologic therapy for heart failure with reduced ejection fraction".) Asymptomatic patients with low PVC burden and no structural heart disease Asymptomatic patients with low PVC burden and no underlying heart disease generally do not require treatment. (See 'Asymptomatic patients with low premature ventricular complex burden' above.) Low-risk patients with symptoms and/or high PVC burden Initial medical therapy For most patients with symptomatic PVCs, we suggest first- line therapy with a beta blocker (Grade 2C). A non-dihydropyridine calcium channel blocker is a reasonable alternative in patients without cardiomyopathy (See 'Patient with symptoms and/or high premature ventricular complex burden' above.) Subsequent therapy For patients with persistent PVC-related symptoms on initial medical therapy or not tolerating medical therapy due to adverse effects, we suggest catheter ablation, rather than antiarrhythmic drug therapy, as the next treatment (Grade 2C). Catheter ablation likely has greater long-term efficacy and avoids antiarrhythmic drug toxicity. Class IC antiarrhythmic drug treatment is a reasonable alternative for patients without apparent structural heart disease who do not have access to catheter ablation or prefer to avoid an invasive procedure. Off-label use of ranolazine has also been suggested to effectively suppress PVCs without causing proarrhythmia. (See 'Catheter ablation' above and 'Antiarrhythmic therapy' above.) Prognosis The presence of simple, frequent, complex, or exercise-induced PVCs in patients with apparently normal hearts is associated with increased mortality. (See https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 21/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate 'Prognosis' above.) Exercise-induced PVCs are discussed separately. (See "Prognostic features of stress testing in patients with known or suspected coronary disease", section on 'Premature ventricular complexes'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Philip J Podrid, MD, FACC, Brian Olshansky, MD, and Bernard Gersh, MB, ChB, DPhil, FRCP, MACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Priori SG, Blomstr m-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015; 36:2793. 2. Lip GY, Heinzel FR, Gaita F, et al. European Heart Rhythm Association/Heart Failure Association joint consensus document on arrhythmias in heart failure, endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society. Europace 2016; 18:12. 3. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2018; 15:e190. 4. Dukes JW, Dewland TA, Vittinghoff E, et al. Ventricular Ectopy as a Predictor of Heart Failure and Death. J Am Coll Cardiol 2015; 66:101. 5. Ip JE, Lerman BB. Idiopathic malignant premature ventricular contractions. Trends Cardiovasc Med 2018; 28:295. 6. Dabbagh GS, Bogun F. Predictors and Therapy of Cardiomyopathy Caused by Frequent Ventricular Ectopy. Curr Cardiol Rep 2017; 19:80. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 22/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate 7. Supple GE. Editorial commentary: Malignant PVCs: Revising the 'idiopathic' label. Trends Cardiovasc Med 2018; 28:303. 8. Carballeira Pol L, Deyell MW, Frankel DS, et al. Ventricular premature depolarization QRS duration as a new marker of risk for the development of ventricular premature depolarization-induced cardiomyopathy. Heart Rhythm 2014; 11:299. 9. Park KM, Im SI, Lee SH, et al. Left Ventricular Dysfunction in Outpatients with Frequent Ventricular Premature Complexes. Tex Heart Inst J 2022; 49. 10. Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart Rhythm 2012; 9:1460. 11. Yamada T. Twelve-lead electrocardiographic localization of idiopathic premature ventricular contraction origins. J Cardiovasc Electrophysiol 2019; 30:2603. 12. Park KM, Kim YH, Marchlinski FE. Using the surface electrocardiogram to localize the origin of idiopathic ventricular tachycardia. Pacing Clin Electrophysiol 2012; 35:1516. 13. Olgun H, Yokokawa M, Baman T, et al. The role of interpolation in PVC-induced cardiomyopathy. Heart Rhythm 2011; 8:1046. 14. Viskin S, Lesh MD, Eldar M, et al. Mode of onset of malignant ventricular arrhythmias in idiopathic ventricular fibrillation. J Cardiovasc Electrophysiol 1997; 8:1115. 15. Leenhardt A, Glaser E, Burguera M, et al. Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias. Circulation 1994; 89:206. 16. Sadek MM, Benhayon D, Sureddi R, et al. Idiopathic ventricular arrhythmias originating from the moderator band: Electrocardiographic characteristics and treatment by catheter ablation. Heart Rhythm 2015; 12:67. 17. Lin CY, Chang SL, Lin YJ, et al. Long-term outcome of multiform premature ventricular complexes in structurally normal heart. Int J Cardiol 2015; 180:80. 18. Bradfield JS, Homsi M, Shivkumar K, Miller JM. Coupling interval variability differentiates ventricular ectopic complexes arising in the aortic sinus of valsalva and great cardiac vein from other sources: mechanistic and arrhythmic risk implications. J Am Coll Cardiol 2014; 63:2151. 19. Limpitikul WB, Dewland TA, Vittinghoff E, et al. Premature ventricular complexes and development of heart failure in a community-based population. Heart 2022; 108:105. 20. Shimizu W. Arrhythmias originating from the right ventricular outflow tract: how to distinguish "malignant" from "benign"? Heart Rhythm 2009; 6:1507. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 23/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate 21. Noda T, Shimizu W, Taguchi A, et al. Malignant entity of idiopathic ventricular fibrillation and polymorphic ventricular tachycardia initiated by premature extrasystoles originating from the right ventricular outflow tract. J Am Coll Cardiol 2005; 46:1288. 22. Abdalla IS, Prineas RJ, Neaton JD, et al. Relation between ventricular premature complexes and sudden cardiac death in apparently healthy men. Am J Cardiol 1987; 60:1036. 23. Sajadieh A, Nielsen OW, Rasmussen V, et al. Ventricular arrhythmias and risk of death and acute myocardial infarction in apparently healthy subjects of age >or=55 years. Am J Cardiol 2006; 97:1351. 24. Bikkina M, Larson MG, Levy D. Prognostic implications of asymptomatic ventricular arrhythmias: the Framingham Heart Study. Ann Intern Med 1992; 117:990. 25. Gopinathannair R, Etheridge SP, Marchlinski FE, et al. Arrhythmia-Induced Cardiomyopathies: Mechanisms, Recognition, and Management. J Am Coll Cardiol 2015; 66:1714. 26. Lee AK, Deyell MW. Premature ventricular contraction-induced cardiomyopathy. Curr Opin Cardiol 2016; 31:1. 27. Latchamsetty R, Yokokawa M, Morady F, et al. Multicenter Outcomes for Catheter Ablation of Idiopathic Premature Ventricular Complexes. JACC Clin Electrophysiol 2015; 1:116. 28. Giles K, Green MS. Workup and management of patients with frequent premature ventricular contractions. Can J Cardiol 2013; 29:1512. 29. Manolis AA, Manolis TA, Apostolopoulos EJ, et al. The role of the autonomic nervous system in cardiac arrhythmias: The neuro-cardiac axis, more foe than friend? Trends Cardiovasc Med 2021; 31:290. 30. Yokokawa M, Siontis KC, Kim HM, et al. Value of cardiac magnetic resonance imaging and programmed ventricular stimulation in patients with frequent premature ventricular complexes undergoing radiofrequency ablation. Heart Rhythm 2017; 14:1695. 31. Yamada T. Idiopathic ventricular arrhythmias: Relevance to the anatomy, diagnosis and treatment. J Cardiol 2016; 68:463. 32. Oebel S, Dinov B, Arya A, et al. ECG morphology of premature ventricular contractions predicts the presence of myocardial fibrotic substrate on cardiac magnetic resonance imaging in patients undergoing ablation. J Cardiovasc Electrophysiol 2017; 28:1316. 33. Brunetti G, Cipriani A, Perazzolo Marra M, et al. Role of Cardiac Magnetic Resonance Imaging in the Evaluation of Athletes with Premature Ventricular Beats. J Clin Med 2022; 11. 34. Muser D, Santangeli P, Castro SA, et al. Risk Stratification of Patients With Apparently Idiopathic Premature Ventricular Contractions: A Multicenter International CMR Registry. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 24/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate JACC Clin Electrophysiol 2020; 6:722. 35. Hosseini F, Thibert MJ, Gulsin GS, et al. Cardiac Magnetic Resonance in the Evaluation of Patients With Frequent Premature Ventricular Complexes. JACC Clin Electrophysiol 2022; 8:1122. 36. Pellegrino PL, Casavecchia G, Gravina M, et al. Concealed structural heart disease discovered at cardiac magnetic resonance in patients with ventricular extrasystoles from ventricular outflow tract and apparently normal hearts. J Interv Card Electrophysiol 2021; 61:45. 37. Lip GYH, Coca A, Kahan T, et al. Hypertension and cardiac arrhythmias: a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulaci n Card aca y Electrofisiolog a (SOLEACE). Europace 2017; 19:891. 38. Muser D, Tritto M, Mariani MV, et al. Diagnosis and Treatment of Idiopathic Premature Ventricular Contractions: A Stepwise Approach Based on the Site of Origin. Diagnostics (Basel) 2021; 11. 39. Ghannam M, Siontis KC, Kim MH, et al. Risk stratification in patients with frequent premature ventricular complexes in the absence of known heart disease. Heart Rhythm 2020; 17:423. 40. Tang JKK, Andrade JG, Hawkins NM, et al. Effectiveness of medical therapy for treatment of idiopathic frequent premature ventricular complexes. J Cardiovasc Electrophysiol 2021; 32:2246. 41. Zhong L, Lee YH, Huang XM, et al. Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a single-center retrospective study. Heart Rhythm 2014; 11:187. 42. Chandraratna PA. Comparison of acebutolol with propranolol, quinidine, and placebo: results of three multicenter arrhythmia trials. Am Heart J 1985; 109:1198. 43. Hasdemir C, Ulucan C, Yavuzgil O, et al. Tachycardia-induced cardiomyopathy in patients with idiopathic ventricular arrhythmias: the incidence, clinical and electrophysiologic characteristics, and the predictors. J Cardiovasc Electrophysiol 2011; 22:663. 44. Baman TS, Lange DC, Ilg KJ, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm 2010; 7:865. 45. Takemoto M, Yoshimura H, Ohba Y, et al. Radiofrequency catheter ablation of premature ventricular complexes from right ventricular outflow tract improves left ventricular dilation https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 25/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate and clinical status in patients without structural heart disease. J Am Coll Cardiol 2005; 45:1259. 46. Wijnmaalen AP, Delgado V, Schalij MJ, et al. Beneficial effects of catheter ablation on left ventricular and right ventricular function in patients with frequent premature ventricular contractions and preserved ejection fraction. Heart 2010; 96:1275. 47. Yarlagadda RK, Iwai S, Stein KM, et al. Reversal of cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract. Circulation 2005; 112:1092. 48. Yokokawa M, Good E, Crawford T, et al. Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes. Heart Rhythm 2013; 10:172. 49. Marcus GM. Evaluation and Management of Premature Ventricular Complexes. Circulation 2020; 141:1404. 50. Lamba J, Redfearn DP, Michael KA, et al. Radiofrequency catheter ablation for the treatment of idiopathic premature ventricular contractions originating from the right ventricular outflow tract: a systematic review and meta-analysis. Pacing Clin Electrophysiol 2014; 37:73. 51. Deyell MW, Park KM, Han Y, et al. Predictors of recovery of left ventricular dysfunction after ablation of frequent ventricular premature depolarizations. Heart Rhythm 2012; 9:1465. 52. Im SI, Voskoboinik A, Lee A, et al. Predictors of long-term success after catheter ablation of premature ventricular complexes. J Cardiovasc Electrophysiol 2021; 32:2254. 53. Oomen AWGJ, Dekker LRC, Meijer A. Catheter ablation of symptomatic idiopathic ventricular arrhythmias : A five-year single-centre experience. Neth Heart J 2018; 26:210. 54. Wang JS, Shen YG, Yin RP, et al. The safety of catheter ablation for premature ventricular contractions in patients without structural heart disease. BMC Cardiovasc Disord 2018; 18:177. 55. Cojocaru C, Penela D, Berruezo A, Vatasescu R. Mechanisms, time course and predictability of premature ventricular contractions cardiomyopathy-an update on its development and resolution. Heart Fail Rev 2022; 27:1639. 56. Penela D, J uregui B, Fern ndez-Armenta J, et al. Influence of baseline QRS on the left ventricular ejection fraction recovery after frequent premature ventricular complex ablation. Europace 2020; 22:274. 57. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 1997; 349:675. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 26/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate 58. Julian DG, Camm AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 1997; 349:667. 59. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995; 333:77. 60. Murray GL. Ranolazine is an Effective and Safe Treatment of Adults with Symptomatic Premature Ventricular Contractions due to Triggered Ectopy. Int J Angiol 2016; 25:247. 61. Yeung E, Krantz MJ, Schuller JL, et al. Ranolazine for the suppression of ventricular arrhythmia: a case series. Ann Noninvasive Electrocardiol 2014; 19:345. 62. Nanda S, Levin V, Martinez MW, Freudenberger R. Ranolazine treatment of ventricular tachycardia and symptomatic ventricular premature beats in ischemic cardiomyopathy. Pacing Clin Electrophysiol 2010; 33:e119. 63. Murdock DK, Kaliebe JW. Suppression of frequent ventricular ectopy in a patient with hypertrophic heart disease with ranolazine: a case report. Indian Pacing Electrophysiol J 2011; 11:84. 64. Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST- segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007; 116:1647. 65. Polytarchou K, Manolis AS. Ranolazine and its Antiarrhythmic Actions. Cardiovasc Hematol Agents Med Chem 2015; 13:31. 66. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 67. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left

34. Muser D, Santangeli P, Castro SA, et al. Risk Stratification of Patients With Apparently Idiopathic Premature Ventricular Contractions: A Multicenter International CMR Registry. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 24/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate JACC Clin Electrophysiol 2020; 6:722. 35. Hosseini F, Thibert MJ, Gulsin GS, et al. Cardiac Magnetic Resonance in the Evaluation of Patients With Frequent Premature Ventricular Complexes. JACC Clin Electrophysiol 2022; 8:1122. 36. Pellegrino PL, Casavecchia G, Gravina M, et al. Concealed structural heart disease discovered at cardiac magnetic resonance in patients with ventricular extrasystoles from ventricular outflow tract and apparently normal hearts. J Interv Card Electrophysiol 2021; 61:45. 37. Lip GYH, Coca A, Kahan T, et al. Hypertension and cardiac arrhythmias: a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulaci n Card aca y Electrofisiolog a (SOLEACE). Europace 2017; 19:891. 38. Muser D, Tritto M, Mariani MV, et al. Diagnosis and Treatment of Idiopathic Premature Ventricular Contractions: A Stepwise Approach Based on the Site of Origin. Diagnostics (Basel) 2021; 11. 39. Ghannam M, Siontis KC, Kim MH, et al. Risk stratification in patients with frequent premature ventricular complexes in the absence of known heart disease. Heart Rhythm 2020; 17:423. 40. Tang JKK, Andrade JG, Hawkins NM, et al. Effectiveness of medical therapy for treatment of idiopathic frequent premature ventricular complexes. J Cardiovasc Electrophysiol 2021; 32:2246. 41. Zhong L, Lee YH, Huang XM, et al. Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a single-center retrospective study. Heart Rhythm 2014; 11:187. 42. Chandraratna PA. Comparison of acebutolol with propranolol, quinidine, and placebo: results of three multicenter arrhythmia trials. Am Heart J 1985; 109:1198. 43. Hasdemir C, Ulucan C, Yavuzgil O, et al. Tachycardia-induced cardiomyopathy in patients with idiopathic ventricular arrhythmias: the incidence, clinical and electrophysiologic characteristics, and the predictors. J Cardiovasc Electrophysiol 2011; 22:663. 44. Baman TS, Lange DC, Ilg KJ, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm 2010; 7:865. 45. Takemoto M, Yoshimura H, Ohba Y, et al. Radiofrequency catheter ablation of premature ventricular complexes from right ventricular outflow tract improves left ventricular dilation https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 25/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate and clinical status in patients without structural heart disease. J Am Coll Cardiol 2005; 45:1259. 46. Wijnmaalen AP, Delgado V, Schalij MJ, et al. Beneficial effects of catheter ablation on left ventricular and right ventricular function in patients with frequent premature ventricular contractions and preserved ejection fraction. Heart 2010; 96:1275. 47. Yarlagadda RK, Iwai S, Stein KM, et al. Reversal of cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract. Circulation 2005; 112:1092. 48. Yokokawa M, Good E, Crawford T, et al. Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes. Heart Rhythm 2013; 10:172. 49. Marcus GM. Evaluation and Management of Premature Ventricular Complexes. Circulation 2020; 141:1404. 50. Lamba J, Redfearn DP, Michael KA, et al. Radiofrequency catheter ablation for the treatment of idiopathic premature ventricular contractions originating from the right ventricular outflow tract: a systematic review and meta-analysis. Pacing Clin Electrophysiol 2014; 37:73. 51. Deyell MW, Park KM, Han Y, et al. Predictors of recovery of left ventricular dysfunction after ablation of frequent ventricular premature depolarizations. Heart Rhythm 2012; 9:1465. 52. Im SI, Voskoboinik A, Lee A, et al. Predictors of long-term success after catheter ablation of premature ventricular complexes. J Cardiovasc Electrophysiol 2021; 32:2254. 53. Oomen AWGJ, Dekker LRC, Meijer A. Catheter ablation of symptomatic idiopathic ventricular arrhythmias : A five-year single-centre experience. Neth Heart J 2018; 26:210. 54. Wang JS, Shen YG, Yin RP, et al. The safety of catheter ablation for premature ventricular contractions in patients without structural heart disease. BMC Cardiovasc Disord 2018; 18:177. 55. Cojocaru C, Penela D, Berruezo A, Vatasescu R. Mechanisms, time course and predictability of premature ventricular contractions cardiomyopathy-an update on its development and resolution. Heart Fail Rev 2022; 27:1639. 56. Penela D, J uregui B, Fern ndez-Armenta J, et al. Influence of baseline QRS on the left ventricular ejection fraction recovery after frequent premature ventricular complex ablation. Europace 2020; 22:274. 57. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 1997; 349:675. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 26/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate 58. Julian DG, Camm AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 1997; 349:667. 59. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995; 333:77. 60. Murray GL. Ranolazine is an Effective and Safe Treatment of Adults with Symptomatic Premature Ventricular Contractions due to Triggered Ectopy. Int J Angiol 2016; 25:247. 61. Yeung E, Krantz MJ, Schuller JL, et al. Ranolazine for the suppression of ventricular arrhythmia: a case series. Ann Noninvasive Electrocardiol 2014; 19:345. 62. Nanda S, Levin V, Martinez MW, Freudenberger R. Ranolazine treatment of ventricular tachycardia and symptomatic ventricular premature beats in ischemic cardiomyopathy. Pacing Clin Electrophysiol 2010; 33:e119. 63. Murdock DK, Kaliebe JW. Suppression of frequent ventricular ectopy in a patient with hypertrophic heart disease with ranolazine: a case report. Indian Pacing Electrophysiol J 2011; 11:84. 64. Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST- segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007; 116:1647. 65. Polytarchou K, Manolis AS. Ranolazine and its Antiarrhythmic Actions. Cardiovasc Hematol Agents Med Chem 2015; 13:31. 66. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 67. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996; 348:7. 68. Hyman MC, Mustin D, Supple G, et al. Class IC antiarrhythmic drugs for suspected premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 2018; 15:159. 69. Penela D, Acosta J, Aguinaga L, et al. Ablation of frequent PVC in patients meeting criteria for primary prevention ICD implant: Safety of withholding the implant. Heart Rhythm 2015; 12:2434. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 27/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate 70. Podrid PJ, Fogel RI, Fuchs TT. Ventricular arrhythmia in congestive heart failure. Am J Cardiol 1992; 69:82G. 71. Chadda K, Goldstein S, Byington R, Curb JD. Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation 1986; 73:503. 72. Lichstein E, Morganroth J, Harrist R, Hubble E. Effect of propranolol on ventricular arrhythmia. The beta-blocker heart attack trial experience. Circulation 1983; 67:I5. 73. Manolis AS. The clinical challenge of preventing sudden cardiac death immediately after acute ST-elevation myocardial infarction. Expert Rev Cardiovasc Ther 2014; 12:1427. 74. Hayes DL, Boehmer JP, Day JD, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm 2011; 8:1469. 75. Lakkireddy D, Di Biase L, Ryschon K, et al. Radiofrequency ablation of premature ventricular ectopy improves the efficacy of cardiac resynchronization therapy in nonresponders. J Am Coll Cardiol 2012; 60:1531. 76. Yokokawa M, Kim HM, Good E, et al. Relation of symptoms and symptom duration to premature ventricular complex-induced cardiomyopathy. Heart Rhythm 2012; 9:92. 77. Lee AKY, Andrade J, Hawkins NM, et al. Outcomes of untreated frequent premature ventricular complexes with normal left ventricular function. Heart 2019; 105:1408. 78. Latchamsetty R, Bogun F. Premature Ventricular Complex-Induced Cardiomyopathy. JACC Clin Electrophysiol 2019; 5:537. 79. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 80. Madias C, Estes NAM 3rd. Class IC antiarrhythmic agents in structural heart disease: Is nothing CAST in stone? Heart Rhythm 2018; 15:164. 81. Lee V, Hemingway H, Harb R, et al. The prognostic significance of premature ventricular complexes in adults without clinically apparent heart disease: a meta-analysis and systematic review. Heart 2012; 98:1290. 82. Lin CY, Chang SL, Lin YJ, et al. An observational study on the effect of premature ventricular complex burden on long-term outcome. Medicine (Baltimore) 2017; 96:e5476. 83. Agarwal SK, Heiss G, Rautaharju PM, et al. Premature ventricular complexes and the risk of incident stroke: the Atherosclerosis Risk In Communities (ARIC) Study. Stroke 2010; 41:588. 84. Agarwal SK, Chao J, Peace F, et al. Premature ventricular complexes on screening electrocardiogram and risk of ischemic stroke. Stroke 2015; 46:1365. 85. Boas R, Thune JJ, Pehrson S, et al. Prevalence and prognostic association of ventricular arrhythmia in non-ischaemic heart failure patients: results from the DANISH trial. Europace https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 28/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate 2021; 23:587. 86. Ruwald AC, Aktas MK, Ruwald MH, et al. Postimplantation ventricular ectopic burden and clinical outcomes in cardiac resynchronization therapy-defibrillator patients: a MADIT-CRT substudy. Ann Noninvasive Electrocardiol 2018; 23:e12491. 87. Bhonsale A, James CA, Tichnell C, et al. Incidence and predictors of implantable cardioverter-defibrillator therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy undergoing implantable cardioverter-defibrillator implantation for primary prevention. J Am Coll Cardiol 2011; 58:1485. 88. Manolis TA, Manolis AA, Apostolopoulos EJ, et al. Cardiac arrhythmias in pregnant women: need for mother and offspring protection. Curr Med Res Opin 2020; 36:1225. 89. Cox JL, Gardner MJ. Treatment of cardiac arrhythmias during pregnancy. Prog Cardiovasc Dis 1993; 36:137. 90. Newcombe PF, Renton KW, Rautaharju PM, et al. High-dose caffeine and cardiac rate and rhythm in normal subjects. Chest 1988; 94:90. 91. Myers MG. Caffeine and cardiac arrhythmias. Ann Intern Med 1991; 114:147. 92. Newby DE, Neilson JM, Jarvie DR, Boon NA. Caffeine restriction has no role in the management of patients with symptomatic idiopathic ventricular premature beats. Heart 1996; 76:355. 93. Tong C, Kiess M, Deyell MW, et al. Impact of frequent premature ventricular contractions on pregnancy outcomes. Heart 2018; 104:1370. Topic 122361 Version 25.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 29/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate GRAPHICS 12-lead electrocardiogram of epicardial premature ventricular complex Courtesy of Antonis Manolis, MD. Graphic 139336 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 30/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Single lead electrocardiogram (ECG) showing an interpolated ventricular premature beat (VPB) The third beat is a ventricular premature beat (VPB). It is called an interpolated VPB since it does not alter the underlying sinus RR interval. Graphic 72768 Version 3.0 Sinus rhythm The normal P wave in sinus rhythm is slightly notched since activation of the right atrium precedes that of the left atrium. The P wave is upright in a positive direction in leads I and II. A P wave with a uniform morphology precedes each QRS complex. The rate is between 60 and 100 beats per minute and the cycle length is uniform between sequential P waves and QRS complexes. In addition, the P wave morphology and PR intervals are identical from beat to beat. Graphic 69872 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 31/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Polymorphic premature ventricular complexes Courtesy of Antonis Manolis, MD. Graphic 139350 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 32/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Left ventricular outflow tract premature ventricular complexes Courtesy of Antonis Manolis, MD. Graphic 139343 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 33/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Right ventricular outflow tract premature ventricular complexes Courtesy of Antonis Manolis, MD. Graphic 139349 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 34/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Triggers for premature ventricular contractions Trigger Patient group Test Alcohol Patients reporting alcohol use, Alcohol screen, urine toxicology physical examination signs of alcohol use Caffeine (eg, coffee or tea Patients reporting caffeine use intake) Recreational/stimulating drugs Patients in whom stimulant drug use is suspected Drug screen (eg, for cocaine, amphetamines) Electrolyte abnormalities (eg, potassium or magnesium) Patients with suspected metabolic derangements (eg, vomiting, diarrhea, diuretic use, Serum electrolytes etc) Hypoxia Patients with COPD or other Pulse oximetry, arterial blood chronic lung disease gas Uncontrolled hypertension Patients with a history of hypertension or risk factors for hypertension Blood pressure measurement Hyper/hypothyroidism Patients with symptoms/signs of hyper- or hypothyroidism TSH High digoxin level Patients taking the drug Digoxin level Heart failure exacerbation Patients with heart failure symptoms or physical examination signs of volume overload Brain-type natriuretic peptide Anemia Patients with symptoms/signs of anemia Complete blood count Psychological stress/anxiety Patients reporting increase in life stressors, anxiety Menopausal transition Females in the perimenopause period COPD: chronic obstructive pulmonary disease; TSH: thyroid-stimulating hormone. Graphic 138370 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 35/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Approach to premature ventricular complex treatment in high-risk patients This algorithm is for high-risk patients with PVCs. The treatment approach and algorithm for low-risk patients with PVCs are presented separately. Refer to UpToDate content for further details. PVC: premature ventricular complex/contraction; BB: beta blockers; HF: heart failure. Refer to UpToDate content for further detail. Mitigating triggers: curtail or eliminate alcohol, coffee, or tea intake; abstain from recreational/stimulating drugs; and correct electrolyte abnormalities, hypoxia, hyperadrenergic state, and uncontrolled hypertension. Refer to UpToDate content for further detail. Sometimes, a patient will prefer to stop the beta blocker after symptom relief is achieved. In this case, one can try to wean the beta blocker after 6 to 12 months of medication treatment. The dose can be gradually reduced, and a 24-hour Holter recording can be repeated periodically. It is preferable to keep the patient on at least a https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 36/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate low dose of beta blocker if they are willing, as this may prevent PVC reoccurrence. Graphic 138294 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 37/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Oral beta blockers and calcium channel blockers for management of premature ventricular complexes in high-risk or symptomatic adult patients Other Medication name Initial dose Maximum dose considerations Beta blockers Metoprolol IR 25 mg twice daily 400 mg daily in 2 or 3 Commonly used divided doses (doses higher than 100 mg twice daily are rarely used) Metoprolol succinate ER 50 mg once daily 400 mg daily (doses higher than 200 mg May be used in patients with HFrEF at once daily are rarely used) lower initial dose of 12.5 to 25 mg once daily Carvedilol IR 3.125 mg twice daily 25 mg twice daily Commonly used; may be used in patients with HFrEF Bisoprolol 2.5 mg once daily 10 mg once daily Nebivolol 5 mg once daily 40 mg once daily Lower doses of 1.25 to 10 mg to be used in patients with HF Atenolol 25 mg once daily 200 mg once daily (doses higher than 100 Avoid in patients with HF mg once daily are rarely used) Nadolol 40 mg once daily 120 mg daily Avoid in patients with HF; first-choice therapy in some channelopathies Betaxolol 5 mg once daily 20 mg once daily Avoid in patients with HF Propranolol IR 10 mg two or three times daily 80 mg daily twice daily Avoid in patients with HF; first-choice therapy in some channelopathies and in hyperthyroidism Propranolol LA 80 mg once daily 160 mg once daily Avoid in patients with HF; first-choice therapy https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 38/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate in some channelopathies and in hyperthyroidism Calcium channel blockers* Diltiazem (12-hour) 60 mg twice daily 180 mg twice daily Diltiazem ER (24- 120 mg once daily 360 mg once daily hour) Verapamil IR 40 or 80 mg three times daily 120 mg three times daily Verapamil ER 120 or 180 mg once daily 360 mg once daily or 180 mg twice daily Initial and usual maximal dosages for reduction of PVC burden. Initial dose may be titrated (eg, at two-week intervals) as necessary for reduction in symptoms that correspond with a reduction in PVCs; refer to UpToDate topic review of PVC treatment and prognosis for additional information, including patient selection and monitoring. IR: immediate release; ER: extended release; LA: long acting; HFrEF: heart failure with reduced ejection fraction; PVC: premature ventricular complex. In patients without reduced left ventricular ejection fraction or structural heart disease, a non- dihydropyridine calcium channel blocker can be substituted if beta blockers are not tolerated or are not successful in reducing symptoms. Patients with a cardiomyopathy, with or without HF symptoms, should not be treated with calcium channel blocker. Graphic 138406 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 39/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Approach to treatment in patients with premature ventricular complexes (PVCs ACE: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta blockers; CCB: cal hypertension; PVC: premature ventricular complex/contraction. It is important to evaluate for potential PVC triggers as simple lifestyle changes may prove effective (eg, cur recreational/stimulating drugs). Other triggers to be considered include electrolyte abnormalities, hypoxia, h The evaluation for structural heart disease and primary electrical disease typically includes close scrutiny o exercise stress testing and/or cardiac magnetic resonance imaging. If monotherapy with BB or CCB results in minimal or no change in symptoms, stop the initial agent and con Patients with a cardiomyopathy, with or without HF symptoms, should not be treated with CCB. Patients w reduction in PVC burden and improvement in left ventricular ejection fraction) should be referred for cathete For patients with ongoing PVC-related symptoms following initial medical therapy, or for those who do not ablation, rather than antiarrhythmic drug therapy, as the next treatment. However, for patients without struc antiarrhythmic drug approach is a reasonable next choice, although the long-term efficacy of catheter ablati Refer to UpToDate content on HF with reduced ejection fraction for additional details of standard HF therap Examples of underlying heart disease include CAD, hypertrophic cardiomyopathy, arrhythmogenic right ve disorder of interest for additional treatment details. https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 40/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Graphic 126128 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 41/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Effect of amiodarone in CAMIAT Effect of amiodarone versus placebo in 1202 postmyocardial infarction patients with ventricular ectopy in the CAMIAT trial. By an intention to treat analysis, amiodarone produced a significant reduction in arrhythmic death (top panel, p = 0.016) but no change in all-cause mortality (bottom panel). Data from: Cairns JA, Connolly SJ, Gent M, et al. Lancet 1997; 349:675. Graphic 67684 Version 2.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 42/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 43/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 44/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 45/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Decreased survival with sotalol in the SWORD trial Results from the Survival With Oral d-Sotalol (SWORD) trial. The administration of d-sotalol to patients with an ejection fraction 40 percent after either recent myocardial infarction (MI) or after symptomatic heart failure with a remote (>42 days) MI was associated with increased mortality compared with placebo (5 versus 3.1 percent). The excess number of deaths was presumed to be primarily due to arrhythmias. Data from: Waldo AL, Camm AJ, DeRuyter H, et al. Lancet 1996; 348:7. Graphic 71934 Version 3.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 46/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Approach to premature ventricular complex treatment in low-risk patients This algorithm is for low-risk patients with PVCs. PVC: premature ventricular complex/contraction; BB: beta blocker; CCB: calcium channel blocker. Examples of other pre-existing heart disease include coronary artery disease, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, etc. Refer to specific UpToDate content for further information. Curtailing or eliminating alcohol, coffee, or tea intake, and abstaining from recreational/stimulating drugs. Correct electrolyte abnormalities, https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 47/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate hypoxia, hyperadrenergic state, and uncontrolled hypertension. Refer to UpToDate for further information. PVC burden can be assessed with 24-hour cardiac monitoring. Refer to UpToDate for further information on cardiac monitoring, PVC burden, and symptom assessment. In a patient with lower or no symptoms and burden after treatment with BB or CCB who prefers to stop or reduce their medications, a trial of weaning and/or stopping may be done after 6-12 months. Refer to UpToDate content for further detail. Refer to UpToDate content for further detail. Graphic 138293 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 48/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Left fascicular premature ventricular complexes Courtesy of Antonis Manolis, MD. Graphic 139331 Version 1.0 https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 49/50 7/6/23, 3:35 PM Premature ventricular complexes: Treatment and prognosis - UpToDate Contributor Disclosures Antonis S Manolis, MD No relevant financial relationship(s) with ineligible companies to disclose. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/premature-ventricular-complexes-treatment-and-prognosis/print 50/50

7/6/23, 3:34 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF : Joseph E Marine, MD, FACC, FHRS, Andrea M Russo, MD, FACC, FHRS : Samuel L vy, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 12, 2021. INTRODUCTION Life-threatening ventricular arrhythmias, including sustained ventricular tachycardia (VT) and ventricular fibrillation (VF), are common in patients with systolic heart failure (HF) and dilated cardiomyopathy and may lead to sudden cardiac death (SCD). Primary prevention of SCD refers to medical or interventional therapy undertaken to prevent SCD in patients who have not experienced symptomatic life-threatening sustained VT/VF or sudden cardiac arrest (SCA) but who are felt to be at an increased risk for such an event. The primary prevention of SCD in patients with HF and cardiomyopathy with reduced ejection fraction, either due to coronary heart disease or a dilated nonischemic etiology, will be reviewed here with emphasis on the role of implantable cardioverter-defibrillators (ICDs). The different types of ventricular arrhythmias, the effects of HF therapy on ventricular arrhythmias, the role of electrophysiologic testing, and the secondary prevention of SCD are discussed separately. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) The approaches to the treatment of ventricular arrhythmias related to specific heart muscle diseases or primary electrical system diseases such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, isolated left ventricular noncompaction, Chagas disease, Brugada syndrome, long QT syndrome, and other channelopathies are discussed elsewhere. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 1/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Recommendations for ICD therapy'.) (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis".) (See "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis".) (See "Chronic Chagas cardiomyopathy: Management and prognosis".) (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) (See "Congenital long QT syndrome: Treatment".) CAUSES OF DEATH IN HEART FAILURE Causes of death in patients with heart failure include: Progressive pump failure. Unexpected SCD (usually from a ventricular tachyarrhythmia, but asystole and pulseless electrical activity [PEA] are also seen less frequently). SCD in the setting of worsening heart failure. The mode of death in patients with HF is more likely to be "sudden" in patients with class II or III HF, while the mode of death is more likely to be related to "pump" failure in patients with class IV HF ( figure 1) [1]. Therefore, primary prevention implantable cardioverter-defibrillator (ICD) trials (in the absence of cardiac resynchronization therapy [CRT]) have excluded patients with NYHA class IV HF. In fact, the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) Guidelines state that "ICD therapy is not indicated for NYHA Class IV patients with medication-refractory HF who are not also candidates for cardiac transplantation, an LVAD (left ventricular assist device), or CRT-D," listing this as a class III indication [2]. (See 'Class IV heart failure' below and "Heart transplantation in adults: Indications and contraindications" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) RISK STRATIFICATION STRATEGIES While implantable cardioverter-defibrillators (ICDs) are highly efficacious in the treatment of ventricular tachyarrhythmias and prevention of SCD, they are costly, require ongoing follow-up, and have numerous risks at the time of implantation (eg, bleeding, pneumothorax, perforation, etc) as well as over the lifetime of the device (eg, infection, device and lead malfunction, etc). In https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 2/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate addition, only a subset of patients with cardiomyopathy develop sustained ventricular tachyarrhythmias or SCD. As such, the risk stratification of patients prior to ICD therapy is important for providing therapy to patients at highest risk of SCD and minimizing the number of ICD implantations in patients who are unlikely to benefit. Numerous patient-related clinical markers as well as data derived from testing have been associated with increased risk of sudden death, and a variety of attempts have been made to develop risk stratification schema to more specifically identify an individual patient's risk of SCD. To date, however, the optimal approach to SCD risk stratification for placement of a primary prevention ICD continues to rely primarily upon the following: Etiology of left ventricular dysfunction Left ventricular ejection fraction Heart failure symptom classification Life expectancy greater than one year Inducible sustained ventricular tachycardia Nonsustained ventricular tachycardia on electrocardiogram (ECG) monitoring LVEF and risk Patients with significant reductions in left ventricular ejection fraction (LVEF) appear to be at greatest risk, and derive the greatest benefit, from primary prevention ICD implantation. (See 'Trials of primary prevention ICDs in ischemic cardiomyopathy' below and 'Trials of primary prevention ICDs in nonischemic dilated cardiomyopathy' below.) Though most studies of prophylactic ICD implantation have included patients with an LVEF 35 percent, the large majority of patients included in most trials have had ejection fractions under 30 percent, resulting in some uncertainty regarding the potential benefit of prophylactic ICD insertion for patients with LVEF between 30 and 35 percent. This issue was addressed in a retrospective cohort study using registry data from the NCDR ICD registry of patients who underwent ICD implantation in 2006 or 2007 (median follow-up 4.4 years) and Get With The Guidelines-Heart Failure (GWTG-HF) patients without an ICD (enrolled between 2005 and 2009 with median follow-up of 2.9 years), in which the benefits of ICD implantation were separately evaluated among patients with LVEF <30 percent and those with LVEF 30 to 35 percent [3]. All- cause mortality was significantly lower in patients with an ICD and any level of LVEF, compared with those without an ICD: LVEF 30 to 35 percent hazard ratio (HR) 0.83, 95% CI 0.69-0.99 LVEF <30 percent HR 0.72, 95% CI 0.65-0.81 While this study is nonrandomized, the data suggest that patients with LVEF between 30 and 35 percent do appear to benefit from prophylactic ICD insertion. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 3/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate SCD risk prediction post-MI A number of clinical features have been evaluated as a means for identifying patients at the greatest risk of SCD following an acute myocardial infarction (MI). These include: Left ventricular (LV) dysfunction or reduced LVEF HF symptoms and the degree of heart failure LV aneurysm Q-waves on the surface ECG Intraventricular conduction delay Spontaneous ventricular premature beats (VPBs) and nonsustained ventricular tachycardia (NSVT) Late potentials on a signal-averaged ECG (SAECG) VT induced by electrophysiologic study (EPS) Reduced heart rate variability (HRV) Microvolt T-wave (repolarization) alternans (TWA) A detailed discussion of the utility of these clinical predictors is presented separately. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) Clinical risk markers A variety of novel risk stratification schemes derived from retrospective studies have shown the ability to predict SCD risk, but none have been prospectively validated in independent populations or have become part of the routine practice for primary prevention ICD placement [4-13]. Therefore, traditional risk stratification based on etiology of cardiomyopathy, LVEF, HF class, and select other risk markers (eg, inducible sustained ventricular arrhythmias) continues to form the basis for recommendations regarding ICD use. Initial studies evaluating the role of ICD therapy in reducing mortality focused on patients with reduced LV systolic function and class II-III heart failure. As the mode of death in patients with class II-III heart failure was more likely sudden (in 59 to 64 percent of cases [1]), and enrollment criteria for ICD trials often included patients with class II-III HF symptoms. In contrast, patients with class IV heart failure were more likely to die from heart failure (56 percent) than from sudden death (33 percent). Studies examining the relationship between one-year mortality and LV function after MI in the pre- and post-thrombolytic era demonstrated a much higher cardiac mortality rate in patients with LVEF <40 percent [14,15]. The presence of NSVT or frequent ventricular ectopy was also associated with increased mortality post-MI, so NSVT was also used as a risk factor for inclusion in some of the randomized ICD trials. Earlier studies also demonstrated that inducible sustained monomorphic VT was associated with an increased risk of sudden death or sustained ventricular arrhythmias [16]. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 4/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Myocardial fibrosis on CMR The presence of myocardial fibrosis, identified by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging appears to be a robust predictor of ventricular arrhythmias or SCD across a wide spectrum of patients with non- ischemic cardiomyopathy, including those with a mean LVEF >35 percent. A 2017 systematic review and meta-analysis, which included 2948 patients from 29 observational studies, assessed the relationship between LGE and ventricular arrhythmias in patients with non-ischemic dilated cardiomyopathy [17]. Over a mean follow-up of three years, the primary endpoint (sustained ventricular arrhythmia, appropriate ICD intervention, or SCD) occurred in 350 patients, including 21 percent of patients with LGE (compared with 4.7 percent of patients without LGE; pooled odds ratio [OR] 4.3, 95% CI 3.3- 5.8). LGE was able to risk stratify patients at all levels of LVEF (both above and below 35 percent) and was most powerful among patients with ICDs previously placed for primary prevention (OR 7.8, 95% CI 1.7-35.8). In a 2019 Australian prospective, nonrandomized study of 452 patients with non-ischemic cardiomyopathy (LVEF 35 percent) who had all undergone CMR imaging and who met ESC/AHA criteria for primary prevention ICD placement, half received a primary prevention ICD according to the judgment of the treating physician and prevailing local practice [18]. Patients with myocardial fibrosis (manifest by LGE on CMR imaging) who received an ICD had lower mortality than those who did not get an ICD (HR 0.45, 95% CI 0.26-0.77). However, there was no difference in survival with or without an ICD for the 175 patients without myocardial fibrosis. The MARVEN (Clinical, Electrocardiographic, and Cardiac Magnetic Resonance Imaging Risk Factors Associated with Ventricular Tachyarrhythmias in Nonischemic Cardiomyopathy) Study is an NHLBI-sponsored prospective, observational study aimed at developing optimal risk stratification strategies to predict ventricular tachyarrhythmias in patients with nonischemic cardiomyopathy undergoing CRT-D implantation to determine whether LGE-CMR will further improve risk stratification in patients with nonischemic cardiomyopathy, LVEF 35 percent, and QRS 120 milliseconds [19]. While not currently utilized in SCD risk stratification guidelines, if these data are confirmed in additional prospective studies, then LGE on CMR may become a criterion used in future risk stratification schemes. USE OF AN ICD Malignant ventricular arrhythmias potentially leading to SCD are more frequently seen in patients with certain cardiomyopathies (compared with the general population), particularly in https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 5/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate association with heart failure (HF) symptoms. As in secondary prevention, randomized clinical trials have established a clear role for primary prevention implantable cardioverter-defibrillators (ICDs) in selected patients ( table 1). In contrast, antiarrhythmic drugs other than beta blockers do not appear to improve outcomes. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) The role of an ICD in the primary prevention of SCD among patients with HF and cardiomyopathy depends upon several factors: The severity of left ventricular (LV) systolic dysfunction. The severity of clinical HF ( table 2). The etiology of LV dysfunction (ie, ischemic or nonischemic cardiomyopathy). Competing co-morbidities that affect longevity and risk of ICD complications (eg, chronic kidney disease, chronic obstructive pulmonary disease, etc). The risk of SCD increases with the severity of both LV systolic dysfunction and clinical HF [20]. However, the risk of death due to other causes (eg, progressive HF) also increases with worsening HF and LV systolic dysfunction, reinforcing the importance of appropriate patient selection prior to primary prevention ICD placement. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Epidemiology'.) Cardiac resynchronization therapy (CRT) may be appropriate treatment for selected HF patients with ischemic or non-ischemic cardiomyopathy and reduced left ventricular ejection fraction (LVEF) ( 35 percent) with a wide QRS complex (especially if left bundle branch block QRS morphology), if left ventricular function does not improve with guideline-directed medical therapy. Ventricular dyssynchrony refers to the loss of coordinated contraction across the left ventricle. Dyssynchrony can further impair the pump function of a failing ventricle and exacerbate HF symptoms. CRT can improve pump performance, reverse the deleterious process of ventricular remodeling, and improve survival in appropriately selected patients. CRT can be achieved with a device designed for pacing only (CRT-P) or can be incorporated into a combination device with an ICD (CRT-D) ( figure 2) [21]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Ischemic cardiomyopathy Our approach for patients with ischemic cardiomyopathy We recommend ICD therapy for primary prevention of SCD in the following groups of patients with ischemic cardiomyopathy: https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 6/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate For patients with cardiomyopathy due to ischemic heart disease, left ventricular ejection fraction (LVEF) 35 percent, and associated HF with New York Heart Association (NYHA) functional class II or III status [2]. For patients with cardiomyopathy due to ischemic heart disease, LVEF 30 percent, and NYHA functional class I status [2]. In both instances, patients should be at least 40 days post-myocardial infarction (MI) and more than three months following revascularization and taking guideline-directed medical therapy. These restrictions recognize that revascularization and medical therapy may result in significant improvement in LVEF and/or HF class. For patients with nonsustained ventricular tachycardia (NSVT) associated with prior MI, LVEF 40 percent, and inducible sustained VT or ventricular fibrillation at electrophysiology study [2,22,23]. Patients should be past the acute phase of MI, on guideline-directed medical therapy, and have reasonable expectation for survival for at least one year. Patients who have had an MI resulting in reduced LVEF are at increased risk of SCD, most often due to a ventricular tachyarrhythmia. Prophylactic ICD implantation for the primary prevention of SCD reduces mortality in selected patients with ischemic cardiomyopathy. Coronary revascularization itself may also reduce the future risk of malignant arrhythmias and SCD, as shown in the early versus late ICD implantation strategies and differing results in various randomized trials. The best approach to selecting patients with ischemic cardiomyopathy for ICD therapy for primary prevention has been explored in several major randomized trials, with the indications for ICD implantation derived largely from the inclusion criteria of these trials. One caveat, however, is that these trials took place prior to the contemporary guideline-based approaches to optimal medical therapy for patients with heart failure and cardiomyopathy. Trials of primary prevention ICDs in ischemic cardiomyopathy MADIT-I trial The Multicenter Automatic Defibrillator Implantation Trial (MADIT, now called MADIT-I) was the first trial to demonstrate that the ICD has a role in primary prevention of SCD in certain high-risk, asymptomatic patients [22]. Patients had a prior MI with reduced LVEF ( 35 percent), NSVT on ECG monitoring, and inducible sustained monomorphic VT during electrophysiology study (EPS) that was also inducible after administration of intravenous procainamide. Among 196 patients who were randomly assigned to pharmacologic therapy (including an antiarrhythmic drug at the discretion of the clinician, with amiodarone administered to most patients) or an ICD and followed for an average of 27 months, patients assigned to ICD therapy had significant reductions in overall mortality, cardiac mortality, and arrhythmic deaths compared with patients assigned to medical therapy ( figure 3). While the https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 7/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate MADIT-I trial remains an important landmark study in the utilization of ICDs for primary prevention, it has largely been supplanted by subsequent studies with larger numbers of patients, better methodologies, and simpler risk stratification schemes for study entry. MUSTT trial The Multicenter Unsustained Tachycardia Trial (MUSTT trial), which was not primarily designed as a randomized ICD clinical trial but rather to study the management of high-risk patients using the results of electrophysiology study (EPS), enrolled patients with prior MI, reduced LVEF ( 40 percent), asymptomatic NSVT on ECG monitoring, inducible sustained VT during EPS, and no history of VT or syncope [23]. A total of 704 patients were randomly assigned to either standard medical therapy (353 patients) or EPS-guided antiarrhythmic therapy, which included either an antiarrhythmic agent (154 patients received a class IA drug with or without mexiletine, propafenone, sotalol, or amiodarone) or an ICD (161 patients) if at least one antiarrhythmic agent was ineffective. After a median follow-up of 39 months, the five-year (25 versus 32 percent, relative risk [RR] 0.73, 95% CI 0.53-0.99) rates for the primary endpoint (arrhythmic death or resuscitated SCD) were significantly lower for EPS-guided therapy compared with standard medical therapy. The reduction in the primary endpoint in the EPS- guided group was largely attributable to ICD therapy; at five years, the primary endpoint occurred in 9 percent of those receiving an ICD, compared with 37 percent of those receiving an antiarrhythmic drug (RR 0.24, 95% CI 0.13-0.45) ( figure 4). Whether inducible arrhythmia might be prognostically important in patients with an LVEF of 30 to 40 percent was addressed in another analysis from MUSTT [24]. The rate of arrhythmic death at five years was significantly increased for patients with inducible VT and LVEF between 30 and 40 percent, suggesting that for patients with LVEF 30 percent only, electrophysiology testing may have useful predictive value. CABG Patch trial The Coronary Artery Bypass Graft (CABG) Patch trial evaluated the efficacy of an epicardial ICD implanted at the time of coronary artery bypass graft surgery among 900 patients with severe coronary artery disease (CAD), reduced LVEF <36 percent, abnormal signal averaged ECG, and no prior sustained VT or syncope [25]. Epicardial ICD systems were predominantly used. Compared with standard medical therapy over an average of 32 months, there was no significant difference in overall or cardiovascular mortality among patients with an ICD (hazard ratio [HR] 1.07 for overall mortality compared with standard medical therapy, 95% CI 0.81-1.42) ( figure 5). This negative trial is a primary reason why current guidelines recommend against primary prevention ICD implantation for patients who have recently undergone coronary revascularization, as revascularization itself may reduce the future risk of malignant arrhythmias and SCD. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 8/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate MADT-II trial The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) enrolled 1232 patients with a prior MI more than 30 days prior to enrollment (and more than three months if bypass surgery was performed) and reduced LVEF ( 30 percent); NSVT and inducible VT during EPS were not required [26]. The study, which randomly assigned patients to a prophylactic ICD or conventional medical therapy, was stopped early due to benefit of ICD therapy after an average follow-up of 20 months. Patients in the ICD group had reduced all- cause mortality (14.2 versus 19.8 percent for conventional therapy; HR 0.65, 95% CI 0.51-0.93) ( figure 6). SCD-HeFT trial The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), which evaluated ICD and amiodarone therapies in patients with both ischemic (52 percent) or nonischemic (48 percent) cardiomyopathy, enrolled patients with NYHA class II or III heart failure (CHF) for at least three months prior to randomization, reduced LVEF ( 35 percent), and treated with angiotensin converting enzyme (ACE) inhibitor and beta-blocker, if tolerated [27]: NYHA class II or III HF. Reduced. Congestive heart failure (CHF) present for at least three months prior to randomization and treated with ACE inhibitor and beta blocker, if tolerated. Among 2521 patients who were randomly assigned to ICD implantation, amiodarone, or placebo, and followed for a median of 46 months, total mortality at five years was significantly reduced with ICD therapy (29 versus 36 percent with placebo; HR 0.77, 95% CI 0.62-0.96). The benefit of an ICD was comparable among patients with either an ischemic or nonischemic cardiomyopathy. A long-term analysis of SCD-HeFT participants, published in July 2020, showed continued survival benefit in the ICD arm over placebo arm at a median follow-up of 11 years (HR 0.87, 95% CI 0.76-0.98) [28]. Long-term benefit was most evident for patients with ischemic cardiomyopathy and those with NYHA functional class II symptoms at enrollment. These results suggest that an ICD is beneficial in patients with chronic HF and a diminished LVEF ( 35 percent), despite appropriate medical therapy for at least three months. In contrast, amiodarone provided no benefit over placebo. DINAMIT trial The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), which evaluated the role of prophylactic ICD implantation compared with standard medical therapy, enrolled 674 patients with MI in the preceding 6 to 40 days (mean of 18 days), reduced LVEF ( 35 percent), and reduced heart rate variability or elevated resting heart rate ( 80 beats/minute) [29]. Patients with sustained VT >48 hours post-MI, NYHA class IV HF, or CABG or three-vessel https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 9/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate percutaneous coronary intervention post-MI were excluded. After a mean follow-up of 30 months, there was no significant difference in annual all-cause mortality between the patients with and without an ICD (7.5 versus 6.9 percent annual mortality; HR 1.08, 95% CI 0.76-1.55). This negative trial provides an important rationale for the current guideline recommendation that ICD implantation should be deferred until at least 40 days after an MI. IRIS trial The Immediate Risk Stratification Improves Survival (IRIS) trial also evaluated the efficacy of ICD therapy versus standard therapy early post-MI and enrolled patients with an MI in the preceding 5 to 31 days and at least one of the following: reduced LVEF ( 40 percent) with a resting heart rate 90 beats/minute or NSVT at a rate of 150 beats/minute or both [30]. Among 898 randomized patients who were followed for an average of 37 months, there was no difference in all-cause mortality between patients randomly assigned to ICD therapy and those assigned to medical therapy (HR 1.04 for ICD therapy, 95% CI 0.81-1.35). Nonischemic dilated cardiomyopathy Our approach for patients with nonischemic dilated cardiomyopathy We recommend ICD therapy for primary prevention of SCD in the following groups of patients with nonischemic dilated cardiomyopathy: For patients meeting SCD-HeFT criteria, including an LVEF 35 percent and NYHA class II to III ( table 2) HF, we suggest ICD implantation rather than guideline-directed optimal medical therapy alone [2]. For most patients with LVEF 35 percent, class III or IV HF, and a QRS duration 120 milliseconds (especially if left bundle branch block [LBBB] QRS morphology), we recommend implantation of a combined CRT-D device (biventricular pacing combined with an ICD). Additionally, many patients with specific non-ischemic cardiomyopathies (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, cardiac amyloidosis, etc) may be candidates for primary prevention ICD based on disease-specific risk markers. The approaches to selection of appropriate patients in a variety of conditions are discussed in the individual UpToDate topics. Ventricular arrhythmias are common in patients with HF and a nonischemic cardiomyopathy. While some small early trials suggested no benefit of ICD therapy in patients with nonischemic cardiomyopathy, subsequent larger trials and a 2004 meta-analysis have demonstrated greater overall survival following prophylactic ICD implantation in selected patients. While ICDs effectively reduce mortality from SCD, the benefit on total mortality appears diminished in the https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 10/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate setting of optimal guideline-directed medical therapy and CRT. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".) Trials of primary prevention ICDs in nonischemic dilated cardiomyopathy DEFINITE trial The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial evaluated the efficacy of an ICD versus standard medical therapy, in 458 patients with nonischemic dilated cardiomyopathy, reduced LVEF ( 35 percent), and premature ventricular beats or NSVT [31]. After mean follow-up of 29 months, there was a trend toward reduction in the primary endpoint of all-cause mortality in patients treated with an ICD (7.9 versus 14.1 percent with medical therapy alone; HR 0.65, 95% CI 0.40-1.06). Fewer sudden deaths occurred in the ICD arm, although the numbers were very small (3 deaths versus 14 deaths in the medical therapy arm; HR 0.20, 95% CI 0.06-0.71). The all-cause mortality rate in the "medical therapy only" arm of DEFINITE (14.1 percent at two years) was lower than had been anticipated when the study was designed, potentially contributing to the trial being underpowered for its primary endpoint. SCD-HeFT trial The Sudden Cardiac Death in Heart Failure trial (SCD-HeFT), which evaluated ICD and amiodarone therapies in patients with both ischemic (52 percent) or nonischemic (48 percent) cardiomyopathy, identified a significant reduction in overall mortality with ICD therapy (29 versus 36 percent with placebo; HR 0.77, 95% CI 0.62-0.96) [27]. The benefit of an ICD was comparable among patients with either an ischemic or nonischemic cardiomyopathy. (See 'Trials of primary prevention ICDs in ischemic cardiomyopathy' above.) COMPANION trial of ICD combined with CRT For most patients with LVEF 35 percent, class III or IV HF, and a QRS duration 120 milliseconds, we recommend implantation of a combined CRT-D device (biventricular pacing combined with an ICD) [32,33]. The benefit appears to be greatest in patients with a left bundle branch block and QRS duration 150 milliseconds [34-36]. Patients with right bundle branch block and a QRS duration <150 ms are much less likely to benefit from CRT. The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial evaluated optimal medical therapy versus CRT with or without an ICD among 682 patients with nonischemic dilated cardiomyopathy, reduced LVEF ( 35 percent), and NYHA class III or IV HF symptoms requiring hospitalization within the prior year [33]. After median follow-up of 16 months, there was a significant reduction in the incidence of the combined endpoint of all-cause mortality and all-cause hospitalization in the two arms receiving CRT compared with the medical therapy only arm (56 versus 68 percent). The CRT-D arm, but not the CRT-P arm, experienced a significant improvement in the secondary endpoint of all-cause mortality alone. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 11/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate DANISH trial The Danish Study to Assess the Efficacy of ICDs in Patients with Non- Ischemic Systolic Heart Failure on Mortality (DANISH) randomly assigned 1116 patients with symptomatic systolic HF (LVEF 35 percent) not caused by ischemic heart disease to an ICD with guideline-directed optimal medical therapy or medical therapy alone [37]. Over a median follow- up of 5.6 years, no significant difference was noted in the primary outcome of total mortality (120 deaths [21.6 percent] in the ICD group compared with 131 deaths [23.4 percent] in the group without an ICD; HR 0.87, 95% CI 0.68-1.12). A significant reduction was noted in the prespecified secondary outcome of SCD in the group receiving ICDs (24 deaths [4.3 percent] compared with 46 sudden deaths [8.2 percent] in the no ICD group; HR 0.50, 95% CI 0.31-0.82), as well as nonsignificant trends toward reduction in total cardiovascular mortality and increased device infections in the ICD group. Compared with prior primary prevention ICD trials, the overall mortality rate of patients in the DANISH trial was low, likely due to improved medical therapy for HF (notably a much higher utilization of ACE-I/ARB and beta blockers than in the older trials) and the use of CRT, which was not available during the older primary prevention trials. Because of this, the DANISH trial may have been underpowered to show a mortality benefit of ICD therapy. Finally, as there are competing causes of death with increasing age, one might not expect the same benefit of ICD therapy in older patients, who may have greater comorbidities which could contribute to nonarrhythmic causes of death. Our experts feel that it would be premature to use data from the DANISH study as the sole basis to withhold potentially life-saving ICD therapy from all patients with nonischemic cardiomyopathy. Instead, the results actually support the use of ICDs in younger patients who have a cardiomyopathy not caused by ischemic heart disease. For those patients who are likely to have a strong response to CRT or who are not considered good candidates for ICD therapy, a CRT-P device may be more suitable and compatible with therapeutic goals. Meta-analyses of ICD trials in nonischemic cardiomyopathy Several updated meta- analyses have been published that include patients with nonischemic cardiomyopathy receiving an ICD for primary prevention from the same original five ICD trials (CAT, AMIOVIRT, DEFINITE, SCD-HeFT, and COMPANION) as well as patients from the DANISH trial [38-46]. When considering all six trials collectively, each of the meta-analyses demonstrated a significant benefit of the ICD on all-cause mortality in patients with nonischemic cardiomyopathy (19 to 24 percent hazard reduction compared with medical therapy alone). When only patients who also received CRT in the COMPANION and DANISH trials were analyzed, there was a nonsignificant trend toward reduction in all-cause mortality among patients with an ICD (approximately 25 to 30 percent hazard reduction with nonsignificant confidence intervals) [38,40,43]. Despite the lack of a significant incremental benefit of the ICD in the two trials that included CRT, it is currently https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 12/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate premature to withhold ICD therapy in all patients with nonischemic cardiomyopathy who require concomitant CRT. Adequately powered randomized studies are needed before recommending a change in current practice guidelines. GUIDELINE-DIRECTED MEDICAL THERAPY For patients who meet criteria for insertion of an implantable cardioverter-defibrillator (ICD) for the primary prevention of SCD, in the absence of a contraindication, we recommend optimizing guideline-directed medical therapy prior to ICD implantation. Heart failure therapy Several of the components of appropriate medical therapy after a myocardial infarction (MI) reduce SCD as well as overall mortality. While these data are derived from trials in patients with ischemic heart disease, we can infer that many of the same benefits should apply to SCD risk reduction in patients with nonischemic cardiomyopathy. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the management of heart failure with reduced ejection fraction in adults".) Beta blockers In addition to reducing overall mortality in patients with an acute MI, beta blockers also reduced the risk of SCD [47,48]. The SCD benefit is better established in patients with chronic HF. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy", section on 'Heart failure therapy'.) Post-MI patients with an ICD also appear to derive a benefit from beta blockers. In a cohort of 691 patients with ischemic cardiomyopathy who received an ICD in the MADIT-II trial, the 433 patients treated with a beta blocker had significantly lower mortality (hazard ratio [HR] 0.43) compared with those not taking beta blockers; additionally, patients in the highest quartile of beta blocker dose had a significant reduction in the risk of ventricular tachyarrhythmias requiring ICD discharge (HR 0.48) [49]. ACE inhibitors A meta-analysis of 15,104 patients in 15 trials of acute MI found that angiotensin-converting enzyme (ACE) inhibitor therapy reduced the risk of SCD (odds ratio 0.80, 95% CI 0.70-0.92, absolute benefit approximately 1.4 percent) as well as overall and cardiovascular mortality [50]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".) Angiotensin II receptor blockers Angiotensin II receptor blockers (ARBs) are often used for patients who cannot tolerate ACE inhibitors. At appropriate doses, it is likely that ARBs https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 13/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate reduce the risk of SCD to the same degree as ACE inhibitors [51]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".) Angiotensin receptor-neprilysin inhibitor The combination of an ARB and neprilysin inhibitor, known as angiotensin receptor-neprilysin inhibitor or ARNI, is another therapy for use in patients with HF and reduced LVEF (HFrEF). A randomized double-blind trial (PARADIGM-HF) in patients with HFrEF found that sacubitril-valsartan reduced cardiovascular mortality and hospitalization for HF as well as all-cause mortality compared with a standard dose of the ACE inhibitor enalapril [52]. The ARNI combination is administered in conjunction with other HF therapies, in place of an ACE inhibitor or ARB.