Probing oral anticoagulation in patients with atrial high rate episodes: Rationale and design of the Non–vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes (NOAH–AFNET 6) trial Rationale and design of the Apixaban for the Reduction of Thrombo‐Embolism in Patients With Device‐Detected Sub‐Clinical Atrial Fibrillation (ARTESiA) trial Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. 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. Evaluation of the safety and efficacy of an edoxaban‐based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST‐AF PCI trial Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: NICE guidance Major progress in anticoagulant uptake for atrial fibrillation at last: does it translate into stroke prevention? Does left atrial appendage closure with a cardiac plug system reduce the stroke risk in nonvalvular atrial fibrillation patients? A single-center case series. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial Comparative Efficacy and Safety of New Oral Anticoagulants in Patients With Atrial Fibrillation Efficacy and safety of percutaneous left atrial appendage closure to prevent thromboembolic events in atrial fibrillation patients with high stroke and bleeding risk Multicenter randomized study of anticoagulation guided by remote rhythm monitoring in patients with implantable cardioverter-defibrillator and CRT-D devices: Rationale, design, and clinical characteristics of the initially enrolled cohort The IMPACT study. Antithrombotic Treatment Patterns in Patients with Newly Diagnosed Nonvalvular Atrial Fibrillation: The GLORIA-AF Registry, Phase II. Anticoagulant and/or Antiplatelet Treatment in Patients with Atrial Fibrillation after Percutaneous Coronary Intervention Prevention of Bleeding in Patients With Atrial Fibrillation Undergoing PCI (PIONEER): Three May End Up Being a Crowd Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF-TIMI 48 trial. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography.
Background Oral anticoagulation prevents ischemic strokes in patients with atrial fibrillation ( AF ) . Early detection of AF and subsequent initiation of oral anticoagulation help to prevent strokes in AF patients . Implanted cardiac pacemakers and defibrillators allow seamless detection of atrial high rate episodes ( AHRE ) , but the best antithrombotic therapy in patients with AHRE is not known . Rationale Stroke risk is higher in pacemaker patients with AHRE than in those without , but the available data also show that stroke risk in patients with AHRE is lower than in patients with AF . Furthermore , only a minority of patients with AHRE will develop AF , many strokes occur without a temporal relation to AHRE , and AHRE can reflect other arrhythmias than AF or artifacts . An adequately powered controlled trial of oral anticoagulation in patients with AHRE is needed . Design The Non – vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes ( NOAH – AFNET 6 ) trial tests whether oral anticoagulation with edoxaban is superior to prevent the primary efficacy outcome of stroke or cardiovascular death compared with aspirin or no antithrombotic therapy based on evidence ‐based indications . The primary safety outcome will be major bleeding . NOAH – AFNET 6 will r and omize 3,400 patients with AHRE , but without documented AF , aged ≥65 years with at least 1 other stroke risk factor , to oral anticoagulation therapy ( edoxaban ) or no anticoagulation . All patients will be followed until the end of this investigator‐driven , prospect i ve , parallel‐group , r and omized , event‐driven , double‐blind , multicenter phase IIIb trial . Patients will be censored when they develop AF and offered open‐label anticoagulation . The sponsor is the Atrial Fibrillation NETwork ( AFNET ) . The trial is supported by the DZHK ( German Centre for Cardiovascular Research ) , the BMBF ( German Ministry of Education and Research ) , and Daiichi Sankyo Europe . Conclusion NOAH – AFNET 6 will provide robust information on the effect of oral anticoagulation in patients with atrial high rate episodes detected by implanted devices . Graphical abstract Figure . No Caption available Background Device‐detected sub clinical atrial fibrillation ( AF ) refers to infrequent , short‐lasting , asymptomatic AF that is detected only with long‐term continuous monitoring . Sub clinical AF is common and associated with an increased risk of stroke ; however , the risk of stroke with sub clinical AF is lower than for clinical AF , and very few patients with sub clinical AF alone have been included in large AF anticoagulation trials . The net benefit of anticoagulation in patients with sub clinical AF is unknown . Design ARTESiA is a prospect i ve , multicenter , double‐blind , r and omized controlled trial , recruiting patients with sub clinical AF detected by an implanted pacemaker , defibrillator , or cardiac monitor , and who have additional risk factors for stroke . Patients with clinical AF documented by surface electrocardiogram will be excluded from the study . Participants will be r and omized to receive either apixaban ( according to st and ard AF dosing ) or aspirin 81 mg daily . The primary outcome is the composite of stroke , transient ischemic attack with diffusion‐weighted magnetic resonance imaging evidence of cerebral infa rct ion , and systemic embolism . Approximately 4,000 patients will be enrolled from around 230 clinical sites , with an anticipated mean follow‐up of 36 months until 248 adjudicated primary outcome events have occurred . Summary ARTESiA will determine whether oral anticoagulation therapy with apixaban compared with aspirin reduces the risk of stroke or systemic embolism in patients with sub clinical AF and additional risk factors The Canadian Cardiovascular Society ( CCS ) published the complete set of 2010 Atrial Fibrillation ( AF ) Guidelines in the January , 2011 issue of the Canadian Journal of Cardiology . During its deliberations , the CCS Guidelines Committee engaged to a timely review of future evidence , with periodic composition of focused up date s to address clinical ly important advances . In 2011 , results were published from 3 pivotal AF trials : the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ( ROCKET-AF ) , the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ( ARISTOTLE ) study , and the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of St and ard Therapy ( PALLAS ) , comparing dronedarone with placebo in patients with permanent AF and additional cardiovascular disease risk-factor burden . Each of these large r and omized trials provided clear results with major implication s for AF management . Other important evidence that has emerged since the 2010 Guidelines includes findings about prediction instruments for AF-associated stroke and bleeding risk , stroke risk in paroxysmal-AF patients , risk-benefit considerations related to oral anticoagulation in patients with chronic kidney disease , and risk/benefit considerations in the use of antiplatelet agents , alone and in combination with each other or with oral anticoagulants , in AF patients . The Guidelines Committee judged that this extensive and important new evidence required focused updating of the 2010 Guidelines with respect to stroke prevention and rate/rhythm control . This report presents the details of the new recommendations , along with the background and rationale ACCF : American College of Cardiology Foundation ACCP : American College of Chest Physicians ACS : acute coronary syndrome ACT : Atrial arrhythmia Conversion Trial ADONIS : American – Australian – African trial with DronedarONe In atrial fibrillation or flutter for the maintenance of Sinus rhythm AF : atrial fibrillation AHA : American Heart Association AND ROMEDA : ANtiarrhythmic trial with DROnedarone in Moderate-to-severe congestive heart failure Evaluating morbidity DecreAse APHRS : Asia Pacific Heart Rhythm Society aPTT : activated partial thromboplastin time ARB : angiotensin-receptor blocker ARISTOTLE : Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation ATHENA : A placebo-controlled , double-blind , parallel arm Trial to assess the efficacy of dronedarone 400 mg b.i.d . for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter ATRIA : AnTicoagulation and Risk factors In Atrial fibrillation AVERROES : Apixaban VErsus acetylsalicylic acid ( ASA ) to Reduce the Rate Of Embolic Stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment AVRO : A prospect i ve , r and omized , double-blind , Active-controlled , superiority study of Vernakalant vs. amiodarone in Recent Onset atrial fibrillation b.i.d : bis in die ( twice daily ) b.p.m . : beats per minute CABANA : Catheter ABlation vs . ANtiarrhythmic drug therapy for Atrial fibrillation CABG : coronary artery bypass graft CAP : Continued Access to Protect AF CHA2DS2-VASc : Congestive heart failure or left ventricular dysfunction Hypertension , Age ≥75 ( doubled ) , Diabetes , Stroke (doubled)-Vascular disease , Age 65–74 , Sex category ( female ) CHADS2 : Congestive heart failure , Hypertension , Age ≥75 , Diabetes , Stroke ( doubled ) CI : confidence interval CRAFT : Controlled R and omized Atrial Fibrillation Trial CrCl : creatinine clearance DAFNE : Dronedarone Atrial FibrillatioN study after Electrical cardioversion DIONYSOS : R and omized Double blind trIal to evaluate efficacy and safety of drOnedarone ( 400 mg b.i.d . ) vs . amiodaroNe ( 600 mg q.d . for 28 daYS , then 200 mg qd thereafter ) for at least 6 mOnths for the maintenance of Sinus rhythm in patients with atrial fibrillation EAST : Early treatment of Atrial fibrillation for Stroke prevention Trial EHRA : European Heart Rhythm Association ECG : electrocardiogram EMA : European Medicines Agency ERATO : Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation EURIDIS : EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maIntenance of Sinus rhythm FAST : atrial Fibrillation catheter Ablation vs . Surgical ablation Treatment FDA : Food and Drug Administration Flec-SL : Flecainide Short-Long trial HAS-BLED : Hypertension , Abnormal renal/liver function , Stroke , Bleeding history or predisposition , Labile INR , Elderly , Drugs/alcohol concomitantly HF-PEF : heart failure with preserved ejection fraction HF-REF : heart failure with reduced ejection fraction HR : hazard ratio HRS : Heart Rhythm Society ICH : intracranial haemorrhage INR : international normalized ratio i.v . : intravenous J-RHYTHM : Japanese RHYTHM management trial for atrial fibrillation LAA : left atrial appendage LoE : level of evidence LVEF : left ventricular ejection fraction MANTRA-PAF : Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation NICE : National Institute for Health and Clinical Excellence NOAC : novel oral anticoagulant NSAID : non-steroidal anti-inflammatory drug NYHA : New York Heart Association OAC : oral anticoagulant or oral anticoagulation o.d . : omni die ( every day ) PALLAS : Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of st and ard therapy PCI : percutaneous coronary intervention PREVAIL : Prospect i ve R and omized EVAluation of the LAA closure device In patients with atrial fibrillation v s. Long-term warfarin therapy PROTECT AF : WATCHMAN LAA system for embolic PROTECTion in patients with Atrial Fibrillation PT : prothrombin time RAAFT : Radio frequency Ablation Atrial Fibrillation Trial RE-LY : R and omized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate ROCKET-AF : Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in atrial fibrillation RRR : relative risk reduction TE : thromboembolism TIA : transient ischaemic attack t.i.d . : ter in die ( three times daily ) TOE : transoesophageal echocardiogram TTR : time in therapeutic range VKA : vitamin K antagonist Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition , taking into account the impact on Background The optimal antithrombotic treatment after percutaneous coronary intervention ( PCI ) with stenting in patients with atrial fibrillation ( AF ) is unknown . In the ENGAGE AF‐TIMI 48 trial , edoxaban was noninferior to a vitamin K antagonist ( VKA ) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF . The effects of edoxaban in combination with single‐ or dual‐antiplatelet therapy in the setting of PCI are unexplored . Design The ENTRUST‐AF PCI trial is a multinational , multicenter , r and omized , open‐label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF . Patients are r and omized between 4 hours and 5 days after successful PCI to either an edoxaban‐based strategy ( experimental arm ; 60 mg [ or 30 mg according to dose reduction criteria ] once daily plus a P2Y12 antagonist [ default clopidogrel , 75 mg once daily ] for 12 months ) or a VKA‐based strategy ( control arm ; VKA plus a P2Y12 antagonist [ as above ] plus acetylsalicylic acid [ 100 mg once daily ] for 30 days to 12 months ) . The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis – defined major or clinical ly relevant nonmajor bleeding . The main efficacy end point is the composite of cardiovascular death , stroke , systemic embolic events , spontaneous myocardial infa rct ion , and definite stent thrombosis . Summary The ENTRUST‐AF PCI trial tests the hypothesis that an edoxaban‐based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual‐antiplatelet therapy in patients with AF in need of oral anticoagulation . The relative risk of ischemic events between groups will be compared Atrial fibrillation ( AF ) is the commonest sustained cardiac arrhythmia , whose importance has been realised given its strong association with stroke and systemic embolism that can be significantly reduced by oral anticoagulation . Until recently , the only oral anticoagulant ( OAC ) available was the vitamin K antagonist ( VKA ) class of drugs — for example , warfarin . Indeed , warfarin provides highly effective prophylaxis against thromboembolism as shown by extensive evidence from r and omised controlled trials , but its effectiveness is dependent upon good anticoagulation control ( as reflected by its high length of time in the therapeutic range).1 The risk of stroke in AF is not homogeneous , and depends upon the presence or absence of several risk factors . These risk factors have been used to formulate stroke risk stratification schemes , so that the focus has been to identify ‘ high-risk ’ patients who could be targeted for this ‘ inconvenient ’ drug , warfarin . The numerous practical limitations which affect a clinician 's willingness to prescribe warfarin , and a patient 's willingness to comply with it ( box 1 ) , have result ed in large numbers of high-risk patients either unprotected against stroke or suboptimally protected with antiplatelet therapy2—despite evidence that aspirin is less effective for stroke prevention and is not without its own bleeding risk , especially in the elderly.3 Box 1 # # # Limitations of warfarin The limitations of warfarin have driven efforts to establish new OACs which can circumvent the shortcomings of the VKAs . The new OACs fall into two classes : the oral direct thrombin inhibitors ( eg , dabigatran ) and the oral factor Xa inhibitors ( eg . rivaroxaban , apixaban).4 The National Institute for Health A number of r and omized controlled trials in atrial fibrillation ( AF ) conducted in the last century showed that vitamin K antagonists , ( VKAs ) , principally warfarin , were remarkably effective in stroke prevention , reducing stroke by 64 % and all-cause mortality by 26 % , figures rarely matched in treatments of other diseases . With the introduction of the non-VKA anticoagulants ( NOACs ) in the last 8 years , stroke reduction in the r and omized trials was similar to VKAs , but with less intracranial haemorrhage and a further 1 % absolute risk reduction in total mortality ; results confirmed in many ‘ real-life ’ studies using administrative or registry data . Many guidelines , including the first joint AHA/ACC/ESC guideline in 2001 , recommended oral anticoagulant ( OAC ) therapy for those with AF at elevated risk of stroke , as have subsequent joint and ESC guidelines and up date s in 2006 , 2010 , 2012 , and 2016 . But OAC uptake has been less than ideal for some time , hovering in the UK at 50 % of those for whom OAC was guideline recommended , in the 10 years from 2001 to 2011 . The data from the Swedish RIKS registry of > 94 000 strokes help identify the two major gaps in prevention of AF-related strokes , which represent 33 % of all ischaemic strokes ( Take home figure ) . In 9 % of all strokes , AF was not known prior to stroke : prevention would require screening to detect and treat unknown AF . In another 20 % , AF was known but patients were either on no antithrombotic therapy ( 8 % ) or on antiplatelet therapy alone ( 12 % ) , which is largely ineffective for AF thrombo-prophylaxis . Thus , up to 20 % of ischaemic strokes might be prevented if the evidence – practice gap of OAC prescription was eliminated . It is therefore very pleasing to see in this issue of the European Heart Journal that in the UK ,  OAC use in patients with elevated stroke risk  has increased from < 50 % to almost 80 % in the 10 years from 2006 to 2016 , mostly in the latter 5 years , while  antiplatelet therapy  has reduced from 43 % to 16 % . This is a great success story , observed to some degree in many countries , but by no means uniformly , even within the same country . Trying to pinpoint the reason for this improvement is not easy . Success has many fathers , while failure is an orphan . Cowan and colleagues postulate that successive ESC and NICE guidelines , quality improvement incentivization programmes such as GRASP and QOF , or licensing and marketing of NOACs , accentuating their ease of use , could all have played a role , but it is difficult to determine which is the major one . ESC guidelines and their up date s were recommending OAC in 2001 , 2006 , and 2010 , and the GRASP quality initiative from 2009 , with little change in OAC uptake , while QOF did not commence until 2012 . It is instructive to look at our own UK data using a higher resolution temporal trend of OAC initiation within 90 days of incident AF ( Figure 1 ) . The graph plots total OAC initiations for patients with CHA2DS2-VASc > _ 2 . A rise in VKA OAC prescription was observed from early 2011 , when limited marketing preceded the availability of NOAC drugs , followed by an accentuated increase due to NOAC prescription accompanied by a plateau in VKA prescription . It is quite likely that at this time point , the availability and marketing of NOACs played a dominant role , with this influence increasing as additional NOACs became available . The final increase from 2013 to 2106 is probably a combination of all three factors : an effective national QOF quality framework , gradual percolation of guidelines and up date s , and continued marketing of NOACs . Ensuring that a high proportion of patients with AF are taking effective doses of OAC rather than aspirin requires first that OAC is offered by the physician and accepted by the patient , secondly that patients are adherent to taking the drugs as prescribed , achieving > 70 % time in the therapeutic international normalized ratio ( INR ) range for VKAs , and finally , that patients persist with taking  OAC therapy long-term . There is a high non-persistence rate for OAC in the first 2 years after initiation , significantly greater for VKAs than BACKGROUND Atrial fibrillation ( AF ) is the most common sustained cardiac arrhythmia and it is associated with an increased stroke risk , due mainly to cardiac embolism from the left atrial appendage ( LAA ) . Percutaneous LAA closure is a method to reduce stroke risk in AF without using anticoagulant agents . In this study we report data from an Italian experience with the LAA occluder Amplatzer Cardiac Plug ( ACP ) device ( Aga Medical Corporation , Plymouth , MN , USA ) . METHODS The study was design ed to evaluate the safety of LAA closure using ACP and the efficacy of the procedure in preventing strokes during a 1-year follow-up . Patients with permanent or paroxysmal AF , high stroke risk , and contraindication to warfarin therapy were selected for the procedure . RESULTS The LAA closure was attempted in 37 patients and succeeded in 34 cases ( 91.9 % ) . Four patients experienced serious complications ( one cardiac tamponade requiring pericardiocentesis , two device embolizations , one low-rate response AF requiring artificial pacing ) . During a 1-year follow-up , ischemic stroke occurred in one of 34 patients , result ing in a stroke rate of 2.94 % ; thus there was a stroke rate reduction of 50.2 % and 26.5 % compared to the expected stroke rate , according to CHADS2 and CHA2 DS2 VASc score . None of the patients who received ACP experienced major bleeding during the follow-up . CONCLUSION LAA closure using ACP is a relatively feasible procedure which can be performed by highly experienced operators to reduce stroke rate in patients with AF , high stroke risk , and contraindication to oral anticoagulants Aim Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation ( AF ) . We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation . Methods and results Patients r and omized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ( ROCKET-AF ) trial ( n = 14 264 ) were grouped by baseline AF category : paroxysmal or persistent . Multivariable adjustment was performed to compare thrombo-embolic events , bleeding , and death between groups , in high-risk subgroups , and across treatment assignment ( rivaroxaban or warfarin ) . Of 14 062 patients , 11 548 ( 82 % ) had persistent AF and 2514 ( 18 % ) had paroxysmal AF . Patients with persistent AF were marginally older ( 73 vs. 72 , P = 0.03 ) , less likely female ( 39 vs. 45 % , P < 0.0001 ) , and more likely to have previously used vitamin K antagonists ( 64 vs. 56 % , P < 0.0001 ) compared with patients with paroxysmal AF . In patients r and omized to warfarin , time in therapeutic range was similar ( 58 vs. 57 % , P = 0.94 ) . Patients with persistent AF had higher adjusted rates of stroke or systemic embolism ( 2.18 vs. 1.73 events per 100-patient-years , P = 0.048 ) and all-cause mortality ( 4.78 vs. 3.52 , P = 0.006 ) . Rates of major bleeding were similar ( 3.55 vs. 3.31 , P = 0.77 ) . Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment ( rivaroxaban vs. warfarin , Pinteraction = 0.6 ) . Conclusion In patients with AF at moderate-to-high risk of stroke receiving anticoagulation , those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF Background — Dabigatran , an oral thrombin inhibitor , and rivaroxaban and apixaban , oral factor Xa inhibitors , have been found to be safe and effective in reducing stroke risk in patients with atrial fibrillation . We sought to compare the efficacy and safety of the 3 new agents based on data from their published warfarin-controlled r and omized trials , using the method of adjusted indirect comparisons . Methods and Results — We included findings from 44 535 patients enrolled in 3 trials of the efficacy of dabigatran  ( R and omized Evaluation of Long-Term Anticoagulation Therapy [ RELY ] ) , apixaban ( Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ ARISTOTLE ] ) , and rivaroxaban ( Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ ROCKET-AF ] ) , each compared with warfarin . The primary efficacy end point was stroke or systemic embolism ; the safety end point we studied was major hemorrhage . To address a lack of comparability between trial population s caused by the restriction of ROCKET-AF to high-risk patients , we conducted a subgroup analysis in patients with a CHADS2 score ≥3 . We found no statistically significant efficacy differences among the 3 drugs , although apixaban and dabigatran were numerically superior to rivaroxaban . Apixaban produced significantly fewer major hemorrhages than dabigatran and rivaroxaban . Conclusions — An indirect comparison of new anticoagulants based on existing trial data indicates that in patients with a CHADS2 score ≥3  dabigatran 150 mg , apixaban 5 mg , and rivaroxaban 20 mg result ed in statistically similar rates of stroke and systemic embolism , but apixaban had a lower risk of major hemorrhage compared with dabigatran and rivaroxaban . Until head-to-head trials or large-scale observational studies that reflect routine use of these agents are available , such adjusted indirect comparisons based on trial data are one tool to guide initial therapeutic choices Aims The r and omized PROTECT AF trial demonstrated non-inferiority of left atrial appendage ( LAA ) closure to oral anticoagulation with warfarin . Current guidelines give a class IIb recommendation for LAA closure . We evaluated the efficacy and safety of LAA closure in a consecutive series of non-valvular atrial fibrillation patients with contraindications to long-term oral anticoagulation or at high bleeding risk . Methods and results 101 consecutive non-valvular atrial fibrillation patients ( age 74.7 ± 7.5 years ) at high risk for stroke ( CHA2DS2-VASc Score 4.4 ± 1.6 ) and high bleeding risk ( HAS-BLED Score 4.2 ± 1.3 ) received LAA closure with either the Watchman closure device ( n = 38 ) or the Amplatzer cardiac plug ( n = 63 ) . Dual antiplatelet therapy with aspirin and clopidogrel was recommended for 3–6 months after device implantation , followed by long-term antiplatelet therapy with aspirin . No anticoagulation was given after device implantation . Mean follow-up was 400 days . One patient ( 1 % ) experienced a transient ischemic attack , and two patients ( 2 % ) suffered from ischemic stroke . While on recommended antiplatelet therapy , bleeding occurred in 12/101 patients ( 12 % ) . Bleeding was significantly reduced with 3 compared with 6 months dual antiplatelet therapy ( 3.0 vs. 16.2 % , p < 0.05 ) while ischemic or thrombotic events were similar . Conclusion Left atrial appendage closure in patients with non-valvular atrial fibrillation and high risk for stroke and bleeding events effectively prevented stroke and reduced cerebral ischemic events compared to expected stroke rate according to CHA2DS2-VASc Score . Dual antiplatelet therapy for 3 months reduced the rate of bleeding events compared to 6 months therapy with no increase of thrombotic events Atrial fibrillation and atrial flutter are common cardiac arrhythmias associated with an increased risk of stroke in patients with additional risk factors .  Anticoagulation ameliorates stroke risk , but because these arrhythmias may occur intermittently without symptoms , initiation of prophylactic therapy is often delayed until electrocardiographic documentation is obtained . The IMPACT study is a multicenter , r and omized trial of remote surveillance technology in patients with implanted dual-chamber cardiac resynchronization therapy defibrillator ( CRT-D ) devices design ed to test the hypothesis that initiation and withdrawal of oral anticoagulant therapy guided by continuous ambulatory monitoring of the atrial electrogram improve clinical outcomes by reducing the combined rate of stroke , systemic embolism , and major bleeding compared with conventional clinical management . For those in the intervention group , early detection of atrial high-rate episodes ( AHRE ) generates an automatic alert to initiate anticoagulation based on patient-specific stroke risk stratification . Subsequently , freedom from AHRE for predefined periods prompts withdrawal of anticoagulation to avoid bleeding . Patients in the control arm are managed conventionally , the anticoagulation decision prompted by incidental detection of atrial fibrillation or atrial flutter during routine clinical follow-up . The results will help define the clinical utility of wireless remote cardiac rhythm surveillance and help establish the critical threshold of AHRE burden warranting anticoagulant therapy in patients at risk of stroke . In this report , we describe the study design and baseline demographic and clinical features of the initial cohort ( 227 patients ) BACKGROUND The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation ( GLORIA-AF ) was design ed to provide prospect ively collected information on patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke , with the aim of addressing treatment patterns and questions of effectiveness and safety . METHODS AND RESULTS In this predefined analysis from GLORIA-AF , the baseline characteristics and initial antithrombotic management of the first 10,000 patients in Phase II of this large Registry Program are presented . Overall , 32.3 % of patients received vitamin K antagonists ( VKAs ) and 47.7 % received non-VKA oral anticoagulants ( NOACs ) , while 12.3 % received antiplatelet treatment and 7.6 % did not receive any antithrombotic treatment . Among patients with CHA2DS2-VASc score ≥2 , 6.7 % received no antithrombotic treatment and 10.0 % received aspirin . In Europe , treatment with dabigatran was as common as treatment with VKAs ( 38.8 % and 37.8 % , respectively ) . More than half of the patients were treated with NOACs ( 52.4 % ) , while antiplatelet treatment was given to 5.7 % , and 4.1 % did not receive any antithrombotic treatment . In North America , treatment with dabigatran  ( 25.0 % ) was as common as with VKAs ( 26.1 % ) , but overall NOAC use was more common ( 52.1 % ) than with VKAs ( 26.1 % ) ; however , 14.1 % received antiplatelet treatment , while 7.6 % received no antithrombotic treatment . In Asia , treatment with VKAs ( 31.9 % ) was more prevalent than NOACs ( 25.5 % ) , but antiplatelet treatment was given to 25.8 % , and 16.9 % did not receive any antithrombotic treatment . In Asia , only 60.7 % of patients with high stroke risk received oral anticoagulants ( OACs ) . Paroxysmal atrial fibrillation and minimally symptomatic ( or asymptomatic ) patients were often undertreated with OACs . CONCLUSION In this analysis , OAC use was high in Europe and North America , with overall NOAC use higher than VKA use . A considerable percentage of high-risk patients in North America still received antiplatelet treatment or were untreated , while Asian patients had a high proportion of aspirin use and nontreatment Background : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia sustained and frequently occurs in patients with coronary heart disease . Thus , a large number of patients requiring percutaneous coronary intervention ( PCI  ) also suffer from AF . An anticoagulant regimen has not been st and ardized for patients with AF after coronary stent implantation . Patients and Methods : The authors investigated data from 159 patients with AF who underwent PCI in their department . Baseline variables and incidence of a combined endpoint ( stroke , myocardial infa rct ion , cardiovascular death , severe bleeding ) were compared in patients receiving clopidogrel and acetylsalicylic acid ( ASA ; group 1 ) versus patients receiving the combination of clopidogrel and ASA with low-molecular-weight heparin ( LMWH ; group 2 ) versus patients receiving the combination of clopidogrel and ASA with oral anticoagulation ( OAC ; group 3 )  at discharge . Results : Patients discharged with triple therapy including OAC seemed to be at higher risk : patients in group 3 had decreased left ventricular ejection fraction and increased inflammatory state as measured by plasma fibrinogen and C-reactive protein . Moreover , previous OAC treatment and strokes were found more often in this subgroup of patients . In a median follow-up of 1.4 years , two severe bleeding events ( both in group 1 ) , four myocardial infa rct ions ( all in group 1 ) , 13 strokes ( nine in group 1 , four in group 2 ) , and nine cardiovascular deaths ( three in group 1 , five in group 2 , one in group 3 ) occurred . Conclusion : In this analysis , no treatment regimen seemed to be clearly superior . It underlines the importance of prospect i ve , r and omized trials to investigate the optimal antithrombotic/antiplatelet treatment for patients with AF after PCI.ZusammenfassungHintergrund : Vorhofflimmern ( VHF ) ist die häufigste Herzrhythmusstörung und wichtige Komorbidität bei Patienten mit koronarer Herzkrankheit . Welche antithrombotische/antithrombozytäre Therapiestrategie bei Patienten mit Vorhofflimmern nach perkutaner Koronarintervention ( PCI ) verfolgt werden sollte , ist aktuell nicht eindeutig zu beantworten . Patienten und Method ik : Die Autoren identifizierten retrospektiv 159 Patienten mit VHF , die in ihrer Abteilung in den Jahren 1999–2004 eine PCI erhalten hatten . Die Grunderkrankungen und die Inzidenz eines kombinierten Endpunkts ( Schlaganfall , Myokardinfarkt , kardiovaskulär bedingter Tod , schwere Blutung ) wurden bei Patienten verglichen , die Clopidogrel und Acetylsalicylsäure ( ASS ; Gruppe 1 ) , Clopidogrel und ASS in Kombination mit niedermolekularem Heparin ( Gruppe 2 ) sowie Clopidogrel und ASS und zusätzlich orale Antikoagulation erhalten hatten ( Gruppe 3).Ergebnisse : Die Grunderkrankungen der Patienten in den drei Gruppen waren nicht signifikant unterschiedlich . In einem medianen Beobachtungszeitraum von 1,4 Jahren konnten zwei schwere Blutungen ( in Gruppe 1 ) , vier Myokardinfarkte ( in Gruppe 1 ) , 13 Schlaganfälle ( neun in Gruppe 1 , vier in Gruppe 2 ) und neun kardiovaskulär bedingte Todesfälle ( drei in Gruppe 1 , fünf in Gruppe 2 , einer in Gruppe 3 ) nachgewiesen werden . Schlussfolgerung : In dieser Untersuchung erwies sich keine Therapiestrategie einer and eren gegenüber als eindeutig überlegen . Die erhobenen Date n zeigen , wie wichtig es ist , prospektive , r and omisierte Studien bezüglich der antithrombotischen/antithrombozytären Therapie durchzuführen , um Patienten mit AF nach PCI optimal beh and eln zu können The PIONEER AF-PCI trial ( Open-Label , R and omized , Controlled , Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with AF who Undergo Percutaneous Coronary Intervention ) is an ambitious , open-label comparison of 3 regimens , almost exclusively in Caucasians , all of whom had coexisting atrial fibrillation and atherosclerotic coronary artery disease requiring stenting ( PCI-S ) . These 2 conditions when they coexist pose a clinical challenge , necessitating concurrent usage of dual antiplatelet and anticoagulation therapy , a cocktail which presents major bleeding risks . Because anticoagulation therapy is suboptimal in preventing stent thrombosis and dual anti platelet therapy is inadequate in averting embolic stroke in atrial fibrillation , neither treatment is sufficient and they must be combined . The study has a unique design and consists of 2 treatment arms and a control ( see Figure 1 for trial design ) , each with about 700 patients and a 20 % dropout rate in groups 1 and 2 but a statistically greater rate of 29 % in group 3 . Both treatment arms are modeled upon previous studies , which involved patients with the need for both antiplatelet therapy and anticoagulation ( see Figure 2 for derivation of trial from WOEST and ATLAS-TIMI 51 ) . The control arm , design ated group 3 in the trial , consists of the US st and ard of practice regimen , in this situation , called “ triple therapy , ” consisting of aspirin 100 mg/d , clopidogrel 75 mg/d , and warfarin maintaining the INR between 2 and 3 . About 7 % of patients in groups 1 and 2 received a different P2Y12 inhibitor , either prasugrel or ticagrelor , and about 4 % in group 3 . Prominent among the numerous exclusions were patients with a previous stroke and a creatinine clearance of under 30 mL/min . In arm 1 , patients with a creatinine clearance between 30 and 60 mL/min received a lower dose of 10 mg of rivaroxaban . The first treatment arm , called arm 1 , is a reprisal of the treatment arm of the Belgian 2013 WOEST trial which showed that clopidogrel 75 mg and warfarin , maintaining an INR of 2 to 3 , were associated with less combined TIMI major and minor bleeding as well as no increase in cardiac or neurological thrombotic complications when compared to the same control arm as is in this study . Despite having studied only 573 patients for just a year , WOEST was influential in generating the recommendation ( level B ) from the European Society of Cardiology to use this regimen in some people at high risk for bleeding with stents who also require anticoagulation . Furthermore in PIONEER , arm 1 , rivaroxaban 15 mg has been substituted for warfarin ; otherwise , the other trial drugs are identical to those in WOEST . A compelling question posed by this arm of the study , although not the primary end point of the study , is whether equivalent stent patency or prevention of atherosclerotic or thromboembolic complications can be achieved with only a single antiplatelet drug throughout the entire 12 months of treatment , including the vital first month poststent . Also addressed is whether the WOEST results can be replicated substituting rivaroxaban , a drug that offers several advantages over warfarin . In treatment group 1 , one would intuitively expect confirmation of the bleeding advantage observed in WOEST , since it contains 2 drugs versus the 3 in the control group , and therefore would be expected to be associated with less bleeding in group 1 versus group 3 . The second treatment group is based on the 2012 ATLAS ACS 2-TIMI 51 trial and consists of very-low-dose rivaroxaban 2.5 mg twice a day along with clopidogrel 75 mg/d and aspirin 100 mg/d . An interesting point of arm 2 versus 3 , although again not the primary end point , is if a dosage of rivaroxaban , which is only 25 % of the FDA -approved dose of that needed to treat atrial fibrillation , would be adequate in preventing embolic strokes . One would anticipate in group 2 that the dual antiplatelet therapy would be equally effective in preventing stent occlusion and recurrent coronary events as the BACKGROUND At the end of 2 previous trials , an excess of stroke and bleeding was observed in patients with AF r and omized to a new oral anticoagulant ( NOAC ) who transitioned to a vitamin K antagonist ( VKA ) .  OBJECTIVES The ENGAGE AF-TIMI 48 ( Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infa rct ion 48 ) trial compared once-daily edoxaban to warfarin for stroke prevention in patients with AF . An end-of-trial transition plan was developed to minimize the risks of stroke due to inadequate anticoagulation and bleeding from excessive anticoagulation during this critical period . METHODS All patients on the blinded study drug at the trial 's conclusion were included in this analysis . In pre-specified analyses , stroke , bleeding , and death that occurred through 30 days after the end-of-trial visit were stratified by r and omized treatment allocation and open-label anticoagulant selected post-trial . RESULTS Of the 13,642 patients taking the blinded study drug at the end of the trial , 9,304 ( 68.2 % ) were transitioned to open-label VKA and 4,258 patients ( 31.2 % ) to an NOAC . There were 21 strokes evenly distributed across the 3 r and omized treatment arms : warfarin 7 ( 1.90%/year ) , edoxaban high dose 7 ( 1.89%/year ) , edoxaban low dose 7 ( 1.85%/year ) . Major bleeding was also similar across the 3 treatment arms : warfarin 11 ( 2.98%/year ) , edoxaban high dose 10 ( 2.69%/year ) , edoxaban low dose 18 ( 4.76%/year ) . In patients transitioned to VKA , 85 % of patients had at least 1 INR ≥ 2 by day 14 after the transition and 99 % by day 30 . CONCLUSIONS The ENGAGE AF-TIMI 48 transition plan protected patients from an excess of thrombotic and bleeding events and should be helpful in clinical practice when patients are transitioned between oral anticoagulants . ( Global Study to Assess the Safety and Effectiveness of Edoxaban [ DU-176b ] vs St and ard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ EngageAFTIMI48 ] ; NCT00781391 ) The risk for ischemic stroke in patients with atrial fibrillation is related to underlying structural heart disease [ 1 - 3 ] . Although most strokes are believed to arise from embolism of left atrial thrombi [ 4 , 5 ] , other mechanisms may contribute . Transesophageal echocardiography ( TEE ) provides a unique diagnostic window for evaluating the left atrium , left atrial appendage , and thoracic aorta , but the manner in which specific TEE findings in patients with atrial fibrillation correlate with thromboembolic risk and response to therapy has not been fully established [ 6 - 13 ] . We performed TEE in patients with nonvalvular atrial fibrillation who were at high intrinsic risk for thromboembolism and were participating in the Stroke Prevention in Atrial Fibrillation ( SPAF-III ) study , a r and omized clinical trial . In that study , adjusted-dose warfarin ( target international normalized ratio [ INR ] , 2 to 3 ) was compared with combination therapy consisting of low-intensity warfarin ( INR , 1.2 to 1.5 ) plus aspirin , 325 mg/d . The trial was stopped after an interim analysis indicated that the efficacy of adjusted-dose warfarin therapy was superior to that of combination therapy . Low anticoagulation intensity in the combination therapy group yielded high stroke rates that were similar to those expected during treatment with aspirin alone [ 14 , 15 ] . In the current analysis , we 1 ) correlate TEE observations among patients with atrial fibrillation at high risk for thromboembolism with rate of subsequent stroke and 2 ) compare treatment responses . Methods Patients Patients were recruited from the SPAF-III multicenter trial , which was design ed to compare two antithrombotic medication regimens for prevention of ischemic stroke and systemic embolism ( primary events ) . The study , whose design is described else-where in detail [ 14 ] , involved patients with nonvalvular atrial fibrillation who were stratified for risk on the basis of clinical and transthoracic echocardiographic criteria derived from previous analyses [ 15 ] . Women older than 75 years of age and patients of any age and either sex with systolic hypertension ( systolic blood pressure > 160 mm Hg ) , previous thromboembolism , or impaired left ventricular function ( M-mode echocardiographic fractional shortening of 0.25 or recent clinical congestive heart failure ) were r and omly assigned to receive adjusted-dose warfarin ( target INR , 2.0 to 3.0 ) or a combination of low-intensity warfarin ( 0.5 to 3.0 mg/d ; dose was initially adjusted to cause deviation of the INR to 1.2 to 1.5 and was then fixed ) and aspirin . Seventy-three percent of the patients were receiving warfarin at various dose intensities before trial entry ; these patients were equally distributed between assigned treatment groups . Antithrombotic treatment was assigned before performance of TEE and was not influenced by TEE findings . Patients were followed monthly by telephone and in clinic every 3 months , and a st and ard question naire on stroke symptoms was administered annually . All patients whose responses to the question naire suggested the occurrence of stroke were referred for clinical examination by a local affiliated neurologist who was blinded to treatment , and all events were adjudicated by a blinded event verification committee [ 14 ] . This project was design ed to supplement the SPAF-III clinical trial on the basis of the hypothesis that spontaneous echocardiographic contrast detected by TEE identifies patients at high risk for thromboembolism for whom adjusted-dose warfarin  would prove superior to  combination therapy . All participants in the parent study were encouraged , but not required , to provide separate , written informed consent for TEE after r and om assignment to antithrombotic treatment . This was done to prevent the results of TEE from influencing recruitment of patients into the trial or from altering treatment . The intended sample size of 412 TEE examinations was selected to detect an absolute difference in event rates of 3.9 % per year ( based on projected event rates of 5.4 % per year in patients with spontaneous echocardiographic contrast and 1.5 % per year in patients without contrast ) over a mean observation period of 2.5 years . Secondary objectives were to correlate clinical thromboembolic events with function of the left atrial appendage , thrombus of the left atrium and left atrial appendage , and atherosclerotic lesions in the thoracic aorta imaged by TEE . Transesophageal Echocardiography Transesophageal echocardiography was performed within 3 months of enrollment with patients under light sedation and topical anesthesia , according to specific protocol s for acquisition and interpretation [ 16 ] . Commercially available ultrasonography equipment incorporated biplane or multiplane transducers with at least 48 crystals operating at a st and ard frequency of 5 MHz with gray-scale imaging . Signal processing , log compression , and persistence values were established for each manufacturer . Images were interpreted locally , and data were entered into st and ardized forms by echocardiographers who were blinded to antithrombotic treatment assignment but not to patient demographic or clinical features . Original videotaped recordings were collected in a central echocardiographic registry for validation and quality control . To assure generalizability of the results to laboratories used in clinical practice , the analyses reported here are based on image interpretation at the local laboratories . The following features were specifically assessed : left atrial appendage size , peak ante grade ( emptying ) velocity of blood flow in the left atrial appendage , spontaneous echocardiographic contrast in the left atrium or left atrial appendage , thrombus of the left atrium or left atrial appendage , and atherosclerotic disease of the thoracic aorta . Spontaneous echocardiographic contrast was defined as a pattern of slowly swirling intracavitary echodensities imaged with gain setting s adjusted to distinguish background noise . Contrast was classified as faint when visualized intermittently during the cardiac cycle or when enhanced gain setting s were required for detection and was classified as dense when continuously present at st and ard gain . Aortic plaque was classified by location and as either simple or complex according to mobility , ulceration , pedunculation , or thickness greater than 4 mm [ 16 ] . We postulated that reduced emptying velocity from the left atrial appendage , which reflects stasis , would be associated with dense spontaneous echocardiographic contrast and thrombus formation , whereas complex aortic plaque would be a consequence of atherosclerotic vascular abnormality . We also postulated that these findings would predispose patients to ischemic stroke through separate pathogenic mechanisms . Statistical Analysis The analyses reported here were limited to variables accessible only by TEE and were hypothesized a priori to have potential predictive relations to clinical thromboembolism . Baseline comparisons between groups were done by using the chi-square test for categorical data and the Student t-test for continuous variables . The Cox proportional-hazards regression model was used to estimate the univariate relative risk associated with TEE characteristics . The primary analysis compared rates of cerebral ischemic events and systemic embolism among patients who had dense spontaneous echocardiographic contrast detected in the left atrium or left atrial appendage with rates in patients who did not have dense contrast ; the log-rank statistic was used to compare the times to events between these groups . Secondary analyses , conducted similarly , compared event rates in groups that were identified by left atrial appendage size , flow velocity , thrombus , and aortic plaque . For these comparisons , the area of the left atrial appendage was dichotomized at the upper quartile ; flow velocity was dichotomized at the lower quartile . When interaction was seen between treatment and TEE characteristics , analysis of the relation of TEE findings to events was confined to the combination therapy group and treatment effect was described separately ; when no interaction was seen , the analysis was stratified by therapy . The relative reduction in event rate associated with adjusted-dose warfarin therapy was computed as the difference between unity and the rate ratio determined by a Poisson regression model [ 17 ] . A Cox proportional-hazards regression model was fit to confirm the independence of TEE characteristics identified as univariate thromboembolic risk factors . Confidence intervals for event rates were calculated by using a Poisson regression model ; tests of significance were two-sided and were not adjusted for multiple comparisons . All analyses were done according to the intention-to-treat principle . Results Of 1044 high-risk patients with atrial fibrillation enrolled in the r and omized trial , 382 ( 37 % ) volunteered for TEE ( range , 10 % to 80 % of SPAF-III participants recruited at 18 clinical centers offering TEE ) . Salient features of these 382 patients were similar to those of the 662 participants who did not undergo transesophageal imaging ( Table 1 ) . The mean patient age was 71 years , 36 % of patients had clinical ischemic heart disease , and almost half had a history of congestive heart failure . Balanced proportions of patients were assigned to therapy with adjusted-dose warfarin ( n = 190 ) or fixed-dose warfarin and aspirin ( n = 192 ) . Time from r and om assignment of treatment to TEE was similar in the two groups ( mean , 23 days ) . The trial was stopped after a mean observation period of 1.1 years because an interim analysis indicated the lack of efficacy of the combination regimen [ 18 ] . Up to that point , 23 primary events ( all of which were ischemic strokes ) occurred in the subset of participants who had undergone TEE ( event rate , 3.1 % per year in patients assigned to adjusted-dose warfarin compared with 7.8 % per year in those assigned to combination therapy ; P = 0.04 ) .
Warfarin Versus Thrombin Inhibitor ( Dabigatran ) The RE-LY trial ( 9 , 18 ) showed that treatment with dabigatran , 150 mg , is superior to warfarin in reducing the incidence of the composite outcome of stroke or systemic embolism .
No statistically significant difference was observed between the 2 therapies with regard to major bleeding , myocardial infa rct ion , or
Atrial fibrillation ( AF ) is characterized by uncoordinated atrial activation with consequent deterioration of mechanical function ( 1 ) .
It is the most common sustained cardiac arrhythmia , and according to estimates , 12.1 million Americans will have AF by 2050 ( 2 ) .
Patients with AF have increased risk for embolic stroke , heart failure , and cognitive impairment ; reduced quality of life ; and higher overall mortality ( 35 ) .
Strokes related to AF have been characterized as more severe ( 6 , 7 ) and translate to a substantial economic burden , costing Medicare approximately $ 8 billion annually ( 8) .
Antithrombotic therapies are the mainstays for preventing thromboembolic events in patients with AF .
Oral anticoagulation with vitamin K antagonists ( VKAs ) has long been the gold st and ard therapy for stroke prevention in these patients .
However , the challenges of monitoring VKA therapy and the many associated food and drug interactions have fueled the development of novel therapeutic options .
Currently , 4 direct-acting oral anticoagulants ( DOACs ) are approved for stroke prevention in patients with nonvalvular AF : the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban , rivaroxaban , and edoxaban .
In addition , procedural interventions , such as left atrial appendage ( LAA ) occlusion devices , are an alternative treatment for patients who are at high risk for bleeding while receiving anticoagulation therapy .
This systematic review up date s previous review s ( 13 ) and aims to compare the effectiveness of the available medical and procedural therapies in preventing thromboembolic events and bleeding complications in patients with AF .