Discontinue lisinopril and initiate sacubitril/valsartan.

75-year-old woman with a history of heart failure with an ejection fraction of 25% who comes for a check-up, being stable in NYHA functional class III. She has an implanted cardioverter defibrillator. Current medication consists of lisinopril, carvedilol and spironolactone at maximum tolerated doses. On physical examination he has BP 118/74 mmHg, HR 78 bpm. On cardiac auscultation a third tone is detected, pulmonary auscultation is normal and there is no edema. Which of the following is the most appropriate step in his management?

Discontinue lisinopril and start sacubitril/valsartan.

Discontinue carvedilol and start ivabradine.

Update of treatment of heart failure with reduction of left ventricular ejection fraction.

Underlying and precipitating causes of heart failure (HF) with reduced left ventricular ejection fraction (HFrEF) should be identified and treated when possible. Hypertension should be treated with diuretics, angiotensin-converting enzyme (ACE) inhibitors, and β-blockers. Diuretics are the first-line drugs in the treatment of patients with HFrEF and volume overload. Angiotensin-converting enzyme inhibitors and β-blockers (carvedilol, sustained-release metoprolol succinate, or bisoprolol) should be used in treatment of HFrEF. Use an angiotensin II receptor blocker (ARB) (candesartan or valsartan) if intolerant to ACE inhibitors because of cough or angioneurotic edema. Sacubitril/valsartan may be used instead of an ACE inhibitor or ARB in patients with chronic symptomatic HFrEF class II or III to further reduce morbidity and mortality. Add an aldosterone antagonist (spironolactone or eplerenone) in selected patients with class II-IV HF who can be carefully monitored for renal function and potassium concentration. (Serum creatinine should be ≤ 2.5 mg/dl in men and ≤ 2.0 mg/dl in women. Serum potassium should be < 5.0 mEq/l). Add isosorbide dinitrate plus hydralazine in patients self-described as African Americans with class II-IV HF being treated with diuretics, ACE inhibitors, and β-blockers. Ivabradine can be used in selected patients with HFrEF.

[Ivabradine for Treatment of Heart Failure with Preserved Ejection Fraction].

Aim      To evaluate the effect of combination ivabradine-containing therapy for chronic heart failure (CHF) with preserved ejection fraction on quality of life (QoL) and the primary composite endpoint during a one-year follow-up.Material and methods  This study included 160 patients aged 45 to 65 years with NYHA functional class (FC) II-III CHF with preserved left ventricular ejection fraction (CHF-PEF) and grade I and II diastolic dysfunction associated with FC III stable angina with sinus rhythm and a heart rate (HR) higher than 70 bpm. Presence of CHF-PEF was confirmed by results of echocardiography and myocardial tissue Doppler imaging. During one year of prospective observation, effects of bisoprolol and ivabradine as a part of the combination therapy on the primary composite endpoint, including death from cardiovascular complications (CVC) and hospitalizations for myocardial infarction (MI) or CHF, were evaluated in patients with CHF-PEF. Patients were randomized to three groups: A, bisoprolol with dose titration from 2.5 to 10 mg; В, combination of bisoprolol 2.5-10 mg and ivabradine 10-15 mg/day; and С, ivabradine 10-15 mg/day. All patients were on a chronic background therapy, including angiotensin-converting enzyme inhibitors (lisinopril) or, if not tolerated, angiotensin II receptor blockers (valsartan), antiaggregants, statins (atorvastatin, rosuvastatin), and short-acting nitrates as required. If edema developed diuretics were added. The follow-up duration was one year.Results After 12 weeks of follow-up, the achievement of goal HR in group A was associated with a tendency to increased distance in the 6-min walk test from 279±19 to 341±21 m (р&gt;0,05); in group B the distance increased from 243±25 to 319±29 m (р&lt;0.05); and in group C the distance increased from 268±21 to 323±22 m (р&lt;0.05). In the combination ivabradine and bisoprolol treatment group, results of the 24-h electrocardiogram monitoring showed a more pronounced anti-ischemic effect associated with a decrease in the number of myocardial ischemic episodes (p&lt;0.05). QoL was evaluated with the Minnesota questionnaire against the background of treatment. At 12 weeks of observation, the total score decreased from 44.5±2.6 to 38.4±2.1 in group A; from 45±2.9 to 38±2.2 in group B; and from 50.9±3.2 to 42.7±2.8 in group C (р&lt;0.05). The risk of acute MI and repeated hospitalization for CHF during the year of observation, as evaluated according to the Kaplan-Meier method, decreased in both bisoprolol and ivabradine combination treatment groups.Conclusion      The inclusion of bisoprolol and ivabradine into the background therapy of CHF-PEF patients with stable IHD provided an improvement of QoL and a decrease in the risk of hospitalization for acute MI and CHF during the year of observation.

[Pharmacological therapy of heart failure with reduced ejection fraction].

Pharmacological therapy of heart failure with reduced ejection fraction Abstract. Pharmacological therapy for heart failure has made great progress over the last three decades and evidence-based therapies have significantly improved survival and quality of life. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers are the cornerstone of the heart failure therapy; indicated in virtually every patient with heart failure and reduced ejection fraction. As soon as the left ventricular ejection fraction decreases below 35 % and / or symptoms are still present (NYHA II-IV), a mineralocorticoid receptor antagonist should be added. A rather recent addition to current heart failure therapy with convincing data is the substance combination sacubitril / valsartan. It is indicated for patients with persistent symptomatic heart failure despite optimal medical therapy with ACE inhibitors or ARBs, beta-blockers, and MRAs. Crucial for all mentioned substances is to aim for the maximal tolerated dose. Various additional therapies have no proven survival benefit but are important for symptom control in everyday life. Above all the diuretics, where loop diuretics show a better effect profile compared to thiazide diuretics. Furthermore, achieving an optimal iron status (the limit to start a substitution is significantly higher than in patients without heart failure), decreasing the heart frequency with Ivabradine (if heart rate persists above 70 / min despite fully dosed betablocker) and «lifestyle changes» can add to the success of the medical treatment. The importance of digoxin has been steadily decreasing. The previously advocated therapeutic anticoagulation in patients with severely reduced LVEF is not propagated anymore. Significant arrhythmias (especially atrial fibrillation and ventricular arrhythmias) are common in advanced diseases. In addition to beta-blockers, amiodarone is clearly the antiarrhythmic drug of choice. According to latest data, an early interventional treatment of atrial fibrillation by pulmonary vein ablation may be beneficial and has the potential to reduce mortality in special subgroups of patients. New developments in the field of antidiabetic drugs seem to be promising for reduction of mortality and hospitalization in patients with heart failure.

Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations.

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional cardiac disorder impairing the ability of the ventricles to fill with or eject blood. The approach to pharmacologic treatment has become a combined preventive and symptomatic management strategy. Ideally, treatment should be initiated in patients at risk, preventing disease progression. In patients who have progressed to symptomatic left ventricular dysfunction, certain therapies have been demonstrated to improve survival, decrease hospitalizations, and reduce symptoms. The mainstay therapies are angiotensin-converting enzyme (ACE) inhibitors and beta-blockers (bisoprolol, carvedilol, and metoprolol XL/CR), with diuretics to control fluid balance. In patients who cannot tolerate ACE inhibitors because of angioedema or severe cough, valsartan can be substituted. Valsartan should not be added in patients already taking an ACE inhibitor and a beta-blocker. Spironolactone is recommended in patients who have New York Heart Association (NYHA) class III to IV symptoms despite maximal therapies with ACE inhibitors, beta-blockers, diuretics, and digoxin. Low-dose digoxin, yielding a serum concentration <1 ng/mL can be added to improve symptoms and, possibly, mortality. The combination of hydralazine and isosorbide dinitrate might be useful in patients (especially in African Americans) who cannot tolerate ACE inhibitors or valsartan because of hypotension or renal dysfunction. Calcium antagonists, with the exception of amlodipine, oral or intravenous inotropes, and vasodilators, should be avoided in HF with reduced systolic function. Amiodarone should be used only if patients have a history of sudden death, or a history of ventricular fibrillation or sustained ventricular tachycardia, and should be used in conjunction with an implantable defibrillator [corrected]. Finally, anticoagulation is recommended only in patients who have concomitant atrial fibrillation or a previous history of cerebral or systemic emboli.

Ropinirole-Associated Orthostatic Hypotension as Cause of a Prescribing Cascade in an Elderly Man.

Ropinirole is an overall well-tolerated antiparkinsonian medication that is also used to treat restless leg syndrome (RLS). The incidence of side effects is low, with orthostatic hypotension (OH) only anecdotally reported. Additionally, it is known that the elderly population is very susceptible to adverse drug effects and the prevalence of prescribing cascades that these can trigger is unknown. A 71-year-old male with history of atrial fibrillation, well-controlled diabetes on oral agents, hyperlipidemia, hypertension, ischemic heart failure status post (s/p) implantable cardioverter-defibrillator (ICD) placement with improved ejection fraction (EF), transient ischemic attack (TIA), rheumatoid arthritis, RLS, aortic stenosis s/p mechanical aortic valve replacement on anticoagulation, deep venous thrombosis (DVT), and right knee replacement, presented to the ED with generalized weakness, with difficulty standing from seated position, followed by a fall without head trauma. Over the eight months prior to this presentation, the patient had had similar symptoms that resulted in four falls, two hospital admissions, and new prescriptions of midodrine and compression stockings. On admission, vital signs were remarkable for positive orthostatics with blood pressure (BP) 110/74 mmHg, heart rate (HR) of 86 bpm in supine position and BP 87/51 mmHg, HR of 70 bpm while in standing position. Physical exam was unremarkable except for a known ejection murmur and dry oral mucous membranes. Labs included a creatinine 3.6 mg/dl, blood urea nitrogen (BUN) 66 mg/dl, international normalized ration (INR) of 4.1, B-natriuretic peptide (BNP) of 313 pg/mL, troponin <0.03 ng/mL. A kidney ultrasound was normal, and a transthoracic echocardiogram showed left ventricle ejection fraction (LVEF) of 55-65%, improved compared to a prior study. Furosemide, carvedilol and canagliflozin were discontinued and IV fluids were administered. In the subsequent days, his creatinine improved, and so did the patient's volume status, but he continued to be orthostatic despite midodrine and stockings. On further interview, the patient disclosed starting ropinirole 0.25 mg three times daily approximately 10 months prior to this admission, due to asymptomatic RLS that was reported in a sleep study. Decision was made to discontinue this medication, which resulted in improvement of symptoms. We were able to discontinue IV fluids, midodrine and stockings, and reintroduce carvedilol, furosemide and canagliflozin in a stepwise manner. In a follow-up visit one month after discharge, the patient was symptom-free. This case illustrates two major points. First, this prescribing cascade potentially induced by ropinirole, as well as the increase in health care costs associated to iatrogenic admissions, is major preventable problem faced mostly by the geriatric population. Second, although OH associated with ropinirole has only been reported in patients treated for Parkinson's disease, this side effect should be considered when prescribing ropinirole for other indications, with cautious assessment of risks and benefits. Further studies need to be conducted to establish the frequency of OH related to ropinirole.

The power of optimal medical therapy using angiotensin receptor-neprilysin inhibitor in acute decompensated heart failure, sparing a critical patient open-heart surgery with a device therapy: a case report.

Timely use of Sacubitril/Valsartan has the potential to significantly improve cardiac function and dramatically reduce secondary mitral regurgitation (MR) severity even in patients presenting with acute decompensated heart failure (HF), not only in compensated chronic HF patients. The outstanding impact of echocardiography is obvious in monitoring improvement of cardiac function and MR severity in patients with HF with reduced ejection fraction (HFrEF). We report a relevant case of an elderly patient who presented with acute decompensated HF and severe MR. He was symptomatic despite being on maximally tolerated doses of ACEI, beta-blockers, and diuretics. Left ventricular ejection fraction (LVEF) improved from 15% to 35% 2 weeks following initiation of Sacubitril/Valsartan during second HF hospitalization. There was a dramatic improvement of patient's symptoms from New York Heart Association (NYHA) Class IV to NYHA I. N-terminal pro B-type natriuretic peptide reduced from 9000 pg/mL to 800 pg/mL. Coronary angiography depicted three-vessel coronary artery disease. The patient was advised to undergo coronary artery bypass graft surgery with mitral valve repair, then followed by implantation of a cardiac resynchronization therapy-defibrillator device (CRT-D) if no LV function improvement is observed after revascularization. The electrocardiogram showed Q waves in inferior leads with QRSd ≥ 125 ms, hence a good candidate for CRT. Following an elective percutaneous coronary intervention, LVEF further improved to 50%. The patient became asymptomatic with preserved LVEF on follow-up for 18 months later. This case report documents the swift echocardiographic and symptom improvement in a decompensated end-stage HF patient when Sacubitril/Valsartan initiated during acute setting.

Sacubitril/valsartan effect on left ventricular remodeling: the case of a super-responder.

Sacubitril/valsartan has been shown to improve clinical outcomes in patients with heart failure and reduced ejection fraction (HFrEF), but its effects on left ventricular (LV) systolic function and reverse remodeling parameters remain to be established. We hereby describe the case of a 41 year old man with HFrEF and severe reduction of left ventricular ejection fraction (LVEF). The patient was first treated with triple HF therapy (beta-blocker, angiotensin converting enzyme inhibitor and mineralocorticoid antagonist), but after three months he was still symptomatic and with an LVEF firmly low. In consideration of poor response to therapy, we switched angiotensin converting enzyme inhibitor to sacubitril/valsartan to the maximum tolerated dose (49/51 mg bid) with a marked improvement in LV systolic function and reduction in LV volumes at follow-up. In light of the almost normalized LVEF the patient was also removed from the list for the implantation of a cardiac resynchronization therapy defibrillator. In conclusion, our case showed a strong beneficial effect of sacubitril/valsartan on reverse remodeling and LVEF beyond the benefits of concomitant optimal medical therapy. This result is particular noteworthy because it was obtained although the patient wasn't able to reach the full dose of the drug. Physicians should always consider this drug effect when more demanding therapeutic strategies are needed for their HF patients.

Current treatment of heart failure with reduction of left ventricular ejection fraction.

Heart failure is the commonest cause of hospitalization and of rehospitalization This review paper is a comprehensive review of current treatment of heart failure in 2016. The target of this review is all health care professionals who treat patients with heart failure. Areas covered: This article discusses stages of heart failure, treatment of heart failure with general measures, and drug therapy with diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, aldosterone antagonists, isosorbide dinitrate plus hydralazine, digoxin, other neurohormonal antagonists, sacubitril/valsartan, calcium channel blockers, and ivabradine. This article also discusses treatment of heart failure with use of cardiac resynchronization therapy, implantable cardioverter-defibrillators, and surgical therapy, and management of end-stage heart failure. This paper was written after an extensive Medline search reviewing articles written from 1970 through May, 2016. Expert commentary: Our approach as physicians must emphasize prevention of heart failure as well as treating it. Risk factors for developing heart failure, especially hypertension, must be better controlled starting in childhood. I concur with the current heart failure treatment guidelines (Tables 1 and 2 in this paper).

Left Ventricular Failure -- Treatment / Management

Treating the underlying cause is of extreme importance as some heart failure conditions may be reversible when the precipitating factors are addressed, like cardiomyopathies induced by alcohol, tachycardia or ischemia. Tight control of blood pressure will also help prevent further deterioration. [15] Besides loop diuretics for volume overload, the pharmacologic treatment differs between HFrEF and HFpEF [16] [17] [18] : -For HFrEF, the mainstay of treatment is the combination of an angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) with a beta blocker (carvedilol, metoprolol or bisoprolol). If the patient remains symptomatic on a maximal dose of ACE inhibitor or ARB, an angiotensin receptor-neprilysin inhibitor may be substituted. Other medications include hydralazine, nitrates, mineralocorticoid receptor antagonists such as spironolactone, ivabradine, and digoxin (as a last resort). Nitrates in combination with hydralazine may be especially efficacious in African American patients. Digoxin, ivabradine and the diuretics have not been shown to offer any mortality benefit.

Pharmacology_Katzung

Candesartan, valsartan, many other ARBs: Like losartan Chronic heart failure: To slow failure • many other indications in Chapter 10 Oral • duration 10–12 h • Toxicity: Bronchospasm, bradycardia, atrioventricular block, acute • Metoprolol, bisoprolol, nebivolol: Select group of b blockers that have been shown to reduce heart failure mortality •Digoxin(otherglycosides are used outside the USA) Na+/K+-ATPase inhibition results in reduced Ca2+ expulsion and increased Ca2+ stored in sarcoplasmic reticulum Increases cardiac contractility •cardiacparasympathomimeticeffect (slowed sinus heart rate, slowed atrioventricular conduction) Chronic symptomatic heart failure•rapidventricularrateinatrialfibrillation•hasnotbeen shown to reduce mortality but does reduce rehospitalization Oral,parenteral•duration36–40h•Toxicity: Nausea, vomiting,diarrhea•cardiacarrhythmias CARDIAC GLYCOSIDE Enalapril Generic, Vasotec, Vasotec I.V. Fosinopril Generic, Monopril Lisinopril Generic, Prinivil, Zestril

Sacubitril/valsartan

Research The PARADIGM-HF trial (in which Milton Packer was one of the principal investigators) compared treatment with sacubitril/valsartan to treatment with enalapril. People with heart failure and reduced LVEF (10,513) were sequentially treated on a short-term basis with enalapril and then with sacubitril/valsartan. Those that were able to tolerate both regimens (8442, 80%) were randomly assigned to long-term treatment with either enalapril or sacubitril/valsartan. Participants were mainly white (66%), male (78%), middle aged (median 63.8 +/- 11 years) with NYHA stage II (71.6%) or stage III (23.1%) heart failure.

Spironolactone -- Indications

Spironolactone has indications in both certain cardiovascular diseases and non-cardiovascular disease entities. Spironolactone is FDA approved for the treatment of heart failure with reduced ejection fraction (HFrEF), resistant hypertension, primary hyperaldosteronism, edema secondary to cirrhosis, edema secondary to a nephrotic syndrome that is not adequately controlled using alternative therapies, and hypokalemia. The Randomized Aldactone Evaluation Study (RALES) was a landmark trial that used spironolactone in New York Heart Association (NYHA) class III-IV HFrEF patients with an ejection fraction less than 35%, and the trial was stopped early due to but not limited to positive findings including a 30% relative risk reduction in all-cause mortality. [1] In the 2017 American College of Cardiology heart failure guidelines, spironolactone is indicated in NYHA class II-IV HFrEF patients who have a creatinine clearance greater than 30 mL/min and a serum potassium level less than 5 mEq/L, and the guidelines also mention that select heart failure with preserved ejection fraction (HFpEF) patients may benefit from spironolactone use to help in reducing the number of hospitalizations. [2] There is some evidence that spironolactone may reduce myocardial fibrosis, reduce left ventricular mass, and decrease the amount of extracellular volume expansion in HFpEF patients. [3] This medication is not yet generally recommended for end-stage renal disease patients either on or not on dialysis; even though more large randomized controlled trials are needed, some reports do suggest that it would be well tolerated in chronic kidney disease patients if clinicians carefully manage the risk of hyperkalemia. [4] [5] The definition of resistant hypertension is elevated blood pressure above the goal despite a patient being on optimal doses of three different antihypertensive agents of which one is a diuretic is another condition for which clinicians can prescribe spironolactone. The typical triple antihypertensive regimen in these patients is a thiazide diuretic, calcium channel blocker, and wither an angiotensin-converting enzyme inhibitor or an aldosterone receptor antagonist. Researchers tested low dose spironolactone as an agent added on in both White race and African American patients with resistant hypertension with and without primary hyperaldosteronism, and results showed it to help lower blood pressure when added to these patients' multidrug antihypertensive regimens. [6] Spironolactone was also tested against bisoprolol and doxazosin to determine which of the three was the most effective fourth agent for treating resistant hypertension, and research showed spironolactone to be superior to the other two in reducing systolic home blood pressure in these patients. [7] A study tested spironolactone against clonidine as the fourth agent in treating resistant hypertension and found to be non-inferior base on the primary endpoints of the trial and preferable to clonidine based on secondary endpoints of 24-hour systolic and diastolic blood pressure as well as diastolic daytime ambulatory blood pressure being lowered greater by spironolactone than by clonidine. [8] Spironolactone is considered the main option for the treatment of ascites in cirrhosis after the dietary salt restriction is not sufficient. [9] The typical starting dose ratio of oral furosemide to spironolactone is 40 mg to 100 mg, respectively. A study in children with severe edema secondary to nephrotic syndrome showed that oral spironolactone in conjunction with intravenous furosemide was safe and helpful in treating these children who had edema with volume expansion. [10] Spironolactone was studied concurrently with metolazone in patients with cirrhosis and nephrotic syndrome and found to be effective adjunctively, and it mitigated the hypokalemia associated with metolazone use. [11]

Heart failure

In people with symptomatic heart failure with markedly reduced ejection fraction (anyone with an ejection fraction of 35% or lower or less than 40% if following a heart attack), the use of an mineralocorticoid antagonist, such as spironolactone or eplerenone, in addition to beta blockers and ACE-I (once titrated to the target dose or maximum tolerated dose), can improve symptoms and reduce mortality. Sacubitril/valsartan should be used in those who still have symptoms while on an ACE-I or ARB, beta blocker, and a mineralocorticoid receptor antagonist as it reduces the risks of cardiovascular mortality and hospitalisation for heart failure by a further 4.7% (absolute risk reduction). However, the use of this combination agent requires the cessation of ACE-i or ARB therapy 48 hours before its initiation.

Adoption of Sacubitril/Valsartan for the Management of Patients With Heart Failure.

The US Food and Drug Administration approved the use of sacubitril/valsartan in patients with heart failure with reduced ejection fraction in July 2015. We aimed to assess the adoption and prescription drug costs of sacubitril/valsartan in its first 18 months after Food and Drug Administration approval. Using a large US insurance database, we identified privately insured and Medicare Advantage beneficiaries who filled a first prescription for sacubitril/valsartan between July 1, 2015, and December 31, 2016. We compared them to patients treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Outcomes included adoption, prescription drug costs, and 180-day adherence, defined as a proportion of days covered ≥80%. A total of 2244 patients initiated sacubitril/valsartan. Although the number of users increased over time, the proportion of heart failure with reduced ejection fraction patients taking sacubitril/valsartan remained low (<3%). Patients prescribed sacubitril/valsartan were younger, more often male, with less comorbidity than those taking an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Although a majority of prescription costs were covered by the health plan (mean, $328.37; median, $362.44 per 30-day prescription), out-of-pocket costs were still high (mean, $71.16; median, $40.27). By comparison, median out-of-pocket costs were $2 to $3 for lisinopril, losartan, carvedilol, and spironolactone. Overall, 59.1% of patients were adherent to sacubitril/valsartan. Refill patterns suggested that nearly half of nonadherent patients discontinued sacubitril/valsartan within 180 days of starting. Adoption of sacubitril/valsartan after Food and Drug Administration approval has been slow and may be associated with the high cost.

Recent developments in the management of heart failure.

The typical presentation of heart failure in primary care is insidious, with progressive breathlessness on exertion, ankle swelling, orthopnoea or paroxysmal nocturnal dyspnoea. Not all patients will have all these symptoms, and in many patients there may be other causes. If a GP suspects heart failure, then the key blood test is B-type natriuretic peptide (BNP). If the BNP is normal then heart failure is unlikely and other diagnoses should be considered. If it is raised, or if there is a past history of myocardial infarction, the patient requires further assessment, which must include echocardiography and a specialist assessment. The underlying cardiac abnormality should be identified. An ECG is often very useful and if it is completely normal it makes heart failure less likely. Both the NICE and the ESC guidance emphasise the importance of lifestyle management (regular appropriate exercise, avoiding excessive salt and alcohol consumption). ACE inhibitors (or angiotensin receptor blockers) and beta-blockers licensed for heart failure (carvedilol, bisoprolol, nebivolol) remain the mainstay of treatment in addition to as small a dose of diuretic as possible to control any fluid retention. Aldosterone antagonism is recommended by the 2012 ESC guidance for all patients who remain symptomatic despite an ACE inhibitor and beta-blocker. If the rhythm is sinus but the heart rate is 75 beats per minute, therapy needs to be optimised, perhaps by increasing the beta-blocker dose, if possible, or by the addition of ivabradine.

Rhabdomyolysis After Coadministration of Atorvastatin and Sacubitril/Valsartan (Entresto™) in a 63-Year-Old Woman.

A 63-year-old woman previously stable on a regimen of atorvastatin 40 mg daily, carvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily, spironolactone 25 mg daily, rivaroxaban 15 mg daily, and enalapril 20 mg twice daily for heart failure developed rhabdomyolysis 26 days after enalapril was stopped and sacubitril/valsartan (Entresto™) started. The patient received sacubitril/valsartan at 24/26 mg twice daily for heart failure; however, after 26 days she developed muscle and skin pain. Investigations revealed elevated creatine kinase and liver function tests, and rhabdomyolysis with raised transaminases was diagnosed. Sacubitril/valsartan and atorvastatin were discontinued and the patient was hydrated. She returned to baseline in 23 days and has not had any reoccurrence of rhabdomyolysis and elevated transaminases for 46 days. A Naranjo assessment score of 5 was obtained, indicating a probable relationship between the patient's rhabdomyolysis and her use of sacubitril/valsartan. The Drug Interaction Probability Scale score was 3, consistent with a possible interaction as a cause for the reaction, with sacubitril/valsartan as the precipitant drug and atorvastatin as the object drug.

Nemaline myopathy and heart failure: role of ivabradine; a case report.

Nemaline myopathy (NM) is a rare congenital myopathy characterized by muscle weakness, hypotonia and the presence in muscle fibers of inclusions known as nemaline bodies and a wide spectrum of clinical phenotypes, ranging from severe forms with neonatal onset to asymptomatic forms. The adult-onset form is heterogeneous in terms of clinical presentation and disease progression. Cardiac involvement occurs in the minority of cases and little is known about medical management in this subgroup of NM patients. We report a rare case of heart failure (HF) in a patient with adult-onset NM in whom ivabradine proved to be able to dramatically improve the clinical picture. We report a case of a 37-year-old man with adult-onset NM, presenting with weakness and hypotonia of the proximal limb muscles and shoulder girdle, severely limiting daily activities. He developed progressive HF over a period of 6 months while attending a rehabilitation program, with reduced left ventricular ejection fraction (LVEF = 20%), manifested by dyspnea and signs of systemic congestion. The patient was started HF therapy with enalapril, carvedilol, spironolactone and loop diuretics. Target HF doses of these drugs (including carvedilol) were not reached because of symptomatic hypotension causing a high resting heart rate (HR) ≥70 beats per minute (bpm). Further deterioration of the clinical picture occurred with several life-threatening arrhythmic episodes requiring external defibrillation. An implantable cardioverter defibrillator (ICD) was then implanted. Persistent high resting HR was successfully treated with ivabradine with HR lowering from 90 bpm to 55 bpm at 1 month follow up, LVEF rising to 50% at 3 month follow up and to 54% at 2,5 year follow up. To date no more hospitalizations for heart failure occurred. A single hospitalization due to aspiration pneumonia required insertion of a tracheostomy tube to protect airways from further aspiration. At present, the patient is attending a regular rehabilitation program with net improvement in neuromotor control and less limitations in daily activities. HF is a rare feature of NM, but it can negatively influence prognosis. Conventional HF therapy and/or heart transplant are the only reasonable strategy in these patients. Ivabradine is a useful, effective and safe drug for therapy in NM patients with HF and should be considered when resting HR remains high despite beta-blockers' full titration or beta-blockers' underdosing due to intolerance or side effects.

InternalMed_Harrison

Ivabradine, an inhibitor of the If current in the sinoatrial node, slows the heart rate without a negative inotropic effect. The Systolic Heart Failure Treatment with Ivabradine Compared with Placebo Trial (SHIFT) was conducted in patients with class II or III HFrEF, a heart rate >70 beats/min, and history of hospitalization for heart failure during the previous year. Ivabradine reduced hospitalizations and the combined endpoint of cardiovascular-related death and heart failure hospitalization. The study population was not necessarily representative of North American patients with HFrEF since, with a few exceptions, most did not receive internal cardioverter-defibrillation or cardiac resynchronization therapy and 40% did not receive a mineralocorticoid receptor antagonist. Although 90% received beta blockers, only a quarter were on full doses. Whether this agent, now available outside the United States, would have been effective in patients receiving robust, guideline-recommended

Sacubitril/valsartan use in a real-world population of patients with heart failure and reduced ejection fraction.

Practice guidelines recommend sacubitril/valsartan for heart failure with reduced ejection fraction. The aim of our study was to describe the use of sacubitril/valsartan in real-world clinical practice to help identify patients best able to tolerate titration to higher doses. We retrospectively analyzed clinical data for 201 patients with heart failure with reduced ejection fraction prescribed sacubitril/valsartan at our heart failure clinic (Centro Cardiologico Monzino) between September 2016/December 2018. Patients had a mean age of 67.2 years, mean left ventricular ejection fraction of 30.1%, New York Heart Association class II (65%), class III (35%), and poor cardiopulmonary exercise capacity. Median 2-year risk of death/urgent cardiac transplantation was 8.9% [Metabolic Exercise Cardiac Kidney Index (MECKI) score]. After a median follow-up of 230 (interquartile interval: 105-366) days, 57 patients achieved higher-dose sacubitril/valsartan, 103 tolerated medium/low doses, nine died, and 20 interrupted treatment. The highest dose of sacubitril/valsartan was reached by younger patients with better hemoglobin (Hb) levels, renal function, and blood pressure (BP). Patients continuing on sacubitril/valsartan had significantly higher serum Hb and sodium, better BP, and lower MECKI scores than patients who discontinued treatment or died during follow-up. Our patients were older and frailer than those in the pivotal PARADIGM-HF trial. In our experience, more than one-third of the patients were able to tolerate the higher dose of sacubitril/valsartan, and these patients were younger, had higher Hb, and better BP and renal function. MECKI score stratification was useful to discriminate patients who continued treatment from those who did not. Future prospective studies should test if these clinical variables can guide the up-titration of sacubitril/valsartan.

The management of heart failure--an overview.

National and international societies have issued guidelines on the management of heart failure: The European Society of Cardiology, WHO, ACC/AHA Task Force Report, US Department of Health and Human Services, German Society of Cardiology. The therapeutic approaches to heart failure have undergone considerable changes during the last few years. The guidelines have to be updated almost yearly due to new results from prospective randomized studies. Although an agreement could be reached with respect to general measures and drug treatment, no agreement on mechanical devices, pacemakers and surgical interventions has been reached. The basis for medical treatment of chronic heart failure depends on diuretics, digitalis, ACE inhibitors, and beta-blockers. Calcium antagonists and other positive inotropic drugs, other than digitalis, should be avoided as far as possible. Thiazides, loop diuretics and aldosterone antagonists are needed for acute and chronic treatment of heart failure, alone or in combination (diuretic resistant heart failure!). Digitalis glycosides are needed in patients with atrial fibrillation with a fast ventricular rate or atrial flutter and in patients with systolic dysfunction, large hearts and symptomatic failure class NYHA III and IV. However, digitalis does not convert atrial fibrillation to sinus rhythm. Today there is no question that ACE inhibitors improve the prognosis of all patients with heart failure in all stages, if ejection fraction is reduced. Therefore, most patients after myocardial infarction or after having experienced pump failure due to myocarditis or cardiomyopathy are treated with ACE inhibitors and diuretics. The beneficial effects of ACE inhibitors seem to be most pronounced the worse the situation is. Relative risk reductions (mortality!) between 10% and 40% have been published depending on the severity of symptomatic left ventricular dysfunction. Those patients with high absolute risk have more to gain than those with low risk for any given "risk reduction", of course. Recent studies also indicate that most high risk cardiac patients profit from ACE inhibitors even if pump function is normal (i.e., patients with coronary heart disease, diabetes mellitus, cerebral vascular disease, hypertension) (15). AT1 antagonists can substitute for ACE inhibitors, if the latter are not tolerated due to cough. Up to now, beta-blocking agents apart from diuretics seem to be the best investigated drugs in heart failure. Large controlled studies with bisoprolol, carvedilol and metoprolol in addition to diuretics, digitalis and ACE inhibitors convincingly yielded positive results in chronic left ventricular failure patients. Reduction of mortality by 35% and even of sudden cardiac deaths by 40% have been proven beyond doubt. Thus, heart failure patients today should also receive beta-blocking agents in all stages of the disease. In the era of controlled prospective studies (evidence-based medicine), physicians are well advised to use only drugs that have been proven beneficial in large controlled studies.

Pharmacist- or Nurse Practitioner-Led Assessment and Titration of Sacubitril/Valsartan in a Heart Failure Clinic: A Cohort Study.

Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor indicated in the management of heart failure with reduced ejection fraction, based on the results of the PARADIGM-HF trial. Practice-based studies are needed to validate its effect in real-world settings. Clinical pharmacists are ideally situated to assess and titrate sacubitril/valsartan. To evaluate the utilization, safety, and tolerability of sacubitril/valsartan in a multidisciplinary heart failure clinic, with assessment and titration by a clinical pharmacist or a nurse practitioner. A retrospective cohort study was conducted at a heart failure clinic in Abbotsford, Canada. Included were adult patients with heart failure who were currently or formerly taking sacubitril/valsartan. Data collected for the period October 2015 to February 2019 included patient characteristics, New York Heart Association (NYHA) classification, concurrent medications, sacubitril/valsartan dose, adverse effects, and discontinuation rate. In total, 128 patients were included. Mean age was 70.1 years, 98 (77%) of the patients were men, and 79 (62%) had NYHA class 2 heart failure. The clinical pharmacist managed care for 78 (61%) of the patients, and the nurse practitioner managed care for 50 (39%). Forty-one (32%) of the patients met modified PARADIGM-HF inclusion criteria. Eighty-five (66%) of the patients achieved the target dose of sacubitril/valsartan, with similar proportions for the clinical pharmacist and nurse practitioner groups, over a mean of 2.2 clinic visits. Patients who achieved the sacubitril/valsartan target dose, relative to those who did not, were significantly younger and had higher mean systolic blood pressure at baseline. Twenty-nine percent of patients (35/119) had an improvement in NYHA classification from before initiation of sacubitril/valsartan to achievement of target or maximally tolerated dose. Eighty-five (66%) of the patients experienced an adverse effect, primarily hypotension, and 12 (9%) required a dose reduction. Only 9 (7%) patients discontinued therapy. This study demonstrates the real-world safety and tolerability of sacubitril/valsartan in the treatment of heart failure, and reinforces that clinical pharmacists can effectively assess and titrate medications in a multidisciplinary heart failure clinic.

Stable patient with heart failure - the fact or the myth?

A treated patient with heart failure (HF), whose signs and symptoms have remained generally unchanged for at least 1 month is said to be 'stable'. Majority of patients with heart failure who are properly treated complain of slight symptoms described as functional class I and II NYHA. There is a belief that oligosymptomatic patients with heart failure have a good prognosis. Nevertheless, results of registries and randomized trials (e.g. ESC-HF-LT-R, CHARM, EMPHASIS-HF, PARADIGM-HF) disclosed that there is high risk of death and hospitalization for heart failure. Consequently, risk of every patient with heart failure should be evaluated with the use of validated scales - for example MAGGIC. Even in mild symptoms, remodeling of a left ventricle and dysfunction of the heart is progressing. It was revealed in the TRED-HF trial that withdrawal of guideline-directed medical therapy causes deterioration of clinical state in patients who were devoid of HF symptoms and presented improvement of echocardiographic parameters (left ventricle ejection fraction, left ventricle end diastolic volume) and laboratory parameters (N-terminal pro-B-type natriuretic peptide). This fact indicates that a chronic therapy in HF is necessary even in a situation where symptoms disappear, and heart function normalizes. An analysis of QUALIFY and ESC-HF-LT-R registries revealed that minority of patients with HF are treated according to current guidelines and doses of medications are not optimized. This management leads to deterioration of patient's prognosis. In addition to standard therapies (beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, ivabradine), novel drugs (e.g. sacubitril/valsartan) and individualized medical procedures should be applied in therapy.

InternalMed_Harrison

Diuretics Thiazides Hydrochlorothiazide 6.25–50 mg (1–2) Diabetes, dyslipidemia, hyperuricemia, gout, hypokalemia Chlorthalidone 25–50 mg (1) Loop diuretics Furosemide 40–80 mg (2–3) CHF due to systolic dysfunc-Diabetes, dyslipidemia, hypertion, renal failure uricemia, gout, hypokalemia Aldosterone antagonists Spironolactone 25–100 mg (1–2) CHF due to systolic dysfunc-Renal failure, hyperkalemia tion, primary aldosteronism Renal failure, hyperkalemia Triamterene 50–100 mg (1–2) Beta blockers Asthma, COPD, 2ndor 3rd-degree heart block, sick- Cardioselective Atenolol 25–100 mg (1) Angina, CHF due to systolic sinus syndrome dysfunction, post-MI, sinus tachycardia, ventricular tachyarrhythmias Metoprolol 25–100 mg (1–2) Nonselective Propranolol 40–160 mg (2) Propranolol LA 60–180 (1) Combined alpha/beta Labetalol 200–800 mg (2) ?Post-MI, CHF Carvedilol 12.5–50 mg (2) Alpha antagonists

The Effect of Sacubitril/Valsartan Treatment on Cardiac and Renal Functions of a Patient With Cardiorenal Syndrome Type 4 and Stage 5 CKD After More Than Three Years of Follow-Up.

It is difficult to treat cardiorenal syndrome (CRS) in clinical practice, which is the common reason for the death of patients. This report aimed to describe the effects of sacubitril/valsartan treatment on cardiac and renal functions of a patient with cardiorenal syndrome type 4 (CRS4) after more than 3 years of follow-up. A 77-year-old Chinese woman was admitted to our hospital because of CRS4 and stage 5 chronic kidney disease (CKD), who had a history of long-term proteinuria and renal failure. The patient's cardiothoracic ratio (CTR) measured by chest X-ray was 0.6. Cardiac ultrasonography showed that the left ventricular ejection fraction (LVEF) was 0.40. The patient had been treated for heart failure (HF) for 5 months, but there was no improvement in clinical manifestations, and the renal function gradually deteriorated. In our hospital, she received sacubitril/valsartan treatment for at least 40 months. The symptoms of HF relieved, and the indices of cardiac function improved. In addition, the patient's renal function was stable. During the treatment, the dosage of sacubitril/valsartan needed to be adjusted to achieve the optimal therapeutic effect. Follow-up results showed that she achieved cardiac function of New York Heart Association (NYHA) class II with an ejection fraction of 0.60 and E/A > 1 indicated by echocardiogram, and did not develop hyperkalemia. In summary, the improvement of cardiac and renal functions of the CRS4 patient was associated with the long-term sacubitril/valsartan treatment.

Left ventricular diastolic heart failure with normal left ventricular systolic function in older persons.

Underlying causes and precipitating causes of congestive heart failure (CHF) should be treated when possible. Older persons with CHF and normal left ventricular (LV) ejection fraction should have maintenance of sinus rhythm, treatment of hypertension and myocardial ischemia, slowing of the ventricular rate below 90 beats/minute, and reduction of salt overload. First-line drug treatment in the management of these persons is the use of loop diuretics combined with beta blockers as tolerated. Angiotensin-converting enzyme (ACE) inhibitors should be administered if CHF persists despite diuretics and beta blockers. If persons are unable to tolerate ACE inhibitors because of cough, rash, or altered taste sensation, angiotensin II type 1 receptor antagonists should be given. If CHF persists despite diuretics, beta blockers, and ACE inhibitors or the person is unable to tolerate beta blockers, ACE inhibitors, and angiotensin II type 1 receptor antagonists, isosorbide dinitrate plus hydralazine should be administered. Calcium channel blockers should be used if CHF persists despite administration of diuretics and the person is unable to tolerate beta blockers, ACE inhibitors, angiotensin II type 1 receptor antagonists, and isosorbide dinitrate plus hydralazine. Digoxin, beta blockers, verapamil, and diltiazem may be used to slow a rapid ventricular rate in persons with supraventricular tachyarrhythmias. Digoxin should not be used in persons with CHF in sinus rhythm with normal LV ejection fraction.

Optimizing heart failure treatment following cardiac resynchronization therapy.

Device therapy in addition to medical treatment improves prognosis in a subset of patients with heart failure and reduced ejection fraction. However, some patients remain symptomatic or their heart failure even progresses despite cardiac resynchronization therapy (CRT). The aim of the study was to evaluate the proportion of patients who could benefit from optimization of medical therapy using sacubitril/valsartan, ivabradine, or both following CRT implantation. We conducted a post hoc analysis of a single-centre, patient and outcome-assessor blinded, randomized-controlled trial, in which patients scheduled for CRT were randomized to empiric (n = 93) or imaging-guided left-ventricular lead placement (n = 89). All patients underwent clinical evaluation and blood sampling at baseline and 6 months following CRT implantation. The proportion of patients meeting the indication for sacubitril/valsartan (irrespective of angiotensin-converting enzyme inhibitor or angiotensin 2 receptor blocker dosage) and/or ivabradine according to current guidelines was evaluated at baseline and after 6 months. Of 182 patients with an indication for CRT, 146 (80%) also had an indication for optimization of medical therapy at baseline by adding sacubitril/valsartan, ivabradine, or both. Of the 179 survivors at 6 months, 136 (76%) were still symptomatic after device implantation; of these, 51 (38%) patients had an indication for optimization of medical therapy: sacubitril/valsartan in 37 (27%), ivabradine in 7 (5%), and both drugs in 7 (5%) patients. Seven (18%) patients without indication at baseline developed an indication for medical optimization 6 months after CRT implantation. In the present study, 38% of those who remained symptomatic 6 months after CRT implantation were eligible for optimization of medical therapy with sacubitril/valsartan, ivabradine, or both. Patients with CRT may benefit from systematic follow-up including evaluation of medical treatment.

[Contemporary approaches to the treatment of chronic heart failure in adults (after materials of recommendations of American College of Cardiology and American Heart Association, 2005)].

Detailed and critical analysis of a novel version of the "Updated Guideline for the Diagnosis and Management of Chronic Heart Failure (CHF) in the Adult" prepared by experts of American College of Cardiology and American Heart Association is given. The novel version contains somewhat modified recommendations on the management of patients with CHF. In particular this relates to the place of various classes of drugs in the treatment of CHF due to systolic left ventricular dysfunction. For the first time recommendations on the treatment of patients with CHF and normal left ventricular ejection fraction are presented in detail. Among statements of the updated guideline the following are considered controversial or deserving special discussion. Perindopril is mentioned among recommended ACE inhibitors despite the fact that it has never been studied in long term trials. Results of SENIORS trial are ignored and nebivolol is not included in the number of beta-blockers with proven efficacy. Despite multiple proofs of beneficial effects of aldosterone receptor blockers on clinical course of CHF wide use of spironolactone and eplerenone is not recommended because of multiple communications about life threatening hyperkalemia. Inherent dangers of digoxin therapy are disregarded and the use of cardiac glycosides in patients with sinus rhythm is not prohibited.

Combination of ivabradine and sacubitril/valsartan in patients with heart failure and reduced ejection fraction.

Ivabradine and sacubitril/valsartan are second-line therapies for patients with heart failure and reduced ejection fraction (HFrEF) based on guideline recommendations. We aimed to evaluate the synergistic effects of these two medications. Patients' data were extracted from a multicentre database between 2016 and 2018. Patients were classified into (1) Simultaneous group: simultaneous prescription of ivabradine and sacubitril/valsartan within 6 weeks; (2A) Sequential group, ivabradine-first: ivabradine was prescribed first, followed by sacubitril/valsartan; and (2B) Sequential group, sacubitril/valsartan-first: sacubitril/valsartan was prescribed first, followed by ivabradine. A total of 464 patients with HFrEF were enrolled. Cardiovascular death and/or unplanned re-hospitalizations for HF were less frequent (28.6% vs. 44.8%, P = 0.01), and the improvement of left ventricular ejection fraction (LVEF) was significantly greater in patients from the Simultaneous group than those from the Sequential group (∆LVEF 12.8 ± 12.9% vs. 9.3 ± 12.6%, P = 0.007). Among Sequential subgroups, the ivabradine-first treatment decreased heart rate and increased systolic blood pressure (SBP) compared with sacubitril/valsartan-first treatment (∆heart rate -9.1 ± 12.9 b.p.m. vs. 2.6 ± 16.0 b.p.m., P < 0.001; ∆SBP 4.6 ± 16.5 mmHg vs. -4.8 ± 17.2 mmHg, P < 0.001), whereas sacubitril/valsartan-first treatment showed a higher degree of LVEF improvement (∆LVEF 3.6 ± 7.8% vs. 0.7 ± 7.7%, P = 0.002) than ivabradine-first treatment. At the end of follow-up, SBP, LVEF, and left ventricular volume were comparable between two Sequential subgroups. Among patients with HFrEF, simultaneous rather than sequential treatment with sacubitril/valsartan and ivabradine was a better strategy to reduce adverse events and achieve left ventricular reverse remodelling. Ivabradine treatment had a more significant benefit on improving haemodynamic stability, whereas sacubitril/valsartan treatment showed a more significant effect on improving LVEF.

Treatment of heart failure with decreased left ventricular ejection fraction.

Class I recommendations for treating patients with current or prior symptoms of heart failure with reduced left ventricular ejection fraction (LVEF) include using diuretics and salt restriction in individuals with fluid retention. Use angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and angiotensin II receptor blockers if intolerant to ACE inhibitors because of cough or angioneurotic edema. Nonsteroidal anti-inflammatory drugs, most antiarrhythmic drugs, and calcium channel blockers should be avoided or withdrawn. Exercise training is recommended. Implant cardioverter-defibrillator (ICD) is recommended in individuals with a history of cardiac arrest, ventricular fibrillation, or hemodynamically unstable ventricular tachycardia. ICD is indicated in patients with ischemic heart disease for at least 40 d post-myocardial infarction or nonischemic cardiomyopathy, an LVEF of 30% or less, New York Heart Association (NYHA) class II or III symptoms on optimal medical therapy, and an expectation of survival of at least 1 yr. Cardiac resynchronization therapy should be used in individuals with an LVEF of 35% or below, NYHA class III or IV symptoms despite optimal therapy, and a QRS duration greater than 120 ms. An aldosterone antagonist can be added in selected patients with moderately severe to severe symptoms of heart failure who can be carefully monitored for renal function and potassium concentration (serum creatinine should be <or=2.5 mg/dL in men and <or=2.0 mg/dL in women; serum potassium should be <5.0 mEq/L).

Impact of sacubitril/valsartan on implantable defibrillator eligibility in heart failure: a real-world experience.

Current guidelines recommend an implantable cardiac defibrillator (ICD) in patients with symptomatic heart failure and reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] ≤35%) despite ≥3 months of optimal medical therapy. Recent observations demonstrated that sacubitril/valsartan induces beneficial reverse cardiac remodeling in eligible HFrEF patients. Given the pivotal role of LVEF in the selection of ICD candidates, we sought to assess the impact of sacubitril/valsartan on ICD eligibility and its predictors in HFrEF patients. We retrospectively evaluated 48 chronic HFrEF patients receiving sacubitril/valsartan and previously implanted with an ICD in primary prevention. We assumed that ICD was no longer necessary if LVEF improved >35% (or >30% if asymptomatics) at follow-up. Over a median follow-up of 11 months, sacubitril/valsartan induced a significant drop in LV end-systolic volume (-16.7 ml/m2, p=0.023) and diameter (-6.8 mm, p=0.022), resulting in a significant increase in LVEF (+3.9%, p<0.001). As a consequence, 40% of previously implanted patients resulted no more eligible for ICD at follow-up. NYHA class improved in 50% of the population. A dose-dependent effect was noted, with higher doses associated to more reverse remodeling. Among patients deemed no more eligible for ICD, lower NYHA class (odds ratio (OR) 3.73 [95% CI 1.05; 13.24], p=0.041), better LVEF (OR 1.23 [95% CI 1.01; 1.48], p=0.032) and the treatment with the intermediate or high dose of sacubitril/valsartan (OR 5.60 [1.15; 27.1], p=0.032) were the most important predictors of status change. In symptomatic HFrEF patients, sacubitril/valsartan induced beneficial cardiac reverse remodeling and improved NYHA class. These effects resulted in a significant reduction of patients deemed eligible for ICD in primary prevention.

Treatment of heart failure with normal left ventricular ejection fraction.

Underlying causes and precipitating causes of heart failure (HF) should be treated when possible. Persons with HF and normal left ventricular ejection fraction (LVEF) should have maintenance of sinus rhythm, treatment of hypertension, myocardial ischemia, dyslipidemia, and anemia, slowing of the ventricular rate below 90 bpm, and reduction of salt overload. First-line drug treatment in the management of these persons is the use of loop diuretics combined with beta blockers and angiotensin-converting enzyme (ACE) inhibitors. If persons are unable to tolerate ACE inhibitors because of cough, angioneurotic edema, rash, or altered taste sensation, angiotensin II type I receptor antagonists (ARBs) should be given. If HF persists despite diuretics, beta blockers, and ACE inhibitors or ARBs, isosorbide dinitrate plus hydralazine should be administered. Beta blockers, verapamil, diltiazem, and digoxin may be used to slow a rapid ventricular rate in persons with supraventricular tachyarrhythmias. Digoxin should not be used in persons with HF in sinus rhythm with normal LVEF. Exercise training should be encouraged in persons with mild to moderate HF to improve functional status and to decrease symptoms.

Early Experience With Sacubitril/Valsartan in Adult Patients With Congenital Heart Disease.

Heart failure (HF) is the leading cause of hospitalizations and death in patients with adult congenital heart disease (ACHD). Sacubitril/valsartan is a new agent in the treatment of HF, but its effects have not been assessed in ACHD. We retrospectively studied all 15 patients with ACHD at our center who were prescribed sacubitril/valsartan between June 2017 and June 2018. We assessed baseline characteristics and clinical and laboratory changes after initiation of sacubitril/valsartan. Adverse events, including renal function, medication intolerance, and worsening HF were documented. The median age was 53.2 (27.6-83.6) years, with a median follow-up duration of 69 (8-419) days. At baseline, all patients had refractory HF despite guideline-directed medical therapy, with ten (67%) patients as New York Heart Association (NYHA) class II, and five (33%) patients NYHA class III. The medication was discontinued in one (7%) patient secondary to worsening kidney function. No patients reported clinical deterioration; four NYHA class III patients with complex CHD, pulmonary hypertension, and cyanosis reported significant improvement to NYHA class II. Baseline creatinine was 1.1 (0.9-1.7) and two weeks after starting sacubitril/valsartan it was 1.3 (0.8-2.5, P = .22). Sacubitril/valsartan seems to be well tolerated in patients with ACHD who present with refractory HF symptoms. Patients with complex CHD associated with cyanosis and pulmonary hypertension could benefit the most, but larger studies are needed to assess the safety as well as the effectiveness of sacubitril/valsartan in this patient population.