Pharmacologic therapy of heart failure with reduced ejection fraction
- Stephen S Gottlieb, MD
Stephen S Gottlieb, MD
- Section Editor — Heart Failure
- Professor of Medicine
- University of Maryland School of Medicine
Heart failure (HF) is a common clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. HF may be caused by disease of the myocardium, pericardium, endocardium, heart valves, vessels, or by metabolic disorders . HF due to left ventricular dysfunction is categorized according to left ventricular ejection fraction (LVEF) into HF with reduced ejection fraction (with LVEF ≤40 percent, known as HFrEF; also referred to as systolic HF) and HF with preserved ejection fraction (with LVEF>40 percent; known as HFpEF; also referred to as diastolic HF).
Pharmacologic therapy of HFrEF will be presented here [1-3]. An overview of the management of HFrEF, the management of acute HF, drugs that should be avoided or used with caution in patients with HF, management of HF during pregnancy, the management of refractory HF, and therapy of HFpEF (diastolic HF) are discussed separately. (See "Overview of the therapy of heart failure with reduced ejection fraction" and "Treatment of acute decompensated heart failure: General considerations" and "Treatment of acute decompensated heart failure: Components of therapy" and "Drugs that should be avoided or used with caution in patients with heart failure" and "Management of heart failure during pregnancy" and "Management of refractory heart failure with reduced ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
GOALS OF THERAPY
The goals of pharmacologic therapy of heart failure with reduced ejection fraction (HFrEF) are to improve symptoms (including risk of hospitalization), slow or reverse deterioration in myocardial function, and reduce mortality (table 1) [1-3]:
●Improvement in symptoms can be achieved by diuretics, beta blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitor (ARNI), hydralazine plus nitrate, digoxin, and aldosterone antagonists.
●Prolongation of patient survival has been documented with beta blockers, ACE inhibitors, ARNI, hydralazine plus nitrate, and aldosterone antagonists. More limited evidence of survival benefit is available for diuretic therapy and digoxin.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128:1810.
- WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2016; 134:e282.
- Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37:2129.
- Fonarow GC, Yancy CW, Hernandez AF, et al. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am Heart J 2011; 161:1024.
- Faris R, Flather MD, Purcell H, et al. Diuretics for heart failure. Cochrane Database Syst Rev 2006; :CD003838.
- Kostis JB, Shelton BJ, Yusuf S, et al. Tolerability of enalapril initiation by patients with left ventricular dysfunction: results of the medication challenge phase of the Studies of Left Ventricular Dysfunction. Am Heart J 1994; 128:358.
- Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999; 100:2312.
- Delahaye F, de Gevigney G. Is the optimal dose of angiotensin-converting enzyme inhibitors in patients with congestive heart failure definitely established? J Am Coll Cardiol 2000; 36:2096.
- SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327:685.
- Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325:303.
- CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316:1429.
- SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293.
- Flather MD, Yusuf S, Køber L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355:1575.
- Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010; 16:e1.
- Gattis WA, O'Connor CM, Gallup DS, et al. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004; 43:1534.
- Eichhorn EJ, Bristow MR. Practical guidelines for initiation of beta-adrenergic blockade in patients with chronic heart failure. Am J Cardiol 1997; 79:794.
- Wikstrand J, Hjalmarson A, Waagstein F, et al. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol 2002; 40:491.
- Gullestad L, Wikstrand J, Deedwania P, et al. What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). J Am Coll Cardiol 2005; 45:252.
- Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med 2001; 134:550.
- Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001.
- Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334:1349.
- Goldstein S, Fagerberg B, Hjalmarson A, et al. Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study. J Am Coll Cardiol 2001; 38:932.
- Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344:1651.
- Willenheimer R, van Veldhuisen DJ, Silke B, et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 2005; 112:2426.
- Sliwa K, Norton GR, Kone N, et al. Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure. J Am Coll Cardiol 2004; 44:1825.
- Fang JC. Angiotensin-converting enzyme inhibitors or beta-blockers in heart failure: does it matter who goes first? Circulation 2005; 112:2380.
- Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 1996; 94:2807.
- Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364:11.
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709.
- Pitt B, White H, Nicolau J, et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol 2005; 46:425.
- Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004; 351:585.
- Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289:871.
- Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525.
- Adams KF Jr, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol 2005; 46:497.
- Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372:1223.
- Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997; 96:856.
- GOALS OF THERAPY
- OUR APPROACH
- INITIAL THERAPY
- ACE inhibitor
- Angiotensin II receptor blocker
- Beta blocker
- ACE inhibitors or beta blockers first
- ADDITIONAL THERAPY
- Mineralocorticoid receptor antagonist
- Angiotensin receptor-neprilysin inhibitor
- Hydralazine plus nitrate
- - N-3 polyunsaturated fatty acids
- OTHER DRUGS
- Antithrombotic therapy
- Calcium channel blockers
- DRUGS TO AVOID
- MANAGEMENT DURING PREGNANCY
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS