Use of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction
- Wilson S Colucci, MD
Wilson S Colucci, MD
- Section Editor — Heart Failure
- Professor of Medicine
- Boston University School of Medicine
- Marc A Pfeffer, MD, PhD
Marc A Pfeffer, MD, PhD
- Dzau Professor of Medicine
- Harvard Medical School
- Brigham and Women’s Hospital
- Section Editors
- Stephen S Gottlieb, MD
Stephen S Gottlieb, MD
- Section Editor — Heart Failure
- Professor of Medicine
- University of Maryland School of Medicine
- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor Emeritus
- University of Rochester School of Medicine and Dentistry
Mineralocorticoid receptor antagonist (MRA) therapy is one component of treatment of patients with systolic heart failure (HF) . Clinical trials have demonstrated that MRA therapy reduces morbidity and mortality in patients with HF due to left ventricular systolic dysfunction.
The indications, efficacy, risks, and mechanisms of benefit of MRA therapy in systolic HF will be reviewed here. Overall management of systolic HF and use of MRAs in patients with diastolic HF are discussed separately. (See "Overview of the therapy of heart failure with reduced ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
MECHANISMS OF ACTION
Two major, not mutually exclusive mechanisms may contribute to the benefits associated with mineralocorticoid receptor antagonist (MRA) therapy in patients with systolic heart failure (HF): maintenance of a higher serum potassium concentration via reduced urinary potassium loss, and blockade of the deleterious effects of aldosterone on the heart. To the degree that the latter effect is important, a similar benefit would not be expected with other potassium-sparing diuretics (such as amiloride).
Raising serum potassium — Mineralocorticoid receptor antagonism may preserve serum potassium concentration and thus counter the risk of hypokalemia and associated arrhythmic risk caused by non-potassium-sparing diuretics. Support for this mechanism comes from observation of increased arrhythmic mortality in patients with HF treated with non-potassium-sparing diuretics alone in a retrospective analysis of data from the SOLVD trial . In this study of data from 6797 patients with symptomatic New York Heart Association (NYHA) (table 1) class II to III HF and a left ventricular ejection fraction (LVEF) less than 36 percent, diuretic use, compared to no diuretic use, was associated with a higher incidence of overall mortality, cardiovascular deaths (11.4 versus 4.6 percent per year), and arrhythmic or sudden death. The risk of arrhythmic death associated with the use of non-potassium-sparing diuretics was significantly elevated (relative risk 1.33) after controlling for disease severity, comorbid illnesses, and concomitant medications, including angiotensin converting enzyme (ACE) inhibitors. In comparison, there was no association between arrhythmic death and use of a potassium-sparing diuretic, either alone or in combination with a non-potassium-sparing agent.
MRA therapy reduced the risk of hypokalemia in patients with systolic HF in clinical trials (eg, in the EPHESUS trial, serum potassium <3.5 mEq/L occurred in 8.4 with eplerenone versus 13.1 percent with placebo) [3,4]
- de Gasparo M, Joss U, Ramjoué HP, et al. Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther 1987; 240:650.
- Cooper HA, Dries DL, Davis CE, et al. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999; 100:1311.
- Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309.
- 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.
- Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation 2001; 103:72.
- Silvestre JS, Heymes C, Oubénaïssa A, et al. Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation 1999; 99:2694.
- Harada E, Yoshimura M, Yasue H, et al. Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes. Circulation 2001; 104:137.
- Lijnen P, Petrov V. Induction of cardiac fibrosis by aldosterone. J Mol Cell Cardiol 2000; 32:865.
- Fullerton MJ, Funder JW. Aldosterone and cardiac fibrosis: in vitro studies. Cardiovasc Res 1994; 28:1863.
- Ouvrard-Pascaud A, Sainte-Marie Y, Bénitah JP, et al. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation 2005; 111:3025.
- Kuster GM, Kotlyar E, Rude MK, et al. Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload. Circulation 2005; 111:420.
- Jaffe IZ, Mendelsohn ME. Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res 2005; 96:643.
- Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45:1243.
- Zannad F, Alla F, Dousset B, et al. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 2000; 102:2700.
- Tsutamoto T, Wada A, Maeda K, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol 2001; 37:1228.
- Izawa H, Murohara T, Nagata K, et al. Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study. Circulation 2005; 112:2940.
- Jorde UP, Vittorio T, Katz SD, et al. Elevated plasma aldosterone levels despite complete inhibition of the vascular angiotensin-converting enzyme in chronic heart failure. Circulation 2002; 106:1055.
- Young DB, Smith MJ Jr, Jackson TE, Scott RE. Multiplicative interaction between angiotensin II and K concentration in stimulation of aldosterone. Am J Physiol 1984; 247:E328.
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147.
- Pitt B, Bakris G, Ruilope LM, et al. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 2008; 118:1643.
- Hamaguchi S, Kinugawa S, Tsuchihashi-Makaya M, et al. Spironolactone use at discharge was associated with improved survival in hospitalized patients with systolic heart failure. Am Heart J 2010; 160:1156.
- 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.
- Schepkens H, Vanholder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med 2001; 110:438.
- Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol 2005; 46:845.
- Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004; 351:585.
- Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 1996; 78:902.
- Ramires FJ, Mansur A, Coelho O, et al. Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol 2000; 85:1207.
- Weintraub WS, Zhang Z, Mahoney EM, et al. Cost-effectiveness of eplerenone compared with placebo in patients with myocardial infarction complicated by left ventricular dysfunction and heart failure. Circulation 2005; 111:1106.
- Krum H, Mohacsi P, Katus HA, et al. Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study. Am Heart J 2006; 151:55.
- McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362:767.
- Wrenger E, Müller R, Moesenthin M, et al. Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases. BMJ 2003; 327:147.
- Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351:543.
- Wei L, Struthers AD, Fahey T, et al. Spironolactone use and renal toxicity: population based longitudinal analysis. BMJ 2010; 340:c1768.
- O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127:e362.
- 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.
- MECHANISMS OF ACTION
- Raising serum potassium
- Blocking aldosterone effect on the heart
- Effect of concurrent ACE inhibitors
- OUR APPROACH
- Selection of patients
- Choice of agent
- Timing of initiation
- Class III or IV heart failure
- Class II heart failure
- Post-myocardial infarction with heart failure and/or diabetes
- Combination with other HF medications
- ADVERSE EFFECTS
- Risk of hyperkalemia
- - Effect of renal dysfunction
- - Clinical usage and risk of hyperkalemia
- Adverse endocrine effects
- MAJOR SOCIETY GUIDELINES
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS