Effects of a New Aldosterone Blocker in Patients with Myocardial Infarction

Abstract & Commentary

Synopsis: The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

Source: Pitt B, et al. N Engl J Med. 2003;348:1309-1321.

It has been clearly demonstrated that aldosterone blockade with spironolactone reduces the rate of death due to heart failure and sudden death from cardiac causes in patients who are being treated with an angiotensin-converting-enzyme (ACE) inhibitor.1 Aldosterone blockade also prevents ventricular remodeling2 and positively affects a number of pathophysiological mechanisms, which affects mortality in patients with acute myocardial infarctions.

Since the effect of aldosterone blockade on mortality and the rate of hospitalization among patients with acute myocardial infarctions complicated by the ventricular dysfunction has not been clearly demonstrated, Pitt and associates from the University of Michigan designed a study to determine whether eplerenone, a selective aldosterone blocking agent, could reduce overall mortality, cardiovascular mortality and/or the incidence of hospitalizations for cardiovascular events among patients with acute myocardial infarctions complicated by left ventricular dysfunction and heart failure who are receiving optimal medical therapy. The primary end points of this double-blind, placebo-controlled study were death from any cause, death from cardiovascular causes, and/or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia. A total of 6642 patients underwent randomization in 674 centers in 37 countries. The results revealed that eplerenone-treated patients had 15% fewer overall deaths and 21% fewer episodes of sudden death from cardiac causes.

Comment by Harold L. Karpman, MD, FACC, FACP

The addition of a new aldosterone-blocking drug, eplerenone, to optimal treatment of patients with acute myocardial infarction significantly reduced overall mortality, rate of death from cardiovascular causes and/or hospitalization for cardiovascular events among patients whose acute myocardial infarction was complicated by left ventricular dysfunction and heart failure. The majority of the placebo group received an ACE inhibitor or angiotensin-receptor blocker, a beta-blocker, a diuretic, or aspirin, and nearly one-half of the patients were treated with a statin. The reduction in cardiovascular mortality was in large part due to a 21% reduction in the rate of sudden death from cardiac causes, whereas reductions in the rate of death due to progressive heart failure and acute myocardial infarctions were similar and not significantly different.

The mechanisms by which eplerenone provided myocardial protection in the study patients are not completely clear. The drug has been demonstrated to reduce coronary vascular inflammation and oxidative stress,3,4 improve endothelial dysfunction,3,4 decrease sympathetic stimuli,5 and improve heart rate variability.6 Since the majority of the placebo group were on optimal therapy as described above, it would appear that the addition of this new aldosterone blocker, eplerenone, to medical therapy, which is currently considered to be optimal for patients with acute myocardial infarctions complicated by left ventricular dysfunction and heart failure, contributed to improved survival and hospitalization rates.

Eplerenone was recently approved by the FDA for marketing as an antihypertension drug and undoubtedly will soon be generally available; however, physicians should consider the possibility that a related, generic drug, spironolactone, which is currently available, may produce similar positive results in the treatment of patients with acute myocardial infarctions complicated by left ventricular dysfunction. Both drugs block aldosterone receptors; however, since spironolactone blocks all aldosterone receptors, certain adverse events such as gynecomastia, impotency in men, and menstrual disorders in females may occur, whereas eplerenone selectively blocks only the mineralocorticoid receptors apparently with resulting fewer adverse side effects. Therefore, in the long run it may prove to be the better agent to use in this very sick group of patients. The guidelines of the American College of Cardiology and the American Heart Association recommend the use of spironolactone in patients with recent or current symptoms of systolic heart failure at rests despite the use of digoxin, diuretics, ACE inhibitors, and beta-blockers. The use of an aldosterone blocker in patients with acute myocardial infarctions and systolic dysfunction should now definitely be considered. However, the accepted pharmacological agents (ie, ACE inhibitor or angiotensin-receptor blocker, beta-blocker, aspirin, statin, diuretics if needed, etc) that have proven to be so beneficial should not be overlooked in favor of an aldosterone blocker in the management of these very sick patients.

Dr. Karpman is Clinical Professor of Medicine, UCLA School of Medicine.

References

1. Pitt B, et al. N Engl J Med. 1999;341:709-717.

2. Rodriguez JA, et al. Rev Med Chile. 1997;125:643-652.

3. Bauersachs J, et al. J Am Coll Cardiol. 2002;39: 351-358.

4. Rajagopalan S, et al. Circulation. 2002;t105:2212-2216.

5. Zhang ZH, et al. Am J Physiol Heart Circ Physiol. 2002;283:H423-H433.

6. Korkmaz B. Am J Cardiol. 2000;86:649-653.