Eplerenone is an aldosterone antagonist that selectively inhibits the mineralocorticoid receptors, leaving the glucocorticoid, progesterone or androgen receptors unaffected. Its selective action is beneficial in preventing side-effects such as sexual dysfunction and gynecomastia that are encountered with the nonselective blockade provided by spironolactone. This study is a multicenter, international, randomized, double-blind, placebocontrolled trial that included patients with acute myocardial infarction (time to randomization 3–14 days) and left ventricular dysfunction (LVEF <40%) with clinical heart failure, except in diabetics in whom the symptoms of heart failure did not have to be demonstrated. Exclusion criteria were the use of potassium-sparing diuretics, a serum creatinine level of 2.5 mg/dl or above, and a serum potassium concentration of >5 mmol/L. The potassium level was monitored on subsequent follow-up visits. Six thousand six hundred forty-two patients were randomized to eplerenone (25 mg/day initially, titrated to a maximum of 50 mg/day; 3319 patients), or placebo (3313 patients). The study continued until 1012 deaths occurred. At baseline, the 2 groups were not significantly different and were receiving optimal medical therapy including ACE inhibitors or angiotensin-receptor blockers (87%), betablockers (75%), aspirin (88%), and diuretics (60%).

The primary end-points were death from any cause and death from cardiovascular causes, or first hospitalization for a cardiovascular event including heart failure, recurrent acute myocardial infarction (AMI), stroke, or ventricular arrhythmia.

In the mean follow-up period of 16 months, 478 deaths occurred in the eplerenone group (14.4%) and 554 deaths in the placebo group (16.7%) (relative risk [RR] 0.85; p=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (RR: 0.83; p=0.005), which included sudden cardiac death, acute myocardial infarction, and heart failure. The reduction in risk of sudden death from cardiac causes was statistically significant (RR 0.79; p=0.03). There was a relative reduction of 15% in the risk of hospitalization for heart failure and there were 23% fewer episodes of hospitalization in those receiving eplerenone compared to placebo. The rate of death from any cause or any hospitalization was 8% lower in the eplerenone than in the placebo group (RR: 0.92; p=0.02). During the study period, 493 patients in the placebo group and 528 patients in the eplerenone group discontinued the drug. There was a significantly greater increase in the serum creatinine concentration in the eplerenone group than in the placebo group, but the difference was clinically small. Serious hyperkalemia occurred in 5.5% of patients in the eplerenone group, as compared with 3.9% of patients in the placebo group.The incidence of hyperkalemia was more in patients with a baseline creatinine clearance of <50 ml/min. Though there were 12 hospitalizations for serious hyperkalemia in the eplerenone group, there were no deaths. Three patients in the placebo group were admitted because of hyperkalemia and there was 1 death. In conclusion, the study showed that eplerenone significantly reduces morbidity and mortality in patients with AMI and LV dysfunction.

Comments

The Randomized Aldactone Evaluation Study (RALES) proved the importance of aldosterone antagonists in the management of patients with heart failure. In addition to reducing mortality by 30%, small doses of spironolactone resulted in an improvement in the ejection fraction and enhanced treatment tolerance. It has been shown that patients with heart failure have high levels of plasma aldosterone because of increased production and decreased hepatic clearance. Sustained aldosterone levels promote endothelial dysfunction and oxidative stress in the vasculature and also organ fibrosis. The beneficial effect on ventricular remodeling is evidenced by this study, in which the relative risk of death was reduced by 15% and the risk of hospitalization was also reduced by 15%. The reduction in cardiovascular mortality is mainly due to 21% reduction in the rate of sudden death due to cardiac causes. An important point in the EPHESUS trial is that patients were already receiving optimal therapy (ACE inhibitors in 87% and beta-blockers in 75%). In RALES, beta-blockers were used in only about 11%, although ACE inhibitors were given to 94%. One-year mortality among the placebo group was higher in RALES (25%) as compared with EPHESUS (13.6%). This difference in mortality may reflect the more severely depressed systolic function in patients enrolled in RALES (LVEF averaged 25% in RALES as compared to 33% in EPHESUS). Taken together, these 2 trials of aldosterone blockade have enrolled more than 8000 patients with systolic dysfunction and symptoms of heart failure, and have shown that the addition of aldosterone antagonists to these patients can substantially reduce overall mortality and rate of sudden death. Currently, the guidelines of the American College of Cardiology and American Heart Association specify that the use of spironolactone for patients with mild-to-moderate heart failure has not been tested. After the RALES and EPHESUS, their beneficial role in the management of heart failure is quite evident, with just a little extra effort to monitor the potential side-effects, especially hyperkalemia. Further studies would determine whether this class of drugs will prove as efficacious in patients with less severe symptoms or in those with heart failure due to diastolic dysfunction.