The EPHESUS trial: Eplerenone in heart failure after myocardial infarction [Classics Series]

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1. Eplerenone significantly reduces all-cause mortality in patients with heart failure and left ventricular dysfunction (LVEF≤40%) after myocardial infarction when compared with placebo

2. Eplerenone treatment in this setting also significantly reduced mortality from cardiovascular causes and hospitalizations for cardiovascular issues

Original Date of Publication: April 3, 2003

Study Rundown: At the time of the EPHESUS trial, it had been demonstrated that aldosterone blockade reduces mortality in severe systolic heart failure (as demonstrated in the RALES trial) and prevents ventricular remodeling in patients after an acute myocardial infarction (MI). It was hypothesized that starting a mineralocorticoid antagonist after an acute MI would be beneficial, and the EPHESUS trial was designed to test this proposition. In summary, the trial demonstrated that treatment with eplerenone 3-14 days after an acute MI significantly reduced mortality (RR 0.85; 95%CI 0.75-0.96) and the rate of hospitalization for heart failure (RR 0.85; 95%CI 0.74-0.99).

It has been noted that EPHESUS started randomization several months after data from the RALES trial was published, and one criticism that has been leveled at the EPHESUS trial was regarding their choice of mineralocorticoid antagonist. While the rates of gynecomastia have been lower with eplerenone as compared with spironolactone, the costs of treatment with eplerenone are considerably higher. Moreover, the RALES trial had demonstrated a much larger relative risk reduction in all-cause mortality with spironolactone, thus, some have suggested that EPHESUS should have been conducted with spironolactone instead.

Click to read the study in NEJM

In-Depth [randomized, controlled study]: This multicentre, randomized, controlled study was conducted at 674 centres in 37 countries. In all, 6,642 patients were recruited and randomized to be treated with either eplerenone or placebo in addition to optimal management 3-14 days after suffering an acute MI. Other inclusion criteria were left ventricular ejection fraction (LVEF) ≤40% and clinical findings of heart failure (i.e., pulmonary rales, pulmonary congestion on x-ray, third heart sound). Patients with diabetes did not need clinical evidence of heart failure in order to be included, because of their increased risk of cardiovascular events. Patients were excluded if they were using potassium-sparing diuretics, had serum creatinine >220 µmol/L, or had serum potassium >5.0 mmol/L. There were two primary endpoints: 1) time to death from any cause, and 2) time to death from cardiovascular causes or first hospitalization for a cardiovascular event.

The incidence of both primary endpoints – death from any cause (RR 0.85; 95%CI 0.75-0.96) and death from/hospitalization for cardiovascular causes (RR 0.87; 95%CI 0.79-0.95) – were significantly lower in the eplerenone group as compared to the placebo group. Interestingly, patients in the eplerenone group also had a significantly lower rate of sudden cardiac death (RR 0.79; 95%CI 0.64-0.97) and significantly fewer hospitalizations for heart failure (RR 0.85; 95%CI 0.74-0.99). Not surprisingly, there were significantly more episodes of serious hyperkalemia noted in the eplerenone group compared to the placebo group (5.5% vs. 3.9%, P=0.002). Patients on eplerenone also had significantly more gastrointestinal issues (19.9% vs. 17.7%, P=0.02).

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