NEJM 2003;348:1309-21.Background In patients with chronic systolic heart failure, aldosterone blockade reduced death and cardiovascular hospitalizations when added to an ACE inhibitor (RALES trial), which will be reviewed in the section involving trials in patients with chronic heart failure. Efficacy of aldosterone blockade in patients with acute myocardial infarction, complicated by LV dysfunction, had not yet been tested. Aldosterone blockade was believed to prevent ventricular remodeling and collagen formation after AMI as well as a number of other important pathophysiological mechanisms. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) was designed to test the hypothesis that the selective aldosterone blocker, eplerenone, would reduce mortality and cardiovascular hospitalizations in patients with AMI complicated by LV dysfunction and heart failure.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Patients were eligible for randomization 3 to 14 days after AMI with LV dysfunction based on an EF of ≤40% and clinical heart failure based on the presence of pulmonary rales, chest X-ray showing pulmonary venous congestion or the presence of a third heart sound. In patients with diabetes, the presence of clinical heart failure was not a requirement. Exclusion criteria included the use of potassium-sparing diuretics, serum creatinine >2.5 mg/dl, or serum potassium >5 mmol/l.Baseline characteristics The average age of patients was 65 years and over 70% were men; 90% were white. Approximately one quarter of patients had a prior MI, more than 30% had diabetes and 60% had hypertension. The average ejection fraction was 34%. Patients were hemodynamically stable with an average blood pressure of 119/72 mmHg. The average time to randomization from AMI was 7 days. Nearly 50% of patients underwent thrombolysis or angioplasty for the primary MI and at the time of randomization 86% of patients were on an ACE inhibitor, 88% on aspirin, 47% on statins, 75% on beta-blockers, and 60% on diuretics.Procedures Patients received either eplerenone 25 mg daily or a matching placebo for 4 weeks and then the dose was increased to 50 mg daily. If at any time during the study the serum potassium was >5.5 mmol/l, the dose of the study drug was reduced or temporarily discontinued until the serum potassium was <5.5 mmol/l. Follow-up visits took place at 1 and 4 weeks, 3 months, and every 3 months thereafter until the termination of the study. Serum potassium was measured 48 hr after the initiation of treatment, at 1, 4 and 5 weeks, at all scheduled study visits, and within 1 week after any dose change.Endpoints There were 2 primary endpoints. The first was all-cause death, which was tested at the 0.04 level of significance. The second was a composite of death from cardiovascular causes or hospitalizations for cardiovascular events, which was tested at the 0.01 level of significance. The trial was designed to enroll 6200 patients and to continue until 1012 deaths occurred. With testing all-cause death at the 0.04 level of significance, the study had 88.3% power to detect an 18.5% relative difference between groups.Results About 3300 patients were enrolled in the eplerenone and placebo groups. The mean follow-up was 1.3 years (16 months). Compared to placebo, eplerenone significantly reduced all-cause death (RR 0.85; 14.4% vs 16.7%; 95% CI 0.75-0.96; p=0.008) and the composite of cardiovascular death or cardiovascular hospitalization (RR 0.87; 26.7% vs 30.0%; 95% CI 0.79-0.95; p=0.002).For the secondary endpoints, there were significant reductions in the composite of death from any cause or any hospitalization, cardiovascular death, patients with a hospitalization for heart failure and total number of heart failure hospitalizations. There were no significant differences in the number of patients experi