Review of the EPHESUS Trial

Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction

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.

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 experiencing any hospitalization or the total number of any hospitalizations.

Four subgroups groups demonstrated treatment effect heterogeneity in that eplerenone did not reduce all-cause death: patients with a pulse pressure <45 mmHg, baseline serum creatinine ≥1 mg/dl, no history of hypertension at baseline and inability to take an ACE or beta blocker. The p values for the interaction terms were <0.05 in each case.

During the study, 16% of the eplerenone group permanently discontinued the study drug compared to 15% in the placebo group. Withdrawals due to adverse events were the same in both groups. Serious hyperkalemia (potassium ≥6 mm/l) was significantly higher in the eplerenone group (5.5% vs 3.9%; p=0.002) but serious hypokalemia (potassium <3.5 mm/l) was significantly lower (8.4% vs 13.1%; p<0.001). The mean dose of eplerenone during the study was 43 mg in the intervention group.

Conclusions In patients with AMI complicated by heart failure and significant LV dysfunction, eplerenone significantly reduced the primary endpoints of all-cause death and the composite of cardiovascular death and cardiovascular hospitalizations, with NNTs of 43 and 30, respectively.

There did appear to be subgroups of patients who did not benefit from eplerenone; particularly patients with low pulse pressure, serum creatinine ≥1 mg/dl, no history of hypertension or inability to take an ACE inhibitor or beta blocker - in essence, patients who are less robust and/or with more severe heart failure following AMI benefited less or not at all.

Hyperkalemia occurred more often in patients on eplerenone but was countered by lower rates of hypokalemia. The external validity of the trial is limited by the frequency of outpatient visits and laboratory monitoring, which is likely challenging to replicate in real-world settings. Furthermore, treatment response variation discussed above makes it unlikely that many patients in clinical practice would benefit from the drug.

In EPHESUS, we begin to see the diminishing effects of adding more and more medical therapies to the repertoire for the same medical condition. Despite it being a clearly positive trial for the most important outcome of all-cause death and the composite of cardiovascular death or hospitalization, there was no difference in patients hospitalized for any cause or the total number of hospitalizations.

Eplerenone use in post-MI patients with reduced EF needs to be individualized to patients who are robust enough to benefit from it. The phenotypical patient, most likely to benefit, is someone <65 years of age who is hypertensive or normotensive (hypertensive better), despite being on an ACE, ARB or ARNI, with normal kidney function.