Eplerenone Reduces Risk of Death, Hospitalization in Patients with Mild Systolic Heart Failure

A placebo-controlled study has found that eplerenone, a selective mineralocorticoid-receptor antagonist, reduced the risk of both cardiovascular-related death and heart failure hospitalizations in patients with chronic systolic heart failure and mild symptoms. The study was published in the New England Journal of Medicine [2011;364(1):11-21]. Based on available clinical evidence, mineralocorticoid-receptor antagonists such as eplerenone are recommended in current guidelines for patients with systolic heart failure and moderate-to-severe symptoms (New York Heart Association [NYHA] class III or IV), as well as those with acute myocardial infarction complicated by left ventricular systolic dysfunction and heart failure, according to the study authors. The reported study, EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), aimed to characterize the effects of eplerenone, when added to evidence-based therapy, in patients with systolic heart failure and mild symptoms (NYHA class II). Investigators randomly assigned patients with NYHA class II heart failure and an ejection fraction of ≤30% (≤35% if also exhibiting a QRS duration of >130 msec on electrocardiography) to eplerenone or placebo, in addition to standard recommended therapy. The primary outcome identified for the study was a composite of death from cardiovascular causes or hospitalization for heart failure. The study protocol dictated a starting eplerenone dose of 25 mg daily, with an increase to 50 mg daily after 4 weeks as long as the patient’s serum potassium level was ≤5.0 mmol/L. Patients with a glomerular filtration rate of 30 to 49 mL/min/1.73 m2 were to begin eplerenone therapy at a dose of 25 mg on alternate days and increase to 25 mg daily. Patients were evaluated every 4 months for changes in potassium levels. Participating clinicians were instructed to decrease the eplerenone dose in patients with a serum potassium level of 5.5 to 6.9 mmol/L, and withhold eplerenone in patients with a serum potassium level of ≥6.0 mmol/L. A total of 2737 patients were included in the trial and randomized to eplerenone therapy or placebo. The randomized groups exhibited similar baseline characteristics, and all patients were receiving recommended pharmacologic therapy for systolic heart failure. The trial was discontinued prematurely after an interim analysis found that a prespecified threshold for a statistically overwhelming benefit with eplerenone therapy had been reached. The overall median follow-up time for the trial was 21 months. The primary end point of death from cardiovascular causes or hospitalization for heart failure was reported in 18.3% and 25.9% of the eplerenone and placebo groups, respectively. Death linked to cardiovascular events occurred in 10.8% and 13.5% of those randomized to eplerenone and placebo, respectively. Mortality rates from any cause were 12.5% and 15.5% in eplerenone and placebo groups, respectively. The heart failure–related hospitalization rate was 12.0% in eplerenone patients, compared with a rate of 18.4% in the placebo group. Patients treated with eplerenone also had a significant 24% reduction in total number of hospitalizations and a 29% reduction in hospitalizations due to heart failure, compared with patients given placebo. The study drug was discontinued due to adverse events in 13.8% of patients receiving eplerenone and 16.2% of patients receiving placebo. Eplerenone therapy was associated with an increase in potassium levels compared with placebo. Eplerenone also resulted in a greater decrease in systolic blood pressure from baseline. The study authors cautioned that their findings may not be applicable to all patients with systolic heart failure and mild symptoms because their study design specified that eligible patients must have additional factors associated with increased cardiovascular risk, such as age >55 years, an ejection fraction of ≤30% in most cases, and a recent cardiovascular-related hospitalization. The studied population had a relatively low rate of implantable cardioverter-defibrillator use, which was consistent with other registries and trials, according to the authors. Finally, the investigators noted that the early trial termination could have overestimated the treatment benefit of eplerenone, adding that their results were consistent with previous findings.