Eplerenone Reduces Deaths and Hospitalizations in Mild Heart Failure

Chicago—Eplerenone added to standard therapy for heart failure (HF) significantly reduced the risk of cardiovascular death or HF in patients with mild HF versus placebo. These findings of the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial extend the use of eplerenone to a new group of HF patients—those with mild symptoms. Eplerenone was previously found of benefit in patients with severe HF and in post–myocardial infarction (MI) patients with HF. “Severe HF is one end of the HF spectrum and post-MI HF is the other end. EMPHASIS-HF improves mild HF and fills in the gap,” stated Faiez Zannad, MD, Nancy University, Nancy, France, who presented results of this phase 3 trial at the AHA meeting. EMPHASIS-HF showed a statistically significant 37% relative risk reduction versus placebo (P<.0001) for the primary composite end point of death from cardiovascular causes or HF hospitalization. Eplerenone achieved a 24% reduction in the rate of death from any cause (P=.0081), a 23% reduction in the rate of hospitalization for any cause (P<.0001), and a 42% reduction in the rate of HF hospitalization (P<.0001). The effect of eplerenone on the primary end point was consistent across all prespecified subgroups. “The internal consistency [of the effect of eplerenone] was robust,” Dr. Zannad said. The study enrolled 2584 patients with New York Heart Association class II HF, ejection fraction <30%, who were treated with recommended doses of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), or both, and a beta-blocker unless contraindicated. Patients were entered in the trial within 6 months of a cardiovascular hospitalization or with elevated B-type natriuretic peptide (>250 pg/mL); 2737 patients were randomized to eplerenone 25 to 50 mg/day (n=1364) or placebo (n=1373). The study was stopped prematurely after the second interim analysis on May 6, 2010, due to an overwhelming benefit for eplerenone. Data presented at AHA were based on this cut-off date. Median follow-up was 21 months (4783 patient-years of follow-up). Demographic characteristics of both groups were well balanced at baseline. Mean age was 68 years, about 22% were female, about 83% where white, and two thirds had hypertension. Median blood pressure was 124/75 mm Hg. About 30% had diabetes. At baseline, about 69% had ischemic heart disease, about 50% had an MI history, and about 52% had a history of HF hospitalization. Mean left ventricular ejection fraction was 26%, about 30% had atrial fibrillation or flutter, about 26% had prolonged QRS duration >130 msec, and about 25% had left bundle branch block. At baseline, about 13% had an implantable cardioverter defibrillator, about 2.8% of the eplerenone group and 1.6% of the placebo group had cardiac resychronization therapy (pacemaker), 5.4% of the eplerenone group and 7.2% of the placebo group had cardiac resychronization therapy (defibrillator), 84% were on a diuretic, about 93% were on an ACEI or ARB or both, 87% were on a beta-blocker, about 26% were on digitalis glycosides, about 14% were on an antiarrhythmic drug, and about 88% were on an antithrombotic drug. Eplerenone was safe. Hyperkalemia was the only side effect that was significantly more frequent with eplerenone compared with placebo (8.0% vs 3.7%, respectively; P<.001); hyperkalemia is an expected side effect of the drug. No significant difference in drug discontinuation was observed during the study between eplerenone-treated and placebo patients. No deaths occurred that were attributed to hospitalization for worsening renal failure or hyperkalemia. “We believe that the robustness of these findings, in conjunction with consistent results from earlier HF trials, provides compelling evidence to change medical practice,” Dr. Zannad said.