ABSTRACT
BACKGROUND: Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. METHODS: Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia. RESULTS: During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001). CONCLUSIONS: The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
Subject(s)
Mineralocorticoid Receptor Antagonists , Myocardial Infarction/drug therapy , Spironolactone/analogs & derivatives , Spironolactone/therapeutic use , Ventricular Dysfunction, Left/etiology , Aged , Blood Pressure/drug effects , Death, Sudden, Cardiac/etiology , Double-Blind Method , Eplerenone , Female , Heart Failure/drug therapy , Heart Failure/etiology , Hospitalization , Humans , Male , Middle Aged , Mineralocorticoid Receptor Antagonists/adverse effects , Mineralocorticoid Receptor Antagonists/therapeutic use , Myocardial Infarction/complications , Myocardial Infarction/mortality , Potassium/blood , Spironolactone/adverse effects , Survival Analysis , Ventricular Dysfunction, Left/drug therapyABSTRACT
BACKGROUND: Although quantification of the impact of treatment on survival remains the cornerstone of clinical research, the assessment of a broader range of disease outcomes is growing increasingly important. This manuscript provides an overview of the considerations made regarding quantification of a range of clinical and economic outcomes in the EPHESUS (EPlerenone's neuroHormonal Efficacy and SUrvival Study) study, a 6200-patient, randomized, controlled trial of aldosterone blockade in patients with heart failure as a complication of acute myocardial infarction. METHODS AND RESULTS: Relevant clinical outcomes include disease progression (mortality, hospitalization), health status (symptoms, functioning, and quality of life), and costs. The primary hypothesis for the quality of life component of EPHESUS is that eplerenone will improve health status as defined by the Kansas City Cardiomyopathy Questionnaire summary score. In addition to the Kansas City Cardiomyopathy Questionnaire, the Short Form-12, the EuroQOL, the Medical Outcomes Study-Depression Scale and an Anxiety measure will be collected throughout the trial. Health care resource utilization including hospitalizations, emergency room visits, outpatient procedures and tests, and medications will also be collected. Analyses will estimate and describe the effect of aldosterone blockade on costs over time. If both the clinical effect and costs are greater for patients receiving aldosterone blockade, then eplerenone's cost-effectiveness will be estimated. CONCLUSION: The EPHESUS trial has been designed to quantify a wide range of clinical outcomes. This broad range of data will allow a comprehensive assessment of the potential benefits of aldosterone blockade on patient health status and costs.
