Authors
Pitt B, Remme WJ, Zannad F et al.
Title
Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms
References
N Engl J Med 2003;348:1309-21
Background
Aldosterone blockade has been demonstrated to decrease mortality and hospitalization rates in patients with severe left-sided heart failure and on an ACE inhibitor. Its role in patients with an acute myocardial infarction (AMI) and left ventricular dysfunction has not been established.
Purpose
To determine whether eplerenone, when added to optimal medical therapy, decreases mortality and hospitalization rates in patients with an AMI and left ventricular dysfunction with heart failure.
Design
Randomized, double-blind, placebo-controlled trial 6642 randomized patients: 3319 eplerenone and 3313 placebo eligible for randomization 3-14 days after AMI if also documentation for left ventricular dysfunction (ie LVEF ≤40%) and heart failure (ie. rales, pulmonary venous congestion on chest x-ray or third heart sound); as well as diabetics with documented left ventricular dysfunction after AMI (symptoms of heart failure did not have to be demonstrated) receiving optimal medical therapy which could include ACE inhibitor or ARBs (~85% of randomized patients), diuretic (~60%), beta-blocker (75%), as well as coronary reperfusion therapy
Exclusion Criteria
serum creatinine > 220 umol/L serum potassium > 5 mmol/L potassium sparing diuretics
Follow-Up
Mean 16 months (range, 0-33 months)
Treatment Regimen
Eplerenone 25 mg once daily vs. placebo (increased to 50 mg once daily after 4 wks) if serum potassium >5.5 mmol/L during the study, then dose was reduced or treatment was temporarily discontinued until <5.5 mmol/L serum potassium measured at 48hrs, at week one, four and five, at all scheduled visits (at week one and four, at month three and every three months thereafter), and within one week after any change in dose
Results
Primary Endpoints Death from any cause: 14.4% (eplerenone) vs. 16.7% (placebo); relative risk 0.85 (0.75-0.96), p=0.008. CV Death or CV hospitalizations (heart failure, recurrent AMI, stroke, or ventricular arrhythmia): 26.7% (eplerenone) vs. 30% (placebo); relative risk 0.87 (0.79-0.95), p=0.002. Secondary Endpoints All cause death or any hospitalization: 52.1% (eplerenone) vs. 55.2 % (placebo); relative risk 0.92 (0.86-0.98), p=0.02 CV death (sudden death, AMI, heart failure, stroke, other): 12.3% (eplerenone) vs. 14.6% (placebo); relative risk 0.83 (0.72-0.94), p=0.005 statistically significant for sudden death (relative risk 0.79; p=0.03) Safety: Serious hyperkalemia (> 6 mmol/L), eplerenone (5.5%) vs. placebo (3.9%), p=0.002 Serious hyperkalemia with CrCl <50 mL/min, eplerenone (10.1%) vs. placebo (5.9%), p=0.006 Serious hyperkalemia with CrCl >50 mL/min, eplerenone (4.6%) vs. placebo (3.5%), p=0.04 Similar rates for gynecomastia between the two groups
Summary
When added to optimal medical therapy, eplerenone significantly reduces mortality and hospitalizations in acute myocardial infarction patients with left ventricular dysfunction and heart failure as compared to placebo.