Eplerenone Post-AMI Heart Failure Efficacy and Survival Study - EPHESUS

Oct 14, 2003
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Date Presented:
01/01/2003
Date Published:
01/01/2003
Date Updated:
10/14/2003
Original Posted Date:
10/14/2003
References

Description:

The goal of the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) was to determine the efficacy of the new selective aldosterone receptor blockade eplerenone in patients with acute myocardial infarction (AMI) complicated by heart failure and systolic left ventricular (LV) dysfunction.

Hypothesis:

Treatment with the selective aldosterone receptor blockade eplerenone reduces overall mortality and cardiovascular (CV) mortality or hospitalization for CV events among patients with AMI complicated by LV dysfunction and heart failure who are receiving optimal medical therapy.

Study Design

  • Blinded
  • Parallel
  • Randomized

Patients Enrolled: 6,632
Mean Follow Up: Mean 16 months
Mean Patient Age: Mean age 64 years
Female: 29
Mean Ejection Fraction: Mean 33%

Patient Populations:

AMI; LV dysfunction (ejection fraction ≤40%); radionuclide angiography, or angiography of the LV after the index AMI and before randomization; and heart failure as documented by the presence of pulmonary rales, chest radiography showing pulmonary venous congestion, or the presence of a third heart sound. Presence of heart failure was not required in diabetic patients.

Exclusions:

Use of potassium-sparing diuretics, serum creatinine >2.5 mg/dl, and serum potassium concentration >5.0 mmol/l before randomization.

Primary Endpoints:

1) Death from any cause, and 2) death or hospitalization from CV causes.

Secondary Endpoints:

1) Death from CV causes, and 2) death from any cause or any hospitalization.

Drug/Procedures Used:

Patients were randomized to the new selective aldosterone receptor blockade eplerenone (25 mg titrated to 50 mg/d; n=3313) or placebo (n=3319) in addition to standard heart failure therapy 3-14 days post-AMI.

Concomitant Medications:

Optimal medical therapy could include angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, diuretics, and beta-blockers, as well as coronary reperfusion therapy. Baseline use was as follows: ACE inhibitors or angiotensin-receptor blockers (87%), beta-blockers (75%), aspirin (88%), and diuretics (60%).

Principal Findings:

Fewer deaths occurred in the eplerenone arm compared with the placebo arm (14.4% vs. 16.7%, relative risk [RR] 0.85, p=0.008). The second primary end point, CV deaths or hospitalizations, occurred less frequently in the eplerenone arm (26.7% vs. 30.0%, RR 0.87, p=0.002), as did the secondary end point of death or hospitalization from any cause (RR 0.92, p=0.02).

Sudden death from cardiac causes occurred less in the eplerenone arm (RR 0.79, p=0.03). Serious adverse events were similar between the two arms with the exception of serious hyperkalemia, which was higher in the eplerenone group (5.5% vs. 3.9%, p=0.002).

Interpretation:

Among patients with AMI complicated by heart failure and systolic LV dysfunction, treatment with the new selective aldosterone receptor blockade eplerenone was associated with a reduction in the primary end point of all-cause mortality and the composite of death or hospitalization from CV causes, as well as the prespecified secondary end points. The majority of patients in this trial were already receiving optimal therapy in addition to eplerenone. With the exception of serious hyperkalemia, there were no serious additional side effects in the eplerenone arm.

This is unlike data reported in the RALES trial using the aldosterone antagonist spironolactone, which was associated with gynecomastia and sexual dysfunction. However, no head to head data are available as to which aldosterone antagonists are optimal. No data are currently available on the cost difference between eplerenone and the generic spironolactone. Given the higher rate of hyperkalemia associated with eplerenone, serum potassium should be carefully monitored.

References:

Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.

Presented at Late-Breaking Clinical Trials, ACC 2003.

Presented at the European Society of Cardiology, Vienna, Austria, September 2003.

Keywords: Myocardial Infarction, Mineralocorticoid Receptor Antagonists, Death, Sudden, Hyperkalemia, Spironolactone, Hyperemia, Gynecomastia, Heart Sounds, Potassium, Receptors, Mineralocorticoid, Heart Failure, Respiratory Sounds, Hospitalization, Ventricular Dysfunction, Left, Radionuclide Angiography, Diabetes Mellitus


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