Article Identification

• Article Title: Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction
• Citation: Pitt B, Remme WJ, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321.
• DOI/PMID: DOI: 10.1056/NEJMoa022757 | PMID: 12485749

Quick Reference Summary

• In the EPHESUS trial, eplerenone significantly reduced all-cause mortality by 15% (relative risk 0.85; 95% CI, 0.75–0.96; P=0.008) and cardiovascular mortality or hospitalization for cardiovascular events by 13% (relative risk 0.87; 95% CI, 0.79–0.95; P=0.002) compared to placebo in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
• Additionally, eplerenone was associated with a significant reduction in sudden cardiac death (relative risk 0.79; 95% CI, 0.64–0.97; P=0.03) but increased the rate of serious hyperkalemia.

Core Clinical Question

In patients with acute myocardial infarction and left ventricular dysfunction with heart failure (Population), does administration of eplerenone, a selective aldosterone blocker (Intervention), compared to placebo (Comparison), reduce all-cause mortality and cardiovascular morbidity (Outcome)?

Background

• Disease Overview:
  • Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide.
  • Patients with AMI complicated by left ventricular dysfunction and heart failure are at heightened risk for adverse cardiovascular events and death.
• Prior Data:
  • RALES Trial: Demonstrated that spironolactone, an aldosterone blocker, reduces mortality in patients with severe chronic heart failure.
  • ACE Inhibitors and Beta-Blockers: Established as standard therapies improving survival in post-MI patients with left ventricular dysfunction.
• Current Standard of Care:
  • Optimal medical therapy for post-MI patients includes ACE inhibitors or ARBs, beta-blockers, diuretics, and antiplatelet agents to reduce mortality and prevent heart failure progression.
• Knowledge Gaps:
  • The efficacy of selective aldosterone blockers like eplerenone in reducing mortality and morbidity in post-MI patients with left ventricular dysfunction and heart failure, especially when added to current optimal medical therapy, remains uncertain.
• Study Rationale:
  • Eplerenone, offering greater selectivity and fewer side effects compared to spironolactone, may provide additional mortality and morbidity benefits in the targeted patient population. The EPHESUS trial was designed to test this hypothesis.

Methods Summary

• Study Design: Multicenter, international, randomized, double-blind, placebo-controlled trial.
• Setting and Time Period: Conducted at 674 centers across 37 countries between December 1999 and December 2001.
• Population Characteristics:
  • 6,642 patients with acute myocardial infarction (3 to 14 days post-MI).
  • Left ventricular ejection fraction ≤40%.
  • Heart failure evidenced by pulmonary rales, pulmonary venous congestion, or a third heart sound.
• Inclusion/Exclusion Criteria:
  • Inclusion: Post-MI patients with left ventricular dysfunction and heart failure.
  • Exclusion: Use of potassium-sparing diuretics, serum creatinine >2.5 mg/dL, or serum potassium >5.0 mmol/L before randomization.
• Intervention Details:
  • Eplerenone Group: 25 mg per day initially, titrated to a maximum of 50 mg per day.
  • Placebo Group: Matching placebo.
• Control/Comparison Group Details: Placebo administered in addition to standard medical therapy.
• Primary and Secondary Outcomes:
  • Primary Endpoints: Death from any cause; death from cardiovascular causes or first hospitalization for a cardiovascular event.
  • Secondary Endpoints: Death from cardiovascular causes; death from any cause or any hospitalization.
• Basic Statistical Analysis Approach:
  • Cox Proportional-Hazards Regression: Stratified by geographic region.
  • Intention-to-Treat Principle: Applied for all primary and secondary endpoint analyses.
• Sample Size Calculations:
  • Designed to enroll 6,200 patients and continue until 1,012 deaths occurred.
  • Power: 88.3% to detect an 18.5% difference in all-cause mortality at α=0.05.
• Ethics and Funding Information:
  • Approved by institutional review boards at each site.
  • All patients provided written informed consent.
  • Trial conducted by the study sponsor with declared conflicts of interest among investigators.

Detailed Results

• Participant Flow and Demographics:
  • Randomization: 6,642 patients randomized (3,313 to placebo, 3,319 to eplerenone).
  • Baseline Characteristics: Comparable between groups; majority receiving ACE inhibitors/ARBs (87%), beta-blockers (75%), aspirin (88%), and diuretics (60%).
  • Follow-Up: Mean duration of 16 months (range, 0 to 33 months).
• Primary Outcome Results:
  • All-Cause Mortality:
    • Eplerenone: 478 deaths (14.4%)
    • Placebo: 554 deaths (16.7%)
    • Relative Risk: 0.85 (95% CI, 0.75–0.96)
    • P-value: 0.008 (Statistically Significant)
  • Cardiovascular Mortality or Hospitalization:
    • Eplerenone: 885 events (26.7%)
    • Placebo: 993 events (30.0%)
    • Relative Risk: 0.87 (95% CI, 0.79–0.95)
    • P-value: 0.002 (Statistically Significant)
• Secondary Outcome Results:
  • Cardiovascular Mortality:
    • Eplerenone: 407 deaths (12.3%)
    • Placebo: 483 deaths (14.6%)
    • Relative Risk: 0.83 (95% CI, 0.72–0.94)
    • P-value: 0.005 (Statistically Significant)
  • Death from Any Cause or Any Hospitalization:
    • Relative Risk: 0.92 (95% CI, 0.86–0.98)
    • P-value: 0.02 (Statistically Significant)
  • Sudden Death from Cardiac Causes:
    • Relative Risk: 0.79 (95% CI, 0.64–0.97)
    • P-value: 0.03 (Statistically Significant)
• Adverse Events/Safety Data:
  • Serious Hyperkalemia:
    • Eplerenone: 5.5%
    • Placebo: 3.9%
    • P-value: 0.002 (Statistically Significant)
  • Hypokalemia:
    • Eplerenone: 8.4%
    • Placebo: 13.1%
    • P-value: <0.001 (Statistically Significant)
  • Other Lab Changes:
    • Serum Creatinine: Increased by 0.06 mg/dL in eplerenone vs. 0.02 mg/dL in placebo (P<0.001)
    • Potassium Levels: Increased by 0.3 mmol/L in eplerenone vs. 0.2 mmol/L in placebo (P<0.001)

Authors' Conclusions

The addition of eplerenone to optimal medical therapy significantly reduces both all-cause mortality and the composite endpoint of cardiovascular mortality or hospitalization for cardiovascular events in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. These benefits are accompanied by a reduction in sudden cardiac death and heart failure hospitalizations. However, eplerenone treatment increases the risk of serious hyperkalemia, highlighting the necessity for vigilant monitoring of serum potassium and renal function during therapy.

Critical Analysis

A. Strengths

• Large Sample Size: With over 6,600 patients enrolled from 37 countries, the study's findings are highly generalizable to diverse populations.
• Rigorous Study Design: The randomized, double-blind, placebo-controlled methodology minimizes bias and enhances internal validity.
• Comprehensive Outcome Measures: Evaluation of multiple clinically meaningful endpoints, including all-cause mortality, cardiovascular mortality, and hospitalizations, provides a thorough assessment of eplerenone's efficacy.

B. Limitations

• Increased Risk of Hyperkalemia: The significant rise in serious hyperkalemia among eplerenone-treated patients poses a safety concern, particularly for those with underlying renal impairment.
• Exclusion Criteria: Patients with elevated serum potassium or creatinine levels were excluded, potentially limiting the applicability of results to sicker or more diverse patient populations.
• Shorter Follow-Up Duration: The mean follow-up of 16 months is relatively short compared to other trials like RALES, possibly missing long-term outcomes and adverse effects.

Literature Review

Eplerenone in Post-Myocardial Infarction Left Ventricular Dysfunction

The Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), conducted by Pitt et al. (2003), was a seminal randomized controlled trial investigating the role of eplerenone, a selective aldosterone blocker, in reducing mortality and morbidity in patients with acute myocardial infarction (AMI) complicated by left ventricular dysfunction and heart failure. Over a mean follow-up of 16 months, eplerenone demonstrated significant reductions in all-cause mortality and the composite of cardiovascular mortality or hospitalization for cardiovascular events, establishing aldosterone antagonism as a critical component of post-MI therapy.

Clinical Application

• The EPHESUS trial supports the incorporation of eplerenone into the standard post-MI treatment regimen for patients with left ventricular dysfunction and heart failure, particularly enhancing survival and reducing cardiovascular hospitalizations.
• Clinicians should consider initiating eplerenone early post-MI in eligible patients, especially those with diabetes and reduced ejection fraction, while carefully monitoring serum potassium and renal function to mitigate the risk of hyperkalemia.

How To Use This Info In Practice

Practitioners should integrate eplerenone into the treatment plan for post-MI patients with left ventricular dysfunction and heart failure as per current ESC guidelines, reinforcing its role alongside standard therapies to improve survival and reduce hospitalizations, while ensuring appropriate patient monitoring and adherence to guideline-recommended safety protocols.