EPHESUS Trial Summary

Article Identification

Article Title: Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction

Authors (Top 5): Bertram Pitt, M.D.; Willem Remme, M.D.; Faiez Zannad, M.D.; James Neaton, Ph.D.; Felipe Martinez, M.D.

Journal Name: The New England Journal of Medicine

Year: 2003

Volume: 348

Issue: 14

Type of Study: Double-blind, placebo-controlled, randomized clinical trial

DOI/PMID: PMID: 12668699 DOI: 10.1056/NEJMoa030207

Quick Reference Summary

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) in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

The number needed to treat (NNT) to save one life in one year was estimated at 50, while the NNT to prevent one death from cardiovascular causes or one hospitalization was 33.

Core Clinical Question

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

Background

Disease Overview:

Acute myocardial infarction (AMI) can lead to left ventricular dysfunction and heart failure, significantly increasing morbidity and mortality.

Prior Data:

Aldosterone blockade has been shown to reduce mortality in severe chronic heart failure (RALES trial).

Eplerenone selectively blocks mineralocorticoid receptors without affecting glucocorticoid, progesterone, or androgen receptors.

Current Standard of Care:

Optimal medical therapy for AMI with left ventricular dysfunction includes ACE inhibitors, beta-blockers, diuretics, and coronary reperfusion.

Knowledge Gaps Addressed:

The efficacy of aldosterone blockade with eplerenone in reducing mortality and hospitalization in AMI patients with left ventricular dysfunction on optimal therapy.

Study Rationale:

To determine if selective aldosterone blockade with eplerenone can provide additional survival benefits and reduce cardiovascular events in this patient population.

Methods Summary

Study Design:

Multicenter, international, randomized, double-blind, placebo-controlled trial.

Setting and Time Period:

674 centers across 37 countries; randomized between December 27, 1999, and December 31, 2001.

Population Characteristics:

6,642 patients with AMI complicated by left ventricular dysfunction (ejection fraction ≤40%) and heart failure.

Inclusion/Exclusion Criteria:

Inclusion: 3-14 days post-AMI, left ventricular ejection fraction ≤40%, evidence of 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 starting at 25 mg/day, titrated to a maximum of 50 mg/day.

Control/Comparison Group Details:

Matching placebo administered under the same regimen.

Primary and Secondary Outcomes:

Primary: Death from any cause; death from cardiovascular causes or first hospitalization for cardiovascular events.

Secondary: Death from cardiovascular causes; death from any cause or any hospitalization.

Statistical Analysis Approach:

Cox proportional-hazards regression, Kaplan–Meier curves, intention-to-treat analysis.

Sample Size Calculations:

Planned enrollment of 6,200 patients, continued until 1,012 deaths occurred.

Ethics and Funding Information:

Approved by institutional review boards; all patients provided written informed consent. Funding sources not explicitly detailed in the provided text.

Detailed Results

Participant Flow and Demographics:

6,642 randomized (3,313 placebo; 3,319 eplerenone; 10 excluded).

Baseline characteristics were similar between groups.

Majority received standard therapies: ACE inhibitors/angiotensin-receptor blockers (87%), beta-blockers (75%), aspirin (88%), diuretics (60%).

Primary Outcome Results:

All-Cause Mortality: 478 deaths (14.4%) eplerenone vs. 554 deaths (16.7%) placebo; relative risk 0.85 (95% CI, 0.75–0.96; P=0.008).

Cardiovascular Mortality or Hospitalization: 885 patients (26.7%) eplerenone vs. 993 patients (30.0%) placebo; relative risk 0.87 (95% CI, 0.79–0.95; P=0.002).

Effect Sizes and Confidence Intervals:

Relative risk reductions were statistically significant for both primary outcomes.

Secondary Outcome Results:

Death from Cardiovascular Causes: 407 deaths (12.3%) eplerenone vs. 483 deaths (14.6%) placebo; relative risk 0.83 (95% CI, 0.72–0.94; P=0.005).

Death from Any Cause or Any Hospitalization: relative risk 0.92 (95% CI, 0.86–0.98; P=0.02).

Sudden Death from Cardiac Causes: relative risk 0.79 (95% CI, 0.64–0.97; P=0.03).

Subgroup Analyses:

Beneficial effects consistent across subgroups; some nominal interactions observed but not significant across both primary endpoints.

Adverse Events/Safety Data:

Serious Hyperkalemia: 5.5% eplerenone vs. 3.9% placebo; P=0.002.

Hypokalemia: 8.4% eplerenone vs. 13.1% placebo; P<0.001.

Increased serum creatinine and potassium levels in eplerenone group.

No significant differences in other laboratory abnormalities or adverse events.

Results Tables

Outcome	Eplerenone Group	Placebo Group	Difference (95% CI)	P-value
Death from Any Cause	478 (14.4%)	554 (16.7%)	RR 0.85 (0.75–0.96)	0.008
Death from Cardiovascular Causes	407 (12.3%)	483 (14.6%)	RR 0.83 (0.72–0.94)	0.005
Death from Cardiovascular Causes or Hospitalization	885 (26.7%)	993 (30.0%)	RR 0.87 (0.79–0.95)	0.002
Sudden Death from Cardiac Causes	-	-	RR 0.79 (0.64–0.97)	0.03
Serious Hyperkalemia	5.5%	3.9%	RR -	0.002
Hypokalemia	8.4%	13.1%	RR -	<0.001

Authors' Conclusions

Primary Conclusions:

Eplerenone, when added to optimal medical therapy, significantly reduces mortality and morbidity in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

Interpretation of Results:

The benefits are primarily due to reductions in cardiovascular mortality, especially sudden cardiac deaths, and hospitalizations for heart failure.

Clinical Implications:

Eplerenone should be considered as an adjunct therapy in appropriate post-MI patients to improve survival and reduce hospitalizations.

Future Research Recommendations:

Further studies to explore the mechanisms of eplerenone’s myocardial protection and its long-term effects in diverse patient populations.

Literature Review

Comparisons to Other Studies:

RALES (Randomized Aldactone Evaluation Study): Showed spironolactone reduced mortality in chronic severe heart failure; EPHESUS demonstrated similar benefits in acute settings with eplerenone.

CAPRICORN and OPTIMAAL: Studies on carvedilol and losartan showed lower mortality rates compared to EPHESUS placebo group, likely due to differences in patient populations and treatments.

Guideline Comparisons:

Current standards include ACE inhibitors and beta-blockers; EPHESUS adds evidence for aldosterone blockers in specific post-MI populations.

Detailed on Literature Context

A. Previous Studies and Meta-Analyses:

RALES: Demonstrated spironolactone reduced mortality in severe chronic heart failure (N Engl J Med. 1999;341(10):709–717).

CAPRICORN: Showed carvedilol benefits post-MI with left ventricular dysfunction (Lancet. 2001;358(9287):1033–1038).

OPTIMAAL: Evaluated losartan in post-MI patients (Lancet. 2002;359(9316):1195–1203).

B. Contrasting Methodological Quality:

RALES focused on chronic heart failure with lower ejection fractions and fewer beta-blocker users; EPHESUS involved acute MI with left ventricular dysfunction and higher beta-blocker use.

C. Comparisons with Guidelines:

2003 ACC/AHA guidelines recommend ACE inhibitors and beta-blockers post-MI; EPHESUS supports adding aldosterone blockers for specific patients.

D. This Trial's Contribution:

EPHESUS extends the benefits of aldosterone blockade to acute MI patients with left ventricular dysfunction on optimal therapy, confirming and expanding on RALES findings (N Engl J Med. 2003;348: 1387–1397).

Critical Analysis

A. Strengths:

• Large Sample Size: 6,642 patients enhances the power and reliability of results.
• Randomized Controlled Design: Minimizes bias and allows for causal inferences.
• Double-Blind and Placebo-Controlled: Reduces placebo effects and observer bias.
• International, Multicenter Setup: Increases generalizability across diverse populations.
• Comprehensive Outcome Measures: Included mortality and hospitalization, providing a broad view of clinical impact.
• Intent-to-Treat Analysis: Preserves randomization benefits and handles dropouts appropriately.

B. Limitations:

• Short Follow-Up Period: Mean of 16 months may not capture long-term effects and rare adverse events.
• Increased Hyperkalemia Risk: Higher incidence of serious hyperkalemia requires careful patient selection and monitoring.
• Generalizability Issues: Predominantly included patients who survived 3-14 days post-MI and met specific criteria, limiting applicability to all post-MI patients.
• Missing Data: 17 patients had unknown vital status; however, this is minimal.
• Funding and Conflicts of Interest: Not explicitly detailed, which may raise questions about potential biases.

C. Literature Context:

A. Previous Studies and Meta-Analyses:

RALES: Spironolactone beneficial in chronic heart failure (N Engl J Med. 1999;341(10):709–717).

CAPRICORN: Carvedilol reduced mortality post-MI (Lancet. 2001;358(9287):1033–1038).

OPTIMAAL: Losartan did not significantly outperform ACE inhibitors (Lancet. 2002;359(9316):1195–1203).

B. Contrasting Methodological Quality:

RALES vs. EPHESUS: RALES focused on chronic heart failure with lower ejection fractions; EPHESUS included acute MI patients with higher ejection fractions and more comprehensive background therapy.

C. Comparisons with Guidelines:

ACC/AHA 2003 Guidelines: Recommend ACE inhibitors and beta-blockers post-MI; EPHESUS supports adding aldosterone blockers in selected patients.

D. This Trial's Contribution:

EPHESUS confirms and extends the benefits of aldosterone blockade to acute MI settings, complementing RALES and providing evidence for integrating eplerenone into post-MI care protocols (N Engl J Med. 2003;348:1387–1397).

Clinical Application

Eplerenone should be integrated into the treatment regimen for patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure who are already receiving optimal medical therapy, including ACE inhibitors and beta-blockers.

This intervention is particularly applicable to patients without severe renal impairment and requires monitoring of serum potassium levels to mitigate the risk of hyperkalemia.

How to Use This Info In Practice

Clinicians should consider adding eplerenone to the treatment plan for eligible post-MI patients with left ventricular dysfunction and heart failure to enhance survival and reduce hospitalizations, ensuring careful monitoring of electrolyte levels.

Notes for Clarity

• Statistical Significance: All primary and key secondary outcomes reached statistical significance (P<0.05).
• Confidence Intervals: Provided for all relative risks, indicating precision of estimates.
• Number Needed to Treat/Harm: NNT for mortality benefit is 50; NNT to prevent one cardiovascular death or hospitalization is 33; Number Needed to Harm (NNH) for serious hyperkalemia is higher but specific value not provided.
• Funding Sources and Conflicts of Interest: Not detailed in the provided text; typically found in full article disclosures.
• Areas of Uncertainty: Long-term effects beyond the study period and applicability to broader populations.
• Post-Hoc Analyses: Subgroup analyses were exploratory and not powered for definitive conclusions.

This structured summary provides a comprehensive and accessible overview of the EPHESUS trial, facilitating quick understanding and application of its findings in clinical practice.