EPHESUS

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Pitt B, et al. "Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction". The New England Journal of Medicine. 2003. 348(14):1309-21.
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Clinical Question

In patients with acute MI complicated by LV dysfunction and HF symptoms, does eplerenone reduce mortality?

Bottom Line

Eplerenone reduced the rate of mortality among patients with acute MI complicated by LV dysfunction and HF symptoms.

Major Points

While RALES (1999) and EMPHASIS-HF (2011) demonstrated a mortality benefit of aldosterone antagonists in HFrEF, the 2003 Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated a 15% reduced mortality with the aldosterone antagonist eplerenone in LV dysfunction complicating acute MI. Eplerenone was also associated with reductions in sudden cardiac death and hospitalizations for HF. Importantly, this study was done in the era of widespread beta-blocker use, in contrast to the RALES study in which only 10% patients were on beta-blocker therapy.

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[1]

  • Aldosterone antagonists recommended if NYHA class II-IV, LVEF ≤35% unless contraindicated (class I, level A)
    • If NYHA class II, should have prior CV hospitalization or elevated BNP (or analogous test)
  • Aldosterone antagonists recommended after MI if LVEF ≤40% with HF symptoms or DM unless contraindicated (class I, level B)
  • Aldosterone antagonists harmful if creatinine >2.5 mg/dL in men or >2.0 mg/dL in women (GFR <30 mL/min/1.73 m2) or potassium ≥5.0 mEq/L (class III, level B)

Design

  • Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
  • N=6,642
    • Eplerenone (n=3,313)
    • Placebo (n=3,319)
  • Setting: 674 centers in 37 countries
  • Enrollment: 1999-2001
  • Median follow-up: 16 months
  • Primary outcomes:
    • All-cause mortality
    • CV mortality or hospitalization for CV events

Population

Inclusion Criteria

  • MI in prior 3-14 days
  • LVEF <40%
  • HF (defined as pulmonary rales, CXR with pulmonary venous congestion, or S3 heart sound)
    • No symptoms required in diabetic patients

Exclusion Criteria

  • Use of potassium-sparing diuretics
  • Creatinine >2.5 before randomization
  • Serum potassium >5 before randomization

Baseline Characteristics

From the eplerenone group. Groups were similar for each characteristic.

  • Mean age: 64 years
  • Race:
    • White: 90%
    • Black: 1%
    • Other: 9%
  • Female: 28%
  • BP: 119/72 mm Hg
  • LVEF: 33%
  • Days from MI to randomization: 7.3
  • Prior HF hospitalization: 7%
  • Prior PCI: 45%
  • HF symptoms: 90%
  • Serum potassium: 4.3 meq/L
  • Serum creatinine: 1.1 mg/dL (97 umol/L)
  • GFR: 79 mL/min
  • Medical history:
    • Acute MI: 27%
    • Diabetes: 32%
    • HF: 14%
    • HTN: 60%
  • Medications:
    • ACE or ARB: 86%
    • Beta-blocker: 75%
    • Diuretics: 60%
    • Aspirin: 88%
    • Statins: 47%

Interventions

  • Randomized to a group:
    • Eplerenone - Eplerenone 25mg for 4 weeks then titrated to 50mg daily as tolerated, dose held for hyperkalemia >5.5
    • Placebo
  • All patients received optimal medical therapy, including ACE inhibitors, ARBs, diuretics, beta-blockers, and coronary revascularization

Outcomes

Comparisons are eplerenone vs. placebo.

Primary Outcomes

All-cause mortality
14.4% vs. 16.7% (RR 0.85; 95% CI 0.75-0.96; P=0.008)
CV mortality or hospitalization for CV events
26.7% vs. 30.0% (RR 0.87; 95% CI 0.79-0.85; P=0.002)

Secondary Outcomes

All-cause mortality or any hospitalization
52.1% vs. 55.2% (RR 0.92; 95% CI 0.86-0.98; P=0.02)
CV mortality
12.2% vs. 14.6% (RR 0.79; 95% CI 0.64-0.97; P=0.03)
Sudden cardiac death: 4.9% vs. 6.1% (RR 0.79; 95% CI 0.64-0.97; P=0.03)
Acute MI: 2.4% vs. 2.8% (RR 0.82; 95% CI 0.61-1.10; P=0.19)
HF: 3.1% vs. 3.8% (RR 0.80; 95% CI 0.62-1.04; P=0.10)
Any hospitalization
45.0% vs. 46.1% (RR 0.95; 95% CI 0.89-1.02; P=0.20)
Hospitalization for cardiovascular event
18.3% vs. 19.6% (RR 0.91; 95% CI 0.81-1.01; P=0.09)

Additional Analyses

Study Drug Dose Equivalents
42.6mg vs. 43.5mg

Adverse Events

Hyperkalemia
3.4% vs. 2.0% (P<0.001)
Serious hyperkalemia (≥6 meq/L)
5.5% vs. 3.9% (P=0.002)
Hypokalemia
0.5% vs. 1.5% (P<0.001)
Serious hypokalemia (<3.5 meq/L)
8.4% vs. 13.1% (P<0.001)
GI disorder
19.9% vs 17.7% (P=0.02)
Gynecomastia in Males
0.5% vs 0.6% (P=NS)

Funding

Funding provided by Pharmacia, the makers of Inspra (eplerenone).

Further Reading

  1. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.