Safety and Efficacy of Early Treatment With Eplerenone in Patients With Acute Myocardial Infarction - REMINDER

May 07, 2014
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Pfizer
Date Presented:
01/01/2013
Date Published:
01/01/2014
Date Updated:
05/07/2014
Original Posted Date:
05/07/2014
References

Description:

The goal of the trial was to evaluate treatment with the mineralocorticoid receptor antagonist eplerenone compared with placebo among patients with ST-segment elevation myocardial infarction (STEMI) without heart failure or significant left ventricular (LV) systolic dysfunction.

Hypothesis:

Early administration of eplerenone will improve clinical outcomes.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Patients with STEMI without evidence for heart failure or significant LV dysfunction

    Number of enrollees: 1,012
    Duration of follow-up: mean 10.5 months
    Mean patient age: 59 years
    Percentage female: 17%

Exclusions:

  • Known LVEF <40% or prior history of heart failure
  • Defibrillator
  • Significant aortic or mitral valve disease
  • Hypertrophic cardiomyopathy
  • Cardiac surgery 30 days prior to randomization
  • Known renal dysfunction or eGFR ≤30 ml/min/1.73 m2
  • Need for potassium-sparing diuretics

Primary Endpoints:

  • Cardiovascular mortality, ventricular arrhythmia, extended initial hospital stay, heart failure re-hospitalization, LVEF ≤40% at 1 month, or elevated BNP/NT-proBNP at 1 month

Drug/Procedures Used:

STEMI patients without heart failure or significant LV systolic dysfunction were randomized within 24 hours of symptom onset to eplerenone 50 mg daily (n = 506) versus placebo (n = 506).

Patients were initiated on eplerenone 25 mg daily and uptitrated to 50 mg on day 2 if serum potassium was <5.0 mmol/L and estimated glomerular filtration rate (eGFR) >50 ml/min/1.73 m2.

Principal Findings:

Overall, 1,012 patients were randomized. The mean age was 59 years, 17% were women, 13% had diabetes, mean body mass index was 28 kg/m2, mean systolic blood pressure was 126 mm Hg, 85% underwent primary percutaneous coronary intervention, mean serum creatinine was 0.91 mg/dl, and mean serum potassium was 4.1 mmol/L. The target dose of eplerenone 50 mg was achieved in 89%.

At a mean of 10.5 months, the primary outcome of cardiovascular mortality, ventricular arrhythmia, heart failure hospitalization, LV ejection fraction (EF) ≤40% at 1 month, or elevated B-type natriuretic peptide (BNP)/N-terminal-proBNP (NT-proBNP) at 1 month occurred in 18.2% of the eplerenone group vs. 29.4% of the placebo group (p < 0.0001).

There was no evidence for treatment interaction except for the following groups that appeared to derive more benefit from eplerenone vs. placebo: heart rate <73 bpm and reperfusion <6 hours.

- Cardiovascular mortality: 0.4% vs. 0.4%
- Heart failure re-hospitalization or extended initial hospital stay: 1.4% vs. 2.2%
- Ventricular arrhythmia: 0 vs. 0.6%
- LVEF ≤40%: 4.0% vs. 3.8%
- Elevated BNP: 16.0% vs. 25.9%

The change in serum potassium from baseline to 1 month was 0.41 mmol/L in the eplerenone group vs. 0.32 mmol/L in the placebo group (p < 0.0001).

- Serum potassium >5.5 mmol/L: 5.6% vs. 3.2% (p = 0.09), respectively
- Serum potassium >6.0 mmol/L: 1.6% vs. 0.4% (p = 0.11), respectively
- Elevated BNP or NT-proBNP: 16% vs. 26% (p < 0.0002), respectively

Interpretation:

Among relatively low-risk STEMI patients without heart failure or significant LV dysfunction, eplerenone was associated with a reduction in clinical outcomes. This was mainly due to a reduction in BNP or NT-proBNP levels. However, serum potassium was modestly increased.

Eplerenone has previously been shown to be beneficial among patients with LV systolic dysfunction due to acute myocardial infarction and in patients with chronic heart failure and mild symptoms. REMINDER can be considered a "proof-of-concept" clinical trial. Further studies are needed in acute myocardial infarction patients with no signs of congestive heart failure powered for hard clinical outcomes.

References:

Montalescot G, Pitt B, Lopes de Sa E, et al. Early Eplerenone Treatment in Patients With Acute ST-Elevation Myocardial Infarction Wthout Heart Failure: The Randomized Double-Blind REMINDER Study. Eur Heart J 2014;Apr 29:[Epub ahead of print].

Presented by Dr. Gilles Montalescot at ACC.13, San Francisco, March 9, 2013.

Keywords: Myocardial Infarction, Follow-Up Studies, Mineralocorticoid Receptor Antagonists, Blood Pressure, Creatinine, Heart Rate, Spironolactone, Percutaneous Coronary Intervention, Potassium, Body Mass Index, Heart Failure, Glomerular Filtration Rate, Ventricular Dysfunction, Left, Diabetes Mellitus, Natriuretic Peptide, Brain


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