Download this article's Factoid (PDF & PPT for Gold Subscribers)

The addition of eplerenone to standard treatment for ST-segment elevation myocardial infarction (STEMI) within 24 hours of symptom onset is safe and reduces brain natriuretic peptide (BNP) levels, a potential prognostic factor for short- and long-term outcomes, according to a paper published online April 29, 2014, ahead of print in the European Heart Journal.

Findings from the REMINDER trial were presented at the 2013 American College of Cardiology/i2 Scientific Session in San Francisco, CA. Eplerenone, a mineralocorticoid receptor antagonist, is typically used for the treatment of chronic heart failure (HF).

For the study, Gilles Montalescot, MD, PhD, of the Centre Hospitalier Pitié-Salpêtrière (Paris, France), and colleagues randomized 1,012 patients with acute STEMI and no history of HF to standard therapy plus eplerenone (Inspra; Pfizer; New York, NY) or placebo. Patients were recruited from 65 centers in 11 countries between September 2010 and October 2012.

Baseline characteristics were similar in the eplerenone and placebo groups, and an equal proportion of both groups underwent PCI (approximately 86%).

Eplerenone (25 mg daily) was administered 16.4 ± 7.2 hours (0.5-73.2 hours) after the index MI. Most patients (96.5%) were uptitrated to a higher dose (50 mg daily) on the second day with 88.6% receiving the higher dose at the end of the study.

Difference Driven by Biomarker Reduction

At a mean follow-up of 10.5 months, the primary composite endpoint (cardiovascular mortality, rehospitalization, extended initial hospital stay due to diagnosis of HF, sustained ventricular tachycardia [lasting at least 30 seconds at ≥ 100 bpm], ventricular fibrillation, LVEF ≤ 40% at 1 month or later postrandomization, BNP > 200 pg/mL, or NT-proBNP > 450 pg/mL) occurred less often with eplerenone than with placebo. The difference was driven primarily by the reduction of BNP/NT-proBNP (table 1).

Table 1. Outcomes at Mean Follow-up of 10.5 Months

^a≥ 1 month postrandomization.

The favorable effects of eplerenone were present across major prespecified subgroups but were most apparent in patients undergoing rapid reperfusion (within 6 hours of symptom onset).

Hyperkalaemia and severe hyperkalaemia occurred more often in the eplerenone group though no deaths resulted. Conversely, hypokalaemia was more likely to occur in the placebo cohort.

The rarity of hyperkalaemia in patients who took eplerenone was “reassuring given the instability of patients with acute STEMI within the first hours of hospitalization,” according to the authors, who added, “Initial concerns about starting the drug during the early course of MI proved not to be justified.”

An editorial accompanying the study by Benjamin M. Scirica, MD, of Brigham and Women’s Hospital (Boston, MA), confirmed the importance of reducing BNP in that elevated levels “are well-recognized markers of increased risk of heart failure and death following an MI.”

Should be Considered a ‘Proof-of-Concept’ Trial

In a press release accompanying the article, Dr. Montalescot explained, “This study suggests that eplerenone can be used early in the course of MI without safety issues. The long-term benefit on remodeling and secondary heart failure is possible [but requires further research].”

“The REMINDER study should be considered a ‘proof-of-concept’ trial, driven by the ‘surrogate’ endpoint of elevated levels of natriuretic peptides,” according to Dr. Scirica, suggesting that the “most appropriate clinical endpoint” would be the composite of cardiovascular death, HF, or sustained ventricular arrhythmia. This outcome, he said, “occurred in 9 patients assigned to eplerenone and 16 patients in the placebo group, which is at least reassuring but insufficient to provide any clinical guidance.”

Both the study authors and Dr. Scirica express the need for more statistical power. According to Dr. Scirica, “A properly powered study, probably 8,000–12,000 patients in size with extended follow-up will be required before a strategy of early [mineralocorticoid receptor antagonist] administration could be recommended for the broader STEMI population.”

Study Details

One patient in each group did not start medication and was not included in the safety analysis. Over the course of the study, 28 patients from the eplerenone group and 24 from the placebo group dropped out of the study because of an adverse event (P = .48).

1. Montalescot G, Pitt B, Lopez de Sa E, et al. Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the randomized double-blind REMINDER study. Eur Heart J. 2014;Epub ahead of print.

2. Scirica BM. Evaluating the efficacy of mineralocorticoid receptor antagonism in patients with STEMI without heart failure [editorial]. Eur Heart J. 2014;Epub ahead of print.