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Better outcome after early eplerenone treatment after acute STEMI without heart failure

Literature - Montalescot et al., Eur Heart J. 2014 - Eur Heart J. 2014 Apr 29

Montalescot G, Pitt B, Lopez de Sa E, et al., for the REMINDER Investigators.
Eur Heart J. 2014 Apr 29


Briefly after the onset of acute myocardial infarction (MI), levels of aldosterone are highest. Aldosterone promotes several deleterious short- and long-term effects, such as sodium retention and potential arrhythmogenenesis, endothelial dysfunction, increased vascular tone, inhibition of neuronal re-uptake of catecholamines, cardiac myocyte necrosis, collagen deposition and cardiac remodelling [1,2]. Despite substantial improvements in the short-term prognosis of patients undergoing revascularisation for acute MI, the effects of high aldosterone levels remain.
Based on the results of the Eplerenone Post-AMI Heart Failure (HF) Efficacy and Survival Study (EPHESUS) [3], guidelines now recommend the use of mineralocorticoid receptor antagonists (MRA) in patients presenting with HF after MI [4]. The observed benefits were more pronounced in patients who received early administration of eplerenone, i. e. within 3-7 days, as compared to administration between 7-14 days [5].
This study evaluated the safety and efficacy of early initiation of eplerenone, within 24 hours of symptom onset when acute reperfusion is delivered to patients presenting with STEMI without known heart failure. 1012 Patients were randomised to eplerenone (starting dose 25 mg once daily and increased to 50 mg once daily if possible) or placebo in addition to standard care in the multi-centre, double-blind study REMINDER. Mean follow-up was 10.5 months. The primary endpoint was time to first occurrence of CV mortality, re-hospitalisation, or extended initial hospital stay due to diagnosis of HF or sustained ventricular tachycardia or ventricular fibrillation, and LVEF < 40% at 1 month or later or BNP>200 pg/mL or NT-proBNP above 450 pg/mL in patients younger than 50, above 900 pg/mL in 50-75-year olds, or above 1800 pg/mL in patients over 75 at 1 month.

Main results

  • The first dose of eplerenone was given after a mean duration of 16.4 + 7.2 h (range: 0.5-73.2 h) and the first dose of placebo at 15.4 + 6.6 h (range: 0-34.5 h) post-MI. The vast majority of patients (96.5%) were uptitrated to 50 mg eplerenone.
  • At the end of follow-up, the primary endpoint occurred in 92 (18.2%) patients in the eplerenone group, as compared with 149 (29.4%) in placebo-treated patients (Adj HR: 0.58, 95%CI: 0.45-0.75, P<0.0001).
  • Fewer people showed elevated BNP/NT-proBNP after 1 month in the eplerenone group, and at 6, 12 and 18 months of follow-up.
    No significant differences were seen between the treatment groups in any of the other components of the primary endpoint.
  • Analysis of subgroups showed no significant interactions, except for heart rate, and timing of acute reperfusion.
  • Discontinuation of the study drug due to adverse events was not different for patients receiving eplerenone (5.5%) or placebo (4.8%).
  • Overall mortality was low in both groups (0.6% in both groups).
  • Patients treated with eplerenone more often experienced hyperkalaemia, but this difference was not statistically significant. Hypokalaemia was significantly more frequent in the placebo group.

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Early administration of eplerenone 25-50 mg once daily in addition to recommended treatment in patients with acute STEMI and no history of heart failure or low ejection fraction gave a lower rate of the primary outcome in comparison with placebo, with excellent safety. This effect was consistent in major subgroups, but particularly obvious in patients undergoing rapid reperfusion within 6 hours of symptom onset. The improved clinical outcome seemed mainly driven by a reduction of BNP/NT-proBNP. The role of MRA early after acute STEMI not complicated by heart failure deserves further confirmation in a larger randomised trial.

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left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348: 1309–1321.
4. Task Force on the Management of STseamiotESoC, Steg PG, James SK, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33: 2569–2619.
5. Adamopoulos C, Ahmed A, Fay R, et al. Timing of eplerenone initiation and outcomes in patients with heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction: insights from the EPHESUS trial. Eur J Heart Fail 2009;11:1099–1105.

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