A drug known to reduce mortality rate in patients with heart failure has now been found significantly effective when administered early in patients following an acute (ST elevated) myocardial infarction. This effect,say the investigators, was consistent across all study sub-groups, but was "particularly obvious in patients undergoing reperfusion within six hours of symptom onset."
Eplerenone, a mineralocorticoid receptor antagonist (MRA), has already been investigated and licensed for the use in patients with heart failure post myocardial infarction, but has so far not been investigated following acute STEMI without ongoing heart failure. Such a study, said principal investigator Gilles Montalescot from the Institut de Cardiologie, Pitié-Salpêtrière University Hospital in Paris, would be "a valuable venture both because of the potentially beneficial effects and a proof of safety in the acute phase of MI."
The study was a multicentre placebo-controlled trial in which 1012 acute STEMI patients with no history of heart failure were randomised to either eplerenone (25/50 mg per day) or placebo, initiated within 24 hours of the onset of symptoms and in addition to standard therapy. The primary endpoint of the study was a composite of cardiovascular mortality, re-hospitalisation or extended initial hospital stay as a result of diagnosed heart failure, sustained ventricular tachycardia or fibrillation, and clear signs of heart fialure (ejection fraction ≤40%, or elevated levels of BNP/NT-proBNP [two similar cardiac peptides whose release can be measured as a biomarker of heart failure]).
Results of the study, with an accompanying editorial, are reported today in the European Heart Journal.
After a mean follow-up of 10.5 months, the primary endpoint occurred in 93 patients in the eplerenone group (18.4%) and in 150 patients in the placebo group (29.6%). This difference was statistically significant (adjusted hazard ratio 0.57, 95% CI 0.44-0.74, P<0.0001).
However, the investigators found that this primary endpoint difference was largely driven by changes in levels of BNP/NT-proBNP, with lower overall levels in the treatment group (BNP and NT-pro-BNP levels in blood increase when heart failure symptoms worsen). This difference in levels of BNP and Nt-proBNP was statistically significant. But there was no significant difference in any other components of the primary endpoint -- though the investigators point out that cardiovascular event rates in this study were too small to show statistically significant change. More than 10,000 patients in each arm would have been necessary to demonstrate a 15-20% event reduction -- which is why biomarkers rather than hard clinical endpoints drove the significant outcome.
As background to their report, the authors note that eplerenone has been shown to reduce mortality in patients with heart failure, particularly in those following recent MI. In the EPHESUS trial, for example, eplerenone was more effective with early (3-7 days post MI) administration than with later (7-14 days). However, despite these results (and consequent guideline recommendations), the authors note that the use of eplerenone in post-MI populations has remained low, partly because of safety concerns about hyperkalaemia. However, in this study the adverse event rates were similar in both groups, with serum potassium levels above 5.5mmol/L in 5.6% and 3.2% in the eplerenone and placebo groups, respectively, a non-significant difference. The authors described eplerenone in this study as "safe" and "generally well tolerated."
Commenting on the results, Professor Montalescot said: "This study suggests that eplerenone can be used early in the course of MI without safety issues. The long term benefit on remodelling and secondary heart failure is possible but will deserve further studies."
- G. Montalescot, B. Pitt, E. Lopez de Sa, C. W. Hamm, M. Flather, F. Verheugt, H. Shi, E. Turgonyi, M. Orri, J. Vincent, F. Zannad, G. Noll, R. Weir, B. O'Neill, M. Bohm, W. S. Hillis, A. Grieve, J.-L. Rouleau, F. Gerasimos, D. Fitchett, S. Lepage, M. Madan, B. Sussex, G. Tremblay, R. Welsh, G. Wong, M. Hutyra, J. Kettner, P. Ostadal, J. Spinar, J. Vojacek, M. Barboteu, J.-P. Collet, P. Coste, Y. Cottin, D. Ducos, M. Galinier, E. Teiger, G. Zemour, J. Bauersachs, R. Hambrecht, G. Hauf, H. Heuer, H. Mudra, T. Munzel, S. Steiner, R. Strasser, K. Sydow, C. Tschope, R. Wachter, N. Werner, D. Alexopoulos, D. Babalis, V. Pyrgakis, C. Dezsi, G. Lupkovics, P. Polgar, J. Tomcsanyi, J. Herrman, J. M. ten Berg, J. Gorny, J. Kubica, J. Lewczuk, W. Zmuda, M. Hranai, F. Kovar, R. Margoczy, K. Micko, J. Sumbal, X. B. Genover, A. F. Ortiz, M. F. Sala, C. G. Garcia, C. P. Munoz, J. R. Rey Blas, F. R. Soriano, D. Adamson, F. Alamgir, A. Chauhan, G. Lip, T. Martin, G. McCann, D. Newby, D. Smith. Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: The Randomized Double-Blind Reminder Study. European Heart Journal, 2014; DOI: 10.1093/eurheartj/ehu164
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