Author + information
- Received February 14, 2011
- Revision received April 14, 2011
- Accepted April 27, 2011
- Published online November 1, 2011.
- Patrick Rossignol, MD, PhD⁎,†,‡,
- Joël Ménard, MD, PhD§∥,
- Renaud Fay, PharmD⁎,
- Finn Gustafsson, MD, PhD, DMSci¶,
- Bertram Pitt, MD# and
- Faiez Zannad, MD, PhD⁎,‡,⁎⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Prof. Faiez Zannad, Centre d'Investigation Cliniques CHU de Nancy, Institut Lorrain du Coeur et des Vaisseaux, 4 rue du Morvan, 54500 Vandoeuvre Lès Nancy, Paris, France
Objectives The purpose of this study was to determine whether a diuretic effect may be detectable in patients treated with eplerenone, a mineralocorticoid receptor antagonist, as compared with placebo during the first month of EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival study) (n = 6,080) and whether this was associated with eplerenone's beneficial effects on cardiovascular outcomes.
Background The mechanism of the survival benefit of eplerenone in patients with heart failure post-myocardial infarction remains uncertain.
Methods A diuretic effect was indirectly estimated by changes at 1 month that was superior to the median changes in the placebo group in body weight (−0.05 kg) and in the estimated plasma volume reduction (+1.4%). A potassium-sparing effect was defined as a serum potassium increase greater than the median change in the placebo group: +0.11 mmol/l.
Results In the eplerenone group, body weight (p < 0.0001) and plasma volume (p = 0.047) decreased, whereas blood protein and serum potassium increased (both, p < 0.0001), as compared with the placebo group, suggesting a diuretic effect induced by eplerenone, associated with a potassium-sparing effect. A diuretic effect, as defined by an estimated plasma volume reduction, was independently associated with 11% to 19% better outcomes (lower all-cause death, cardiovascular death or cardiovascular hospitalization, all-cause death or hospitalization, hospitalization for heart failure). Potassium sparing was also independently associated with 12% to 34% better outcomes. There was no statistically significant interaction between the observed beneficial effects of eplerenone (9% to 17%) on cardiovascular outcomes and potassium-sparing or diuretic effects.
Conclusions Eplerenone's beneficial effects on long-term survival and cardiovascular outcomes are independent from early potassium-sparing or diuretic effects, suggesting that mineralocorticoid receptor antagonism provides cardiovascular protection beyond its diuretic and potassium-sparing properties.
The EPHESUS study was funded by Pfizer, Inc. Prof. Ménard was a consultant of Searle, Novartis, and Actelion; and has had occasional consultancies with Roche and Nicox. Profs. Pitt and Zannad have received honoraria from and served on advisory boards for Pfizer Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 14, 2011.
- Revision received April 14, 2011.
- Accepted April 27, 2011.
- American College of Cardiology Foundation