Eplerenone survival benefits in heart failure patients post-myocardial infarction are independent from its diuretic and potassium-sparing effects. Insights from an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) substudy.
OBJECTIVE
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.
INSERM, Centre d'Investigations Cliniques 9501, Nancy, France.
Patrick
P
Rossignol
Joël
J
Ménard
Renaud
R
Fay
Finn
F
Gustafsson
Bertram
B
Pitt
Faiez
F
Zannad
D000368:Aged; D002986:Clinical Trials as Topic; D004231:Diuresis / Q000187:drug effects*; D000077545:Eplerenone; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D011188:Potassium / Q000097:blood*; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone; D011188:Potassium