EPHESUS showed that the addition of the aldosterone antagonist eplerenone (E) to optimal therapy in patients with acute myocardial infarction, heart failure, and low ejection fraction improved survival and cardiovascular outcomes. We aimed at determinating whether a diuretic effect may be detectable in E-treated patients as compared to placebo (P) in EPHESUS (n=6632) and whether this was associated with the beneficial effects of E on cardiovascular outcomes.

A diuretic effect was indirectly defined as a 1 month vs baseline body weight decrease>median change in the P group (-0.05kg), AND a 1 month vs baseline blood protein increase>median change in the P group (+4g/l). A potassium (K) sparing effect was defined as a serum K increase>median change in the P group (+0.11mmol/L).

In the E group, body weight decreased (p<0.0001), whereas blood protein (p<0.0001) and serum K increased (p<0.0001) as compared to P. K-sparing was independently associated with lower all-cause mortality [H.R 0.83(0.71-0.96); p=0.012] as well as lower CV death or CV hospitalization [(0.76 (0.67-0.87); p<0.0001]. A diuretic effect [(1.15(1.02-1.30); p=0.025], was independently associated with a worse CV outcome. There was no statistically 3000 significant interaction between the beneficial effects of E on CV outcomes and K-sparing or diuretic effect.

Although a diuretic effect is associated with worse CV outcome, beneficial effects of E on survival and CV outcome are independent from its K-sparing and diuretic effects. This suggests that aldosterone antagonism provides a cardiovascular protection beyond its diuretic and PSE properties.