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.
OBJECTIVE
To test the hypothesis that an earlier post-acute myocardial infarction (AMI) eplerenone initiation in patients with left ventricular systolic dysfunction (LVSD) and heart failure (HF) is associated with better long-term outcomes.


RESULTS
The 6632 patients of the EPHESUS study were randomized from day 3 to 14 after the index AMI (median = 7 days), of these 3319 were assigned to eplerenone. We analysed the differential effects of time-to-eplerenone initiation vs. placebo, based on the median time to initiation of treatment (<7 days-'earlier', > or =7days-'later'). Effects on outcomes were evaluated over a mean 16-month follow-up, using Cox proportional hazards regression analysis. The earlier eplerenone initiation (<7 days) reduced the risk of all-cause mortality by 31% (P = 0.001) when compared with the 'earlier' placebo' and also reduced the risks of cardiovascular (CV) hospitalization/CV mortality by 24% (P < 0.0001) and sudden cardiac death (SCD) by 34% (P < 0.0001). In contrast, later eplerenone initiation (> or =7 days) had no significant effect on outcomes. Interactions between time-to-randomization and treatment were significant. These associations remained substantially unchanged after risk adjustment in multivariable models.


CONCLUSIONS
An earlier eplerenone administration (3-7days) post-AMI improved outcomes in patients with LVSD and HF. This benefit was not observed when eplerenone was initiated later (> or =7days).
Adamopoulos
Chris
C
Inserm, Centre d'Investigations Cliniques CIC Inserm CHU and U961, Hôpital Jeanne d' Arc, Toul 54200, France.
Ahmed
Ali
A
Fay
Renaud
R
Angioi
Michael
M
Filippatos
Gerasimos
G
Vincent
John
J
Pitt
Bertram
B
Zannad
Faiez
F
D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004311:Double-Blind Method; D000077545:Eplerenone; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models; D012307:Risk Factors; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone