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
1 Inserm, Centre d'Investigations Cliniques CIC Inserm CHU and U961, Hôpital Jeanne d’ Arc, Toul 54200, France
2 University of Alabama at Birmingham and VA Medical Center, Birmingham, AL, USA
3 Hypertension and Heart Failure Division, Department of Cardiovascular Disease, Hôpital Jeanne d’ Arc, Nancy, France
4 Department of Cardiology, Athens University Hospital Attikon, Athens, Greece
5 Pfizer Inc., New York, NY, USA
6 University of Michigan, Ann Arbor, MI, USA
* Corresponding author. Tel: +33 383 65 66 25, Fax: +33 383 65 66 19, Email: f.zannad{at}chu-nancy.fr
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Abstract |
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Aims: 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.
Methods and 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’, 
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 (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.
Conclusion: 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 (7days).
Key Words: Aldosterone antagonists • Myocardial infarction • Heart failure • Mortality • Ventricular remodelling
Received May 3, 2009; Revised September 14, 2009; Accepted September 21, 2009
The complete listing of investigators can be found in Pitt et al., N Engl J Med 2003;348:1309–1321.