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Clin Res Cardiol. 2018 Sep 27. doi: 10.1007/s00392-018-1378-0. [Epub ahead of print]

Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left-ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials.

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Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
London School of Hygiene and Tropical Medicine, London, UK.
CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain.
School of Medicine, Cardiff University, Cardiff, UK.
Centre d'Investigation Clinique Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, Nancy, France.
BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK.
Department of Cardiology, University of Groningen, Groningen, The Netherlands.
Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Centre d'Investigation Clinique Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, Nancy, France.



Sudden cardiac death (SCD) is an important cause of death in patients with left-ventricular systolic dysfunction (LVSD). Mineralocorticoid receptor antagonists (MRAs) may attenuate this risk. We aimed to assess the impact of MRAs on SCD in patients with LVSD.


A fixed-effect meta-analysis at individual patient-level was performed using 11,032 patients recruited in three placebo-controlled randomized trials: Randomized Aldactone Evaluation Study (RALES), Eplerenone Post Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Treatment effect was determined using a Cox proportional hazards model stratified by study.


Patients receiving MRAs were at lower risk of SCD compared with placebo-treated patients after a mean follow-up of 18 months (HR 0.77, 95% CI 0.66-0.89). This effect was consistent across trials and did not change substantially after adjustment for 14 baseline co-variates. Moreover, the benefits of MRAs were consistent across study subgroups, except for a greater effect in those < 65 years old and those using beta-blockers. Using stratified analyses, we also found a consistent effect in relevant subsets of patient defined by heart failure cause, NYHA class or LVEF ≤ 35%.


MRAs reduce the risk for SCD by 23% in patients with heart failure and LVSD. In these patients, the use of MRAs, on top of other evidence-based medications, should be optimized. It might be useful to re-assess the benefit of implantable cardiac defibrillator (ICD) placement, as ICD treatment effect was evaluated in trials enrolling patients not receiving MRAs.


Heart failure; Left-ventricular dysfunction; Meta-analysis; Mineralocorticoid receptor antagonists; Randomized clinical trials; Sudden cardiac death


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