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

Clin Res Cardiol. 2019 May;108(5):477-486. doi: 10.1007/s00392-018-1378-0. Epub 2018 Sep 27.


Background: 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.

Methods: 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.

Results: 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%.

Conclusions: 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.

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

Publication types

  • Meta-Analysis
  • Review

MeSH terms

  • Death, Sudden, Cardiac / etiology
  • Death, Sudden, Cardiac / prevention & control*
  • Heart Failure / complications
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Humans
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Randomized Controlled Trials as Topic / methods*
  • Risk Factors
  • Spironolactone / therapeutic use*
  • Systole
  • Ventricular Dysfunction, Left / complications
  • Ventricular Dysfunction, Left / drug therapy*
  • Ventricular Dysfunction, Left / physiopathology


  • Mineralocorticoid Receptor Antagonists
  • Spironolactone