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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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Abstract

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.

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Funding

Dr Rossello has received support from SEC-CNIC CARDIOJOVEN Program.

Author information

Authors and Affiliations

  1. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

    Xavier Rossello & Stuart J. Pocock

  2. London School of Hygiene and Tropical Medicine, London, UK

    Xavier Rossello, Cono Ariti & Stuart J. Pocock

  3. CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain

    Xavier Rossello

  4. School of Medicine, Cardiff University, Cardiff, UK

    Cono Ariti

  5. Centre d’Investigation Clinique Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, Nancy, France

    João Pedro Ferreira, Nicolas Girerd & Faiez Zannad

  6. BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK

    John J. V. McMurray

  7. Department of Cardiology, University of Groningen, Groningen, The Netherlands

    Dirk J. Van Veldhuisen

  8. Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Bertram Pitt

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  1. Xavier Rossello
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Correspondence to Faiez Zannad.

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Conflict of interest

XR, CA, SJP, and DJVV have nothing to declare. JMcM reports conflicts of interest from Roche Pharmaceuticals, during the conduct of the study; other from Novartis, Cardiorentis, Amgen Oxford University/Bayer, GlaxoSmithKline, Theracos, Abbvie, DalCor, Pfizer, Merck, AstraZeneca Bristol Myers Squibb (BMS), Kidney Research UK (KRUK)/Kings College Hospital, London/Vifor-Fresenius Pharma, outside the submitted work. BP reports personal fees from Bayer, personal fees from KDP pharmaceuticals, and personal fees from Astrazeneca, outside the submitted work; In addition, BP has a patent site-specific delivery of eplerenone to the myocardium pending to university of Michigan. Faiez Zannad received honoraria and/or travel fees for participation in clinical trial committees and meetings/presentations from Amgen, AstraZeneca, Bayer, Boehringer, Boston Scientific, GE Healthcare, CVRx, Relypsa/Vifor-Fresenius, J&J, Pfizer, Novartis, Quantum Genomics, Resmed, Takeda, and received honoraria and/or travel fees for participation in advisory boards from BMS, KBP BioSciences, Livanova, NovoNordisk, Roche, ZS Pharma.

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Rossello, X., Ariti, C., Pocock, S.J. et al. 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 108, 477–486 (2019). https://doi.org/10.1007/s00392-018-1378-0

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