Sex Differences in Outcomes and Responses to Spironolactone in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of TOPCAT Trial

Miranda Merrill, Nancy K. Sweitzer, Jo Ann Lindenfeld, David P. Kao

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

Objectives: This study sought to investigate sex differences in outcomes and responses to spironolactone in patients with heart failure with preserved ejection fraction (HFpEF). Background: HFpEF affects women more frequently than men. Sex differences in responses to effects of mineralocorticoid antagonists have not been reported. Methods: This was an exploratory, post hoc, non-pre-specified analysis of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. Subjects with symptomatic HF and a left ventricular ejection fraction ≥45% were randomized to spironolactone or placebo therapy. Subjects enrolled from the Americas were analyzed. The primary outcome was a composite of cardiovascular (CV) death, cardiac arrest, or HF hospitalization. Secondary outcomes included all-cause mortality, CV, and non-CV mortality and CV, HF, and non-CV hospitalization. Sex differences in outcomes and treatment effects were determined using time-to-event analysis. Results: In total, 882 of 1,767 subjects (49.9%) were women. Women were older with fewer comorbidities but worse patient-reported outcomes. There were no sex differences in outcomes in the placebo arm or in response to spironolactone for the primary outcome or its components. Spironolactone therapy was associated with reduced all-cause mortality in women (hazard ratio: 0.66; p = 0.01) but not in men (p interaction = 0.02). Conclusions: In TOPCAT, women and men presented with different clinical profiles and similar clinical outcomes. The interaction between spironolactone and sex in TOPCAT overall and in the present analysis was nonsignificant for the primary outcome, but there was a reduction in all-cause mortality associated with spironolactone therapy in women, with a significant interaction between sex and treatment arm. Prospective evaluation is needed to determine whether spironolactone therapy may be effective for treatment of HFpEF in women.

Original languageEnglish (US)
Pages (from-to)228-238
Number of pages11
JournalJACC: Heart Failure
Volume7
Issue number3
DOIs
StatePublished - Mar 2019

Keywords

  • heart failure with preserved ejection fraction
  • sex differences
  • spironolactone
  • women

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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