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

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 (pinteraction = 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. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).

Keywords: heart failure with preserved ejection fraction; sex differences; spironolactone; women.

Conflict of interest statement

Disclosure: The authors have no conflicts to disclose.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1 –. Sex- and treatment-specific trends in serum potassium, creatinine, and systolic blood pressure.

Compared to spironolactone was associated with significant increases in serum potassium and creatinine as well as decrease in systolic blood pressure in both men and women. In women there was a significantly greater increase in creatinine at 4 months (pinteraction=0.03) and serum potassium at 12 months (pinteraction=0.04).

Figure 2a –. Kaplan-Meier survival curves for primary outcomes and components according to treatment arm and stratified by sex.

There was no significant association between spironolactone and the primary outcome or HF hospitalization in either women or men. Spironolactone was associated with a significantly reduced risk of CV mortality in multivariate analysis, but the interaction between sex and treatment arm was non-significant.

Figure 2b –. Kaplan-Meier survival curves for secondary outcomes according to treatment arm and stratified by sex.

Spironolactone was associated with a significantly reduced likelihood of all-cause mortality with a significant sex-treatment arm interaction. There was no association between spironolactone and likelihood of non-CV mortality, CV hospitalization, or non-CV hospitalization.

Figure 3 –. Multivariate Cox proportional hazard ratios associated with spironolactone for all outcomes, men versus women.

Spironolactone was associated with a reduced likelihood of all-cause mortality in women but not men with a significant sex-treatment interaction. There were no other significant associations between spironolactone and primary or clinical outcomes.