Author + information
- Received November 29, 2018
- Revision received January 11, 2019
- Accepted January 13, 2019
- Published online February 25, 2019.
- aDepartment of Internal Medicine, University of Colorado School of Medicine, Aurora, Colorado
- bDivision of Cardiology, Sarver Heart Center, University of Arizona College of Medicine, Tucson, Arizona
- cDivision of Cardiovascular Medicine, Vanderbilt University Medical Center, Vanderbilt Heart and Vascular Institute, Nashville, Tennessee
- dDivision of Cardiology, University of Colorado School of Medicine, Aurora, Colorado
- ↵∗Address for correspondence:
Dr. David Kao, Division of Cardiology, University of Colorado School of Medicine, 12700 East 19th Avenue, Campus Box B-139, Aurora, Colorado 80045.
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)
Supported by American Heart Association award 17IG3366030, U.S. National Institutes of Health/National Heart, Lung, and Blood Institute grants 1K08HL125725 and HH SN268200425207C, and Jacqueline’s Research Fund, Center for Women’s Health Research, University of Colorado School of Medicine. Dr. Sweitzer has received grants from Novartis and Merck Sharpe & Dohme; and is a consultant for Myokardia. Dr. Lindenfeld is a consultant for Novartis, Abbott, Edwards Lifesciences, Boston Scientific, Relypsa, VWave, CVRx, Boehringer Ingelheim, and ImpulseDynamics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. John Teerlink, MD, served as Guest Editor for this paper.
- Received November 29, 2018.
- Revision received January 11, 2019.
- Accepted January 13, 2019.
- 2019 American College of Cardiology Foundation
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