Dataset Information

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).

SUBMITTER: Merrill M

PROVIDER: S-EPMC6817333 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Merrill Miranda M Sweitzer Nancy K NK Lindenfeld JoAnn J Kao David P DP

JACC. Heart failure 20190301 3

<h4>Objectives</h4>This study sought to investigate sex differences in outcomes and responses to spironolactone in patients with heart failure with preserved ejection fraction (HFpEF).<h4>Background</h4>HFpEF affects women more frequently than men. Sex differences in responses to effects of mineralocorticoid antagonists have not been reported.<h4>Methods</h4>This was an exploratory, post hoc, non-pre-specified analysis of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure a ...[more]

PMID: 30819379

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Project description:Background The female preponderance in heart failure with preserved ejection fraction (HFpEF) is a distinguishing feature of this disorder, but the association of sex with degree of diastolic dysfunction and clinical outcomes among individuals with HFpEF remains unclear. Methods and Results We conducted a prospective, multicenter, observational study of patients with HFpEF (PURSUIT-HFpEF [Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction]: UMIN000021831). Between 2016 and 2019, 871 patients were enrolled from 26 hospitals (follow-up: 399±349 days). We investigated sex-related differences in diastolic dysfunction and postdischarge clinical outcomes in patients with HFpEF. The echocardiographic end point was diastolic dysfunction according to American Society of Echocardiography/European Association of Cardiovascular Imaging criteria. The clinical end point was a composite of all-cause death and heart failure readmission. Women accounted for 55.2% (481 patients) of the overall cohort. Compared with men, women were older and had lower prevalence rates of hypertension, coronary artery disease, and chronic kidney disease. Women had diastolic dysfunction more frequently than men (52.8% versus 32.0%, P<0.001). The incidence of the clinical end point did not differ between women and men (women 36.1/100 person-years versus men 30.5/100 person-years, P=0.336). Female sex was independently associated with the echocardiographic end point (adjusted odds ratio, 2.839; 95% CI, 1.884-4.278; P<0.001) and the clinical end point (adjusted hazard ratio, 1.538; 95% CI, 1.143-2.070; P=0.004). Conclusions Female sex was independently associated with the presence of diastolic dysfunction and worse clinical outcomes in a cohort of elderly patients with HFpEF. Our results suggest that a sex-specific approach is key to investigating the pathophysiology of HFpEF. Registration URL: https://upload.umin.ac.jp; Unique identifier: UMIN000021831.

Project description:BackgroundLifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.MethodsParticipant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.ResultsWe included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.ConclusionsLifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

Project description:Introduction: Although the impact of sex on patient outcomes for heart failure (HF) with preserved ejection fraction (HFpEF) has been reported, it is still unclear whether this impact is applicable for elderly patients with HFpEF. This study was conducted as a secondary analysis from a large randomized controlled trial-The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT)-to evaluate the impact of sex differences on the baseline characteristics and outcomes of HFpEF patients who were older than 70 years. Methods: Baseline characteristic of elderly patients were compared between men and women. Primary outcomes were cardiovascular (CV) mortality and HF-related hospitalization, whereas secondary outcomes were all-cause mortality and all-cause hospitalization. Cox regression models were used to determine the effect of sex differences on patient outcomes. Results: A total of 1,619 patients were included in the study: 898 (55.5%) women and 721 (44.5%) men. Age was similar between women and men. Women had fewer comorbidities but worse cardiac function than men. The rate of primary outcomes was lower in women than in men (18.4 vs. 27.5%; p < 0.001), including rate of CV mortality (8.9 vs. 14.8%; p < 0.001) and HF-related hospitalization (13.4 vs. 18.2%; p = 0.008). All-cause mortality was also lower in women than in men (15.6 vs. 25.4%; p < 0.001). After adjustment for baseline characteristics, Cox regression analysis showed that female sex was a protective factor for CV mortality [hazard ratio (HR): 0.53; 95% confidence interval (CI): 0.40-0.73], HF-related hospitalization (HR: 0.71; 95% CI: 0.55-0.93), and all-cause mortality (HR: 0.59; 95% CI: 0.47-0.75). Although spironolactone significantly reduced the rate of all-cause mortality in women even after adjusting for baseline characteristics (HR: 0.68; 95% CI: 0.48-0.96; p = 0.028), no significant multivariate association was noted between sex and treatment effects (p = 0.190). Conclusion: Among elderly patients with HFpEF, women had worse cardiac function but better survival and lower HF-related hospitalization rate than men. Clinical Trial Registration: NCT00094302 (TOPCAT). Registered October 15, 2004, https://www.clinicaltrials.gov/ct2/show/NCT00094302.

Dataset Information

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

Publications

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

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