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Original Investigation
March 31, 2021

Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial

Author Affiliations
  • 1Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 2BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland
  • 3Department of Cardiology, Herlev-Gentofte University Hospital, Herlev, Denmark
  • 4St Luke’s Mid America Heart Institute, University of Missouri–Kansas City
  • 5The George Institute for Global Health, University of New South Wales, Sydney, Australia
  • 6Department of Cardiology, Montreal Heart Institute, Montreal, Ontario, Canada
  • 7Clinic of Cardiology, National Cardiology Hospital, Sofia, Bulgaria
  • 8Department of Molecular and Clinical Medicine and Cardiology, Sahlgrenska Academy, Gothenburg, Sweden
  • 9Division of Cardiology, Institute Cardiovascular de Buenos Aires, Buenos Aires, Argentina
  • 10Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
  • 11Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
  • 12Universidad Nacional de Córdoba, Córdoba, Argentina
  • 13Center for Heart Diseases, University Hospital, Wroclaw Medical University, Wrocław, Poland
  • 14TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts
  • 15Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
JAMA Cardiol. 2021;6(6):678-689. doi:10.1001/jamacardio.2021.0379
Key Points

Question  Is the effect of dapagliflozin in patients with heart failure and reduced ejection fraction consistent in men and women?

Findings  In this prespecified subgroup analysis of a randomized clinical trial that included 4744 patients, dapagliflozin, as compared with placebo, increased the proportion of patients with an improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score, clinical summary score, and overall summary score and decreased the proportion with a deterioration, irrespective of sex.

Meaning  Dapagliflozin reduced the risk of worsening heart failure and death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction.

Abstract

Importance  Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men.

Objective  To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).

Design, Setting, and Participants  Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021.

Interventions  Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy.

Main Outcomes and Measures  The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.

Results  A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of ≥5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of ≥5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women.

Conclusions and Relevance  Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex.

Trial Registration  ClinicalTrials.gov Identifier: NCT03036124

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