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Clinical Trial
. 2021 Jun 1;6(6):678-689.
doi: 10.1001/jamacardio.2021.0379.

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

Jawad H Butt  1 , Kieran F Docherty  2 , Mark C Petrie  2 , Morten Schou  3 , Mikhail N Kosiborod  4   5 , Eileen O'Meara  6 , Tzvetana Katova  7 , Charlotta E A Ljungman  8 , Mirta Diez  9 , Modele O Ogunniyi  10 , Anna Maria Langkilde  11 , Mikaela Sjöstrand  11 , Daniel Lindholm  11 , Olof Bengtsson  11 , Felipe A Martinez  12 , Piotr Ponikowski  13 , Marc S Sabatine  14 , Scott D Solomon  15 , Pardeep S Jhund  2 , John J V McMurray  2 , Lars Køber  1
Affiliations
Clinical Trial

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

Jawad H Butt et al. JAMA Cardiol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Docherty reported personal fees from AstraZeneca and the University of Glasgow during the conduct of the study and personal fees from Eli Lilly outside the submitted work. Dr Petrie reported grants from AstraZeneca during the conduct of the study; grants from Boehringer Ingelheim, Novo Nordisk, Novartis, and SQ Innovations and personal fees from Boehringer Ingelheim, Takeda, and Bayer outside the submitted work. Dr Schou reported lecture fees from other from Boehringer Ingelheim, AstraZeneca, and NOVP outside the submitted work. Dr Kosiborod reported grants from Astra Zeneca and Boehringer Ingelheim and personal fees from Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck (Diabetes), Novo Nordisk, Sanofi, and Vifor Pharma outside the submitted work. Dr Katova reported personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca and Novartis outside the submitted work. Dr Ljungman reported personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca, Novartis, and Pfizer outside the submitted work. Dr Ogunniyi reported grants from AstraZeneca during the conduct of the study and grants from AstraZeneca, Boehringer Ingelheim, and Zoll and personal fees from Alnylam, and Pfizer outside the submitted work. Drs Langkilde and Sjostrand reported being a full-time employee and shareholder of AstraZeneca during the conduct of the study. Dr Lindholm reported being an AstraZeneca employee. Dr Bengtsson reported being an AstraZeneca employee. Dr Martinez reported personal fees from AstraZeneca during the conduct of the study. Dr Ponikowski reported personal fees and other support from AstraZeneca during the conduct of the study; personal fees from Boehringer Ingelheim, Vifor Pharma, Amgen, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, Cibiem, Impulse Dynamics, Renal Guard Solutions, Radcliffe-Group, BMS, and Respicardia; and other support from AbbottVascular, Boehringer Ingelheim, Novartis, Amgen, Vifor, and Bayer outside the submitted work. Dr Sabatine reported grants from AstraZeneca Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital and personal fees from AstraZeneca during the conduct of the study; personal fees from Althera, Amgen, Antho, Bristol-Mysers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Dyrnamix, Esperion, IFM, Intarcia, Janssen Research and Development, Medicines Company, Medimmune, Merck, Novartis; grants from Amgen, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Regeneron, Roche, and Zora Biosciences. Dr Solomon reported grants from AstraZeneca Grants to institution during the conduct of the study; grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, National Health Institute/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos; and personal fees from Abbott, Actelion, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GSK, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Sanofi-Pasteur, Tenaya, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent outside the submitted work. Dr Jhund reported other support from AstraZeneca during the conduct of the study; other support from Novartis; and grants and personal fees from Boehringer-Ingelheim outside the submitted work. Dr McMurray reported other support from AstraZeneca; nonfinancial support from Cytokinetics, Bayer, Theracos, Oxford University, Dalcor, Merck, GlaxoSmithKline, Bristol Myers Squibb, Vifor-Fresenius, Kidney Research UK, Alnylam, Abbvie, Cyclerion, Cardurion; and personal fees from Amgen, Abbott, Hickma, Sun Pharmaceuticals, and Servier outside the submitted work. Dr Køber reported personal fees from AstraZeneca during the conduct of the study and from Novo, Boehringer and Novartis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Enrollment, Randomization, and Follow-up of Participants in a Study of the Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes
Figure 2.
Figure 2.. Primary Outcome (Worsening Heart Failure or Cardiovascular Death) According to Randomized Treatment Assignment in Women (A) and Men (B)
See this image and copyright information in PMC

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