Author + information
- Received March 11, 2020
- Revision received April 13, 2020
- Accepted April 14, 2020
- Published online July 8, 2020.
- Scott D. Solomon, MDa,∗ (, )
- Pardeep S. Jhund, MBChB, PhDb,
- Brian L. Claggett, PhDa,
- Pooja Dewan, MBBSb,
- Lars Køber, MDc,
- Mikhail N. Kosiborod, MDd,
- Felipe A. Martinez, MDe,
- Piotr Ponikowski, MDf,
- Marc S. Sabatine, MDg,
- Silvio E. Inzucchi, MDh,
- Akshay S. Desai, MDa,
- Olof Bengtsson, PhDi,
- Daniel Lindholm, MDh,
- Mikaela Sjostrand, MD, PhDa,
- Anna Maria Langkilde, MDi and
- John J.V. McMurray, MDb
- aCardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- bBHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland
- cRiggshospital, Copenhagen, Denmark
- dSt. Luke’s Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Kansas
- eUniversidad Nacional de Córdoba, Córdoba, Argentina
- fCenter for Heart Diseases, University Hospital, Wroclaw Medical University, Wroclaw, Poland
- gTIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts
- hSection of Endocrinology, Yale University Medical School, New Haven, Connecticut
- iAstraZeneca, Gothenburg, Sweden
- ↵∗Address for correspondence:
Dr. Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Objectives This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial.
Background Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown.
Methods DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group.
Results A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan.
Conclusions Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124)
Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, Theracos; and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Dinaqor, Tremeau. Dr. Jhund’s employer, University of Glasgow, has been paid by AstraZeneca for time spent working on DAPA-HF; Dr. Jhund has received consulting fees, advisory board fees, and lecture fees from Novartis; has received advisory board fees from Cytokinetics; and has received grant support from Boehringer Ingelheim. Dr. Claggett has received consulting fees from Boeringer-Ingelheim. Dr. Køber, has received lecture fees from Novartis and Bristol-Myers Squibb. Dr. Kosiborod has received grant support, honoraria, and research support from AstraZeneca; has received grant support and honoraria from Boehringer Ingelheim; and has received honoraria from Sanofi, Amgen, NovoNordisk, Merck (Diabetes), Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia, Novartis, Applied Therapeutics, Amarin, and Eli Lilly. Dr. Martinez has received consulting fees from AstraZeneca. Dr. Ponikowski has received grant support, paid to his institution; has received lecture fees from Pfizer; has participated in clinical trials for Amgen; has received fees for serving on a Speakers Bureau, has received consulting fees, and has participated in clinical trials for Vifor Pharma, Bayer, Bristol-Myers Squibb, Cibiem, Novartis, RenalGuard, and Boehringer Ingelheim; has received fees for serving on a speakers bureau and consulting fees from Servier and Respicardia; and has received fees for serving on a Speakers Bureau from Berlin-Chemie; Dr. Sabatine has received grant support, paid to Brigham and Women’s Hospital; has received consulting fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; has received consulting fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor, Dynamix, Esperion, IFM Therapeutics, and Ionis; has received grant support, paid to Brigham and Woman’s Hospital, from Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; and has served as a member of the TIMI Study Group, which receives grant support, paid to Brigham and Women’s Hospital, from Abbott, Aralez, Roche, and Zora Biosciences. Dr. Inzucchi has received advisory fees from AstraZeneca and Zafgen; has received lecture fees, consulting fees, fees for serving as a clinical trial publications committee member, reimbursement for medical writing, and travel support from Boehringer Ingelheim; has received fees for serving on a steering committee and travel support from Sanofi/Lexicon; has received lecture fees, consulting fees, and travel support from Merck; and has received advisory fees and travel support from VTV Therapeutics and Abbott/Alere. Dr. Desai has received grant support from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Dalcor Pharma, and Regeneron; has received grant support, paid to BWH; has received consulting fees from Alnylam and Novartis; and has received advisory board fees from Corvidia, Relypsa, and AstraZeneca. Dr. Sjostrand holds shares in AstraZeneca. Dr. Langkilde holds shares in AstraZeneca. Dr. McMurray has received fees (all fees listed paid to Glasgow University) for serving on a steering committee from Bayer; has received fees for serving on a steering committee, fees for serving on an endpoint committee, and travel support from Cardiorentis; has received fees for serving on a steering committee and travel support from Amgen, Oxford University/Bayer, AbbVie, and DalCor; has received fees for serving as principal investigator of a trial and travel support from Theracos; has received fees for serving on a data safety monitoring committee from Pfizer; has received fees for serving on a data safety monitoring committee from Merck; has received fees for serving on an executive committee, fees for serving as co-principal investigator of a trial, fees for serving on a steering committee, and fees for serving on an executive committee, travel support, and advisory board fees from Novartis; has received fees for serving as co-principal investigator for a trial, has received fees for serving on a steering committee and travel support from GlaxoSmithKline; and has received fees for serving on a steering committee from Bristol-Myers Squibb; has received fees for serving on a steering committee and fees for serving on an endpoint adjudication committee and travel support from Vifor-Fresenius. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Heart Failure author instructions page.
- Received March 11, 2020.
- Revision received April 13, 2020.
- Accepted April 14, 2020.
- 2020 American College of Cardiology Foundation
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