Mark C Petrie1, Subodh Verma2, Kieran F Docherty1, Silvio E Inzucchi3, Inder Anand4, Jan Belohlávek5, Michael Böhm6, Chern-En Chiang7,8, Vijay K Chopra9, Rudolf A de Boer10, Akshay S Desai11, Mirta Diez12, Jaroslaw Drozdz13, Andre Dukát14, Junbo Ge15, Jonathan Howlett16, Tzvetana Katova17, Masafumi Kitakaze18, Charlotta E A Ljungman19, Béla Merkely20, Jose C Nicolau21, Eileen O'Meara22, Pham Nguyen Vinh23, Morten Schou24, Sergey Tereshchenko25, Lars Køber26, Mikhail N Kosiborod27, Anna Maria Langkilde28, Felipe A Martinez29, Piotr Ponikowski30, Marc S Sabatine11, Mikaela Sjöstrand28, Scott D Solomon11, Per Johanson28, Peter J Greasley31, David Boulton32, Olof Bengtsson28, Pardeep S Jhund1, John J V McMurray1. 1. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. 2. Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. 3. Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut. 4. Department of Cardiology, University of Minnesota, Minneapolis. 5. Second Department of Internal Medicine, Cardiovascular Medicine, General Teaching Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic. 6. Department of Medicine, Saarland University Hospital, Homburg/Saar, Germany. 7. Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan. 8. National Yang-Ming University, Taipei, Taiwan. 9. Department of Cardiology, Medanta, Gurgaon, Haryana, India. 10. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 11. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. 12. Division of Cardiology, Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina. 13. Department Cardiology, Medical University of Lodz, Lodz, Poland. 14. Fifth Department of Internal Medicine, Comenius University in Bratislava, Bratislava, Slovakia. 15. Shanghai Institute of Cardiovascular Disease, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, China. 16. Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 17. Clinic of Cardiology, National Cardiology Hospital, Sofia, Bulgaria. 18. Cardiovascular Division of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan. 19. Institute of Medicine, Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 20. Heart and Vascular Center, Semmelweis University, Budapest, Hungary. 21. Instituto do Coracao (InCor), Hospital das Clínicas Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil. 22. Department of Cardiology, Montreal Heart Institute, Montreal, Ontario, Canada. 23. Department of Internal Medicine, Tan Tao University, Tan Duc, Vietnam. 24. Department of Cardiology, Gentofte University Hospital Copenhagen, Copenhagen, Denmark. 25. Department of Myocardial Disease and Heart Failure, National Medical Research Center of Cardiology, Moscow, Russia. 26. Department of Cardiology Copenhagen University Hospital, Copenhagen, Denmark. 27. St Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City. 28. Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 29. Universidad Nacional de Córdoba, Córdoba, Argentina. 30. Center for Heart Diseases, University Hospital, Wroclaw Medical University, Wroclaw, Poland. 31. Early Discovery and Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 32. Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland.
Abstract
Importance: Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. Objective: To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. Design, Setting, and Participants: Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level lessthan 5.7% vs greater than or equal to 5.7%. Results: Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes. Conclusions and Relevance: In this exploratory analysis of a randomized trial of patients withHFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.
RCT Entities:
Importance: Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. Objective: To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. Design, Setting, and Participants: Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%. Results: Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes. Conclusions and Relevance: In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.
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