Pardeep S Jhund1, Scott D Solomon2, Kieran F Docherty1, Hiddo J L Heerspink3, Inder S Anand4, Michael Böhm5, Vijay Chopra6, Rudolf A de Boer7, Akshay S Desai2, Junbo Ge8, Masafumi Kitakaze9, Bela Merkley10, Eileen O'Meara11, Morten Shou12, Sergey Tereshchenko13, Subodh Verma14, Pham Nguyen Vinh15, Silvio E Inzucchi16, Lars Køber17, Mikhail N Kosiborod18,19, Felipe A Martinez20, Piotr Ponikowski21, Marc S Sabatine22, Olof Bengtsson23, Anna Maria Langkilde23, Mikaela Sjöstrand23, John J V McMurray1. 1. BHF Cardiovascular Research Centre, University of Glasgow, United Kingdom (P.S.J., K.F.D., J.J.V.M.). 2. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S., A.S.D.). 3. Department of Clinical Pharmacy and Pharmacology (H.J.L.H.), University Medical Center Groningen, University of Groningen, The Netherlands. 4. Department of Cardiology, University of Minnesota, Minneapolis (I.S.A.). 5. Department of Medicine, Saarland University Hospital, Homburg-Saar, Germany (M.B.). 6. Department of Cardiology, Max Super Speciality Hospital, Saket, New Delhi, India (V.C.). 7. Department of Cardiology (R.A.d.B.), University Medical Center Groningen, University of Groningen, The Netherlands. 8. Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, China (J.G.). 9. Cardiovascular Division of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (M.K.). 10. Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.). 11. Department of Cardiology, Montreal Heart Institute, Canada (E.O.). 12. Department of Cardiology, Gentofte University Hospital, Copenhagen, Denmark (M. Shou). 13. Department of Myocardial Disease and Heart Failure, National Medical Research Center of Cardiology, Moscow, Russia (S.T.). 14. Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Canada (S.V.). 15. Department of Internal Medicine, Tan Tao University, Tan Duc, Vietnam (P.N.V.). 16. Section of Endocrinology, Yale School of Medicine, New Haven, CT (S.E.I.). 17. Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (L.K.). 18. Saint Luke's Mid America Heart Institute, University of Missouri, Kansas City (M.N.K.). 19. The George Institute for Global Health, University of New South Wales, Sydney, Australia (M.N.K.). 20. Universidad Nacional de Córdoba, Córdoba, Argentina (F.A.M.). 21. Center for Heart Diseases, University Hospital, Wroclaw Medical University, Poland (P.P.). 22. TIMI Study Group, Brigham and Women's Hospital, Boston, MA (M.S.S.). 23. Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (O.B., A.M.L., M. Sjöstrand).
Abstract
BACKGROUND: Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease that complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure). We also examined the effect of dapagliflozin on kidney function after randomization. METHODS: Patients who have HFrEF with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL·min-1·1.73 m-2 were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) according to eGFR category at baseline (<60 and ≥60 mL·min-1·1.73 m-2) and used eGFR at baseline as a continuous measure, as well. Secondary cardiovascular outcomes and a prespecified composite renal outcome (≥50% sustained decline eGFR, end-stage renal disease, or renal death) were also examined, along with a decline in eGFR over time. RESULTS: Of 4742 patients with a baseline eGFR, 1926 (41%) had eGFR <60 mL·min-1·1.73 m-2. The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% CI) for the primary end point in patients with chronic kidney disease was 0.71 (0.59-0.86) versus 0.77 (0.64-0.93) in those with an eGFR ≥60 mL·min-1·1.73 m-2 (interaction P=0.54). The composite renal outcome was not reduced by dapagliflozin (hazard ratio=0.71 [95% CI, 0.44-1.16]; P=0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, -1.09 (-1.40 to -0.77) versus placebo -2.85 (-3.17 to -2.53) mL·min-1·1.73 m-2 per year (P<0.001). This was observed in those with and without type 2 diabetes (P for interaction=0.92). CONCLUSIONS: Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF, and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
BACKGROUND: Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease that complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure). We also examined the effect of dapagliflozin on kidney function after randomization. METHODS: Patients who have HFrEF with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL·min-1·1.73 m-2 were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) according to eGFR category at baseline (<60 and ≥60 mL·min-1·1.73 m-2) and used eGFR at baseline as a continuous measure, as well. Secondary cardiovascular outcomes and a prespecified composite renal outcome (≥50% sustained decline eGFR, end-stage renal disease, or renal death) were also examined, along with a decline in eGFR over time. RESULTS: Of 4742 patients with a baseline eGFR, 1926 (41%) had eGFR <60 mL·min-1·1.73 m-2. The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% CI) for the primary end point in patients with chronic kidney disease was 0.71 (0.59-0.86) versus 0.77 (0.64-0.93) in those with an eGFR ≥60 mL·min-1·1.73 m-2 (interaction P=0.54). The composite renal outcome was not reduced by dapagliflozin (hazard ratio=0.71 [95% CI, 0.44-1.16]; P=0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, -1.09 (-1.40 to -0.77) versus placebo -2.85 (-3.17 to -2.53) mL·min-1·1.73 m-2 per year (P<0.001). This was observed in those with and without type 2 diabetes (P for interaction=0.92). CONCLUSIONS: Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF, and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
Authors: John J V McMurray; Scott D Solomon; Silvio E Inzucchi; Lars Køber; Mikhail N Kosiborod; Felipe A Martinez; Piotr Ponikowski; Marc S Sabatine; Inder S Anand; Jan Bělohlávek; Michael Böhm; Chern-En Chiang; Vijay K Chopra; Rudolf A de Boer; Akshay S Desai; Mirta Diez; Jaroslaw Drozdz; Andrej Dukát; Junbo Ge; Jonathan G Howlett; Tzvetana Katova; Masafumi Kitakaze; Charlotta E A Ljungman; Béla Merkely; Jose C Nicolau; Eileen O'Meara; Mark C Petrie; Pham N Vinh; Morten Schou; Sergey Tereshchenko; Subodh Verma; Claes Held; David L DeMets; Kieran F Docherty; Pardeep S Jhund; Olof Bengtsson; Mikaela Sjöstrand; Anna-Maria Langkilde Journal: N Engl J Med Date: 2019-09-19 Impact factor: 91.245
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