Jawad H Butt1, Carly Adamson2, Kieran F Docherty2, Rudolf A de Boer3, Mark C Petrie2, Silvio E Inzucchi4, Mikhail N Kosiborod5,6, Anna Maria Langkilde7, Daniel Lindholm7, Felipe A Martinez8, Olof Bengtsson7, Morten Schou9, Eileen O'Meara10, Piotr Ponikowski11, Marc S Sabatine12,13, Mikaela Sjöstrand7, Scott D Solomon13, Pardeep S Jhund2, John J V McMurray2, Lars Køber1. 1. Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (J.H.B., L.K.). 2. BHF Cardiovascular Research Centre, University of Glasgow, United Kingdom (C.A., K.F.D., M.C.P., P.S.J., J.J.V.M.). 3. Department of Cardiology, University Medical Center and University of Groningen, the Netherlands (R.A.d.B.). 4. Section of Endocrinology, Yale School of Medicine, New Haven, CT (S.E.I.). 5. Saint Luke's Mid America Heart Institute, University of Missouri, Kansas City (M.N.K.). 6. The George Institute for Global Health, University of New South Wales, Sydney, Australia (M.N.K.). 7. Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (A.M.L., D.L., O.B., M. Sjöstrand). 8. Universidad Nacional de Córdoba, Córdoba, Argentina (F.A.M.). 9. Department of Cardiology, Herlev-Gentofte University Hospital, Herlev, Denmark (M. Schou). 10. Montreal Heart Institute, Université de Montréal, Quebec, Canada (E.O.). 11. Center for Heart Diseases, University Hospital, Wroclaw Medical University, Poland (P.P.). 12. TIMI Study Group (M.S.S.), Brigham and Women's Hospital, Boston, MA. 13. Division of Cardiovascular Medicine (M.S.S., S.D.S.), Brigham and Women's Hospital, Boston, MA.
Abstract
BACKGROUND: Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT-proBNP. METHODS: We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and a NT-proBNP level ≥600 pg/mL (≥600 ng/L; ≥400 pg/mL if hospitalized for HF within the previous 12 months or ≥900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. RESULTS: Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857-2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, -303 pg/mL [95% CI, -457 to -150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88-0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27-0.67), 0.77 (0.56-1.04), 0.78 (0.60-1.01), and 0.78 (0.64-0.95); P for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement (≥5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score (P for interaction=0.99) and decreased the proportion with a deterioration ≥5 points (P for interaction=0.87) across baseline NT-proBNP quartiles. CONCLUSIONS: In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
BACKGROUND: Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT-proBNP. METHODS: We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and a NT-proBNP level ≥600 pg/mL (≥600 ng/L; ≥400 pg/mL if hospitalized for HF within the previous 12 months or ≥900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. RESULTS: Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857-2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, -303 pg/mL [95% CI, -457 to -150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88-0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27-0.67), 0.77 (0.56-1.04), 0.78 (0.60-1.01), and 0.78 (0.64-0.95); P for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement (≥5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score (P for interaction=0.99) and decreased the proportion with a deterioration ≥5 points (P for interaction=0.87) across baseline NT-proBNP quartiles. CONCLUSIONS: In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.