Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER.

Autor:	Butt JH; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.; Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark., Kondo T; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Yang M; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK., Jhund PS; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK., Docherty KF; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK., Vaduganathan M; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Claggett BL; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Hernandez AF; Duke University Medical Center, Durham, NC, USA., Lam CSP; National Heart Centre Singapore, Singapore.; Duke-National University of Singapore, Singapore., Inzucchi SE; Yale School of Medicine, New Haven, CT, USA., Martinez FA; University of Cordoba, Cordoba, Argentina., de Boer RA; Erasmus Medical Center, Rotterdam, The Netherlands., Kosiborod MN; Saint Luke's Mid America Heart Institute, Kansas City, MO, USA., Desai AS; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Køber L; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Ponikowski P; Department of Heart Disease, Wroclaw Medical University, Wroclaw, Poland., Sabatine MS; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA., Shah SJ; Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Zaozerska N; Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Wilderäng U; Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Bengtsson O; Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Solomon SD; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., McMurray JJV; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
Jazyk:	angličtina
Zdroj:	European heart journal [Eur Heart J] 2023 Jun 25; Vol. 44 (24), pp. 2170-2183.
DOI:	10.1093/eurheartj/ehad276
Abstrakt:	Aims: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation. Methods and Results: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD. Conclusion: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation. Competing Interests: Conflict of interest J.H.B. reports advisory board honoraria from Bayer; consultant honoraria from Novartis and AstraZeneca; travel grants from AstraZeneca. Dr Kondo has received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, and Abiomed. M.Y. reports travel grants from AstraZeneca. P.S.J.’s employer the University of Glasgow has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials, personal fees from Novartis and Cytokinetics, and grants from Boehringer Ingelheim. K.F.D. reports receiving honoraria from AstraZeneca and a research grant to his institution from Boehringer Ingelheim. M.V. has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. A.F.H. has received research support from American Regent, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, and Verily and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Myokardia, Merck, Novartis, and Vifor. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development, LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and non-executive director of Us2.ai. S.E.I. has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. F.A.M. has received personal fees from AstraZeneca. R.A.d.B.’s institution, the UMCG, has received research grants and fees (outside the submitted work) from AstraZeneca; Abbott; Boehringer Ingelheim; Cardio Pharmaceuticals Gmbh; Ionis Pharmaceuticals, Inc; Novo Nordisk; and Roche. R.A.d.B. has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside the submitted work). M.N.K. has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma, has received other research support from AstraZeneca, and has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. A.S.D. has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside the submitted work. L.K. reports compensation from Novartis for other services, compensation from Novo Nordisk for other services, and compensation from AstraZeneca for other services. P.P. reports compensation from AstraZeneca for consultant services, compensation from Boehringer Ingelheim for consultant services, compensation from Servier for consultant services, compensation from AstraZeneca for other services, compensation from Pfizer for other services, compensation from Amgen for consultant services, compensation from Vifor Pharma for consultant services, compensation from Novartis for other services, and compensation from Abbott Vascular for other services. M.S.S. reports research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, Ionis, Merck, Novartis, and Pfizer and consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Boehrigner Ingelheim, Reddy’s Laboratories, FibroGen, Intarcia, Merck, Moderna, Novo Nordisk, Precision BioSciences, and Silence Therapeutics. S.J.S. has received either personal or institutional research support for DELIVER from AstraZeneca. N.Z. is an employee and shareholder of AstraZeneca. U.W. is an employee and shareholder of AstraZeneca. O.B. is an employee and shareholder of AstraZeneca. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. J.J.V.M. reports payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis. Personal consultancy fees from Alnylam Pharmaceuticals, Bayer, BMS, George Clinical PTY Ltd, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corporation. Personal lecture fees: Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica health, Intas Pharmaceuticals J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy. He is a director of Global Clinical Trial Partners Ltd. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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