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Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in Patients With Heart Failure: The DETERMINE Randomized Clinical Trials.
- Source :
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Circulation [Circulation] 2024 Mar 12; Vol. 149 (11), pp. 825-838. Date of Electronic Publication: 2023 Dec 07. - Publication Year :
- 2024
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Abstract
- Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk of worsening heart failure (HF) and cardiovascular death in patients with HF irrespective of left ventricular ejection fraction. It is important to determine whether therapies for HF improve symptoms and functional capacity.<br />Methods: The DETERMINE (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure) double-blind, placebo-controlled, multicenter trials assessed the efficacy of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on the Total Symptom Score (TSS) and Physical Limitation Scale (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) in 313 patients with HF with reduced ejection fraction (DETERMINE-Reduced) and in 504 patients with HF with preserved ejection fraction (DETERMINE-Preserved) with New York Heart Association class II or III symptoms and elevated natriuretic peptide levels. The primary outcomes were changes in the KCCQ-TSS, KCCQ-PLS, and 6MWD after 16 weeks of treatment.<br />Results: Among the 313 randomized patients with HF with reduced ejection fraction, the median placebo-corrected difference in KCCQ-TSS from baseline at 16 weeks was 4.2 (95% CI, 1.0, 8.2; P =0.022) in favor of dapagliflozin. The median placebo-corrected difference in KCCQ-PLS was 4.2 (95% CI, 0.0, 8.3; P =0.058). The median placebo-corrected difference in 6MWD from baseline at 16 weeks was 3.2 meters (95% CI, -6.5, 13.0; P =0.69). In the 504 patients with HF with preserved ejection fraction, the median placebo-corrected 16-week difference in KCCQ-TSS and KCCQ-PLS was 3.2 (95% CI, 0.4, 6.0; P =0.079) and 3.1 (-0.1, 5.4; P =0.23), respectively. The median 16-week difference in 6MWD was 1.6 meters (95% CI, -5.9, 9.0; P =0.67). In an exploratory post hoc analysis of both trials combined (DETERMINE-Pooled), the median placebo-corrected difference from baseline at 16 weeks was 3.7 (1.5, 5.9; P =0.005) for KCCQ-TSS, 4.0 (0.3, 4.9; P =0.036) for KCCQ-PLS, and 2.5 meters (-3.5, 8.4; P =0.50) for 6MWD.<br />Conclusions: Dapagliflozin improved the KCCQ-TSS in patients with HF with reduced ejection fraction but did not improve KCCQ-PLS or 6MWD. Dapagliflozin did not improve these outcomes in patients with HF with preserved ejection fraction. In a post hoc analysis including all patients across the full spectrum of ejection fraction, there was a beneficial effect of dapagliflozin on KCCQ-TSS and KCCQ-PLS but not 6MWD.<br />Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224.<br />Competing Interests: Disclosures Dr McMurray has received payments through Glasgow University for work on clinical trials; consulting fees and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; personal lecture fees from Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, and Servier; and has served as director of Global Clinical Trial Partners. Dr Docherty’s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials; he has received speaker honoraria from AstraZeneca and Radcliffe Cardiology, has served on an advisory board for Us2.ai and Bayer AG, has served on a clinical end point committee for Bayer AG, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and AstraZeneca (paid to his institution). Dr De Boer has received research grants or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Drs Hammarstedt, Langkilde, Reicher, and Wilderäng are employees of AstraZeneca. Dr Kitzman reports receiving honoraria as a consultant for AbbVie, Bayer, Merck, Medtronic, Relypsa, Corvia Medical, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Novartis; grant funding from Novartis, Bayer, and AstraZeneca; and stock ownership in Gilead Sciences. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Senni reports consultancy fees from Novartis, Merck, Vifor Pharma, Abbott, Boehringer Ingelheim, Bioventrix, Servier, and Novo Nordisk. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Verma holds a tier 1 Canada research chair in cardiovascular surgery and reports receiving research grants or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Otsuka, Pfizer, PhaseBio, S & L Solutions Event Management Inc, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; and he is president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Solomon 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/National Heart, Lung, and Blood Institute; 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, Sarepta, Lexicon, Anacardio, and Akros.
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 149
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 38059368
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.123.065061