PMID- 38059368
OWN - NLM
STAT- MEDLINE
DCOM- 20240313
LR  - 20240403
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 149
IP  - 11
DP  - 2024 Mar 12
TI  - Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in 
      Patients With Heart Failure: The DETERMINE Randomized Clinical Trials.
PG  - 825-838
LID - 10.1161/CIRCULATIONAHA.123.065061 [doi]
AB  - 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. 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. 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. 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. 
      REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: 
      NCT03877237 and NCT03877224.
FAU - McMurray, John J V
AU  - McMurray JJV
AUID- ORCID: 0000-0002-6317-3975
AD  - BHF Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M., K.F.D.).
FAU - Docherty, Kieran F
AU  - Docherty KF
AUID- ORCID: 0000-0002-5446-9969
AD  - BHF Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M., K.F.D.).
FAU - de Boer, Rudolf A
AU  - de Boer RA
AUID- ORCID: 0000-0002-4775-9140
AD  - Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, the 
      Netherlands (R.A.d.B.).
FAU - Hammarstedt, Ann
AU  - Hammarstedt A
AD  - Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals 
      Research & Development, AstraZeneca, Gothenburg, Sweden (A.H., A.M.L., U.W.).
FAU - Kitzman, Dalane W
AU  - Kitzman DW
AUID- ORCID: 0009-0000-5274-0826
AD  - Sections on Cardiovascular Medicine and Geriatrics/Gerontology, Wake Forest 
      University School of Medicine, Winston-Salem, NC (D.W.K.).
FAU - Kosiborod, Mikhail N
AU  - Kosiborod MN
AUID- ORCID: 0000-0002-3750-9789
AD  - Saint Luke's Mid America Heart Institute, University of Missouri, Kansas City 
      (M.N.K.).
FAU - Maria Langkilde, Anna
AU  - Maria Langkilde A
AD  - Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals 
      Research & Development, AstraZeneca, Gothenburg, Sweden (A.H., A.M.L., U.W.).
FAU - Reicher, Barry
AU  - Reicher B
AD  - AstraZeneca BioPharmaceuticals Research & Development, Late-Stage Development, 
      Cardiovascular, Renal and Metabolic, Gaithersburg, MD (B.R.).
FAU - Senni, Michele
AU  - Senni M
AD  - Cardiovascular Department, Papa Giovanni XXIII Hospital Bergamo, Italy (M.S.).
FAU - Shah, Sanjiv J
AU  - Shah SJ
AUID- ORCID: 0000-0002-5655-8201
AD  - Division of Cardiology, Department of Medicine, Northwestern University Feinberg 
      School of Medicine, Chicago, IL (S.J.S.).
FAU - Wilderang, Ulrica
AU  - Wilderang U
AUID- ORCID: 0000-0002-0939-4128
AD  - Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals 
      Research & Development, AstraZeneca, Gothenburg, Sweden (A.H., A.M.L., U.W.).
FAU - Verma, Subodh
AU  - Verma S
AUID- ORCID: 0000-0002-4018-8533
AD  - Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, 
      Ontario, Canada (S.V.).
FAU - Solomon, Scott D
AU  - Solomon SD
AUID- ORCID: 0000-0003-3698-9597
AD  - Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 
      (S.D.S.).
LA  - eng
SI  - ClinicalTrials.gov/NCT03877237
SI  - ClinicalTrials.gov/NCT03877224
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231207
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 1ULL0QJ8UC (dapagliflozin)
RN  - IY9XDZ35W2 (Glucose)
RN  - 9NEZ333N27 (Sodium)
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Glucosides)
SB  - IM
CIN - Circulation. 2024 Mar 12;149(11):839-842. PMID: 38466791
MH  - Humans
MH  - Stroke Volume
MH  - Ventricular Function, Left
MH  - Quality of Life
MH  - Randomized Controlled Trials as Topic
MH  - *Heart Failure/diagnosis/drug therapy/complications
MH  - *Ventricular Dysfunction, Left/complications
MH  - Glucose
MH  - Sodium
MH  - *Benzhydryl Compounds
MH  - *Glucosides
OTO - NOTNLM
OT  - clinical trial
OT  - exercise
OT  - heart failure
OT  - sodium-glucose transporter 2 inhibitors
COIS- 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 Wilderang 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.
EDAT- 2023/12/07 06:42
MHDA- 2024/03/13 06:46
CRDT- 2023/12/07 05:35
PHST- 2024/03/13 06:46 [medline]
PHST- 2023/12/07 06:42 [pubmed]
PHST- 2023/12/07 05:35 [entrez]
AID - 10.1161/CIRCULATIONAHA.123.065061 [doi]
PST - ppublish
SO  - Circulation. 2024 Mar 12;149(11):825-838. doi: 10.1161/CIRCULATIONAHA.123.065061. 
      Epub 2023 Dec 7.