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. 2022 Dec 1;7(12):1227-1234.
doi: 10.1001/jamacardio.2022.3736.

Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction: A Participant-Level Pooled Analysis of DAPA-HF and DELIVER

Akshay S Desai  1 , Pardeep S Jhund  2 , Brian L Claggett  1 , Muthiah Vaduganathan  1 , Zi Michael Miao  1 , Toru Kondo  2 , Ebrahim Barkoudah  1 , Abdel Brahimi  1 , Eugene Connolly  2 , Peter Finn  1 , Ninian N Lang  2 , Finnian R Mc Causland  3 , Martina McGrath  3 , Mark C Petrie  2 , John J V McMurray  2 , Scott D Solomon  1
Affiliations

Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction: A Participant-Level Pooled Analysis of DAPA-HF and DELIVER

Akshay S Desai et al. JAMA Cardiol. .

Abstract

Importance: In 2 trials enrolling patients with heart failure (HF) across the spectrum of ejection fraction (EF), dapagliflozin has been shown to reduce the rate of the composite of worsening HF events or death from cardiovascular (CV) causes.

Objective: To examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF.

Design, setting, and participants: This was a participant-level, pooled, prespecified secondary analysis of data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, or DAPA-HF trial (participant left ventricular EF [LVEF] ≤40%), and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure, or DELIVER trial (participant LVEF >40%), to assess the effects of randomized treatment on cause-specific mortality. The trials assigned adjacent populations of patients with chronic HF, New York Heart Association class II-IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The primary outcome for each study was a composite of worsening HF events (hospitalization or urgent heart failure visits) or CV death. Clinical outcomes, including all deaths, were adjudicated as to cause by clinical end points committees blinded to treatment assignment.

Intervention: Dapagliflozin vs placebo.

Main outcomes and measures: The mode of death in relation to baseline EF was examined, as well as the effect of randomized treatment on cause-specific death in Cox regression models. Relationships with continuous EF were modeled using Poisson regression.

Results: Of 11 007 patients in the pooled data set, there were 1628 deaths during follow-up (mean [SD] age, 71.7 [10.3] years; 1139 male [70.0%]). Of those who died, 872 (53.5%) were ascribed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) to undetermined causes. Of CV deaths, 289 (33.1%; this represented 17.8% of total deaths) were due to HF, 441 (50.6%; 27.1% of total deaths) were sudden, 69 (7.9%; 4.2% of total deaths) were due to stroke, 47 (5.4%; 2.9% of total deaths) to myocardial infarction, and 26 (3.0%; 1.6% of total deaths) were due to other CV causes. The proportion of non-CV deaths was higher in those with higher EF. In the pooled population, across the spectrum of EF, treatment with dapagliflozin was associated with lower rates of CV death (hazard ratio [HR], 0.86; 95% CI, 0.75-0.98; P = .02), principally due to lower rates of sudden death (HR, 0.84; 95% CI, 0.70-1.01; P = .07) and HF death (HR, 0.88; 95% CI, 0.70-1.11; P = .30), with little difference in rates of death from stroke or MI.

Conclusions and relevance: In a pooled analysis of patients with HF in the DAPA-HF and DELIVER randomized clinical trials, across the full spectrum of LVEF, dapagliflozin significantly reduced risks of CV death with contributions from lower rates of sudden death and death from progressive HF.

Trial registration: ClinicalTrials.gov Identifier: NCT03036124, NCT03619213.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Desai reported receiving grants from AstraZeneca, Abbott, Alnylam, Bayer, and Novartis; consulting fees from AstraZeneca, Abbott, Alnylam, Amgen, Bayer, Biofourmis, Cytokinetics, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Roche, Regeneron, Verily, Axon Therapeutics, Avidity, and New Amsterdam; and fees for data-safety monitoring board participant from Boston Scientific. Dr Jhund reported receiving received consulting, advisory board, and speaker fees from Novartis; advisory board fees from Cytogenetics; a grant from Boehringer Ingelheim; grant support from AstraZeneca and Novartis; advisory board fees from Boehringer Ingelheim; and fees for clinical trial work from Novo Nordisk and Bayer outside the submitted work. Dr Claggett reported receiving consulting fees from Boehringer Ingelheim, Cardurion, Corvia, and Novartis outside the submitted work. Dr Vaduganathan reported receiving grant support or advisory board fees from Amgen, AstraZeneca, American Regent, Baxter HealthCare, Bayer AG, Boehringer Ingelheim, Cytokinetics, Pharmacosmos, Relypsa, Novartis, Roche Diagnostics, Lexicon Pharmaceuticals, Galmed, Occlutech, Impulse Dynamics, Sanofi, and Tricog Health; speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and actively participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics outside the submitted work. Dr Kondo reported receiving lecture fees from Abbott Medical Japan, Ono Pharmaceutical, Otsuka Pharmaceutical, Novartis Pharma, AstraZeneca, Bristol Myers Squibb, and Abiomed Japan outside the submitted work. Dr Barkoudah reported receiving grants from Brigham and Women's Hospital, the National Institutes of Health/National Heart, Lung, and Blood Institute, Bristol Myers Squibb, and Janssen; personal fees from WebMD, Medscape, Janssen, Novartis, and Pfizer; and travel expenses from Alexion outside the submitted work. Dr Connolly reported receiving fees from University of Glasgow during the conduct of the study. Dr Lang reported receiving grants from AstraZeneca, Boehringer Ingelheim, and Roche and speaker/advisory fees from MyoKardia, Roche Pharma, Pharmacosmos, Astra Zeneca, Akero, and Novartis outside the submitted work. Dr Mc Causland reported receiving consulting fees from GlaxoSmithKline; personal fees from Advanced Instruments; and grants from Fifth Eye, the National Institute of Diabetes and Digestive and Kidney Diseases, Satellite Healthcare, and Advanced Medical outside the submitted work. Dr Petrie reported receiving personal fees from Astra Zeneca, Boehringer Ingelheim, Boehringer Ingelheim, Novo Nordisk, Roche, Siemens, Takeda, New Amsterdam, Abbvie, Bayer, Cardiorentis, Vifor, Alnylam, Novartis, and Pharmacosmos; grants from Pharmacosmos, NovoNordisk, SQ Innovations, Roche, Astra Zeneca, Vifor, Medtronic, Boston Scientific, Novartis; and research support from the British Heart Foundation Centre of Research Excellence Award. Dr McMurray reported receiving consultant fees or grant support from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Amgen, Cytokinetics, Servier, Theracos, Dalcor, Pfizer, GlaxoSmithKline, Bristol Myers Squibb, Alnylam, Novartis; personal fees from Abbott, Alkem Metabolics, Corpus, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, Ionis Pharmaceuticals, Cardurion, Boehringer Ingelheim, Sun Pharmaceuticals, Medsca; and research support from the British Heart Foundation Centre of Research Excellence Award outside the submitted work. Dr Solomon reported receiving grants from AstraZeneca, 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, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos; and consultant fees from 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, Akros, Puretech Health outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Number of Deaths by Adjudicated Cause and Ejection Fraction Category for Pooled DAPA-HF and DELIVER Populations
CV indicates cardiovascular; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; HF, heart failure; MI, myocardial infarction.
Figure 2.
Figure 2.. Variation in Incidence Rates of Death by Cause and Continuous Left Ventricular Ejection Fraction for Pooled DAPA-HF and DELIVER Populations
CV indicates cardiovascular; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; HF, heart failure; MI, myocardial infarction.
Figure 3.
Figure 3.. Effect of Dapagliflozin Compared With Placebo on Cause-Specific Mortality for the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) Populations
CV indicates cardiovascular; HR, hazard ratio; MI, myocardial infarction.
Figure 4.
Figure 4.. Effect of Dapagliflozin Across the Spectrum of Ejection Fraction
Effect of dapagliflozin on sudden death (A) and heart failure (B). The solid line depicts the continuous hazard ratio across the range of left ventricular ejection fraction (LVEF) and the dashed lines represent the 95% CIs from the Cox model. The overall effect of treatment in the pooled population is shown in each panel as an HR (95% CI) with the 2-sided P value for interaction between treatment assignment and LVEF.
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