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Randomized Controlled Trial
. 2024 Mar 1;9(3):283-289.
doi: 10.1001/jamacardio.2023.5318.

Dapagliflozin and Mode of Death in Heart Failure With Improved Ejection Fraction: A Post Hoc Analysis of the DELIVER Trial

Orly Vardeny  1 , Akshay S Desai  2 , Pardeep S Jhund  3 , James C Fang, Brian Claggett  2 , Rudolf A de Boer  4 , Adrian F Hernandez  5 , Silvio E Inzucchi  6 , Mikhail N Kosiborod  7 , Carolyn S P Lam  8   9 , Felipe A Martinez  10 , Sanjiv J Shah  11 , Finnian R Mc Causland  12 , Mark C Petrie  13 , Muthiah Vaduganathan  2 , John J V McMurray  3 , Scott D Solomon  2
Affiliations
Randomized Controlled Trial

Dapagliflozin and Mode of Death in Heart Failure With Improved Ejection Fraction: A Post Hoc Analysis of the DELIVER Trial

Orly Vardeny et al. JAMA Cardiol. .

Abstract

Importance: Heart failure with improved ejection fraction (HFimpEF), defined as prior left ventricular ejection fraction (LVEF) 40% or lower that has increased to greater than 40%, is understudied.

Objective: To examine mode of death and the association of dapagliflozin with reductions in cause-specific death in patients with HFimpEF.

Design, setting, and participants: This was a post hoc analysis from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) randomized clinical trial, conducted from August 2018 to December 2020. The trial randomly assigned patients with HF with LVEF greater than 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The presence of HFimpEF was captured through study case report forms. The primary outcome was a composite of worsening HF events (hospitalization or urgent HF visits) or cardiovascular death. Clinical outcomes were adjudicated by a blinded clinical end points committee. Data were analyzed from May 2022 to August 2023.

Intervention: Dapagliflozin vs placebo.

Main outcomes and measures: The mode of death in relation to HFimpEF status was examined, as well as the association of randomized treatment with cause-specific death in Cox regression models.

Results: Of 1151 patients with HFimpEF in DELIVER, 190 (16.5%) died, compared with 833 patients (16.3%) of 5112 with LVEF consistently greater than 40%. The overall distribution of mode of death was similar in those with HFimpEF compared with those with LVEF consistently greater than 40% (noncardiovascular death: 103 of 190 [54%] vs 428 of 833 [51%]; cardiovascular death: 87 of 190 [46%] vs 405 of 833 [49%], respectively). Most deaths in individuals with HFimpEF were noncardiovascular (103 of 180 [54%]). For cardiovascular deaths, sudden deaths were most common (36 of 190 events [19%]), followed by HF-related (29 of 190 events [15%]). Among patients with HFimpEF, treatment with dapagliflozin was associated with lower rates of cardiovascular death relative to placebo, a difference primarily due to lower rates of sudden death (hazard ratio, 0.38; 95% CI, 0.18-0.79; P for interaction = .01).

Conclusions and relevance: The findings in this study support current guideline recommendations for use of sodium-glucose transport protein 2 inhibitor therapy, and further suggest that the addition of a sodium-glucose transport protein 2 inhibitor therapy to other guideline-directed medical therapies may help reduce cardiovascular mortality in patients with HFimpEF.

Trial registration: ClinicalTrials.gov Identifier: NCT03619213.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vardeny reported grants from AstraZeneca (during the conduct of the study and grants from Bayer, personal fees from Cardior, and other from Cardurion (steering committee member with institutional support) outside the submitted work. Dr Desai reported grants from AstraZeneca (to institution) and personal fees from AstraZeneca (personal consulting fees) during the conduct of the study as well as grants from Abbott (to institution), Alnylam (to institution), Bayer (to institution), and Novartis (to institution) and personal consulting fees from Abbott, Alnylam, Biofourmis, Bayer, Cytokinetics, Merck, GSK, Novartis, Parexel, Medpace, Regeneron, River2Renal, Roche, Verily, Veristat, SC Pharma, and Zydus outside the submitted work. Dr Jhund reported grants from Astrazeneca (to institution for work on the DAPA-HF and DELIVER trials) during the conduct of the study as well as grants from Novartis (to institution for work on the PARADIGM and PARAGON trials), Boehringer Ingelheim, Analog Devices Inc, and Roche; personal fees from Boehringer Ingelheim, ProAdwise, Alkem Metablomics, Sun Pharmaceuticals, and Intas Pharma; other from Novonordisk (clinical trial work) and Bayer AG (clinical trial work); and serving as director of outside the submitted work; and Director Global Clinical Trial Partners outside the submitted work. Dr Fang reported personal fees from AstraZeneca (steering committee, DELIVER HF trial) during the conduct of the study; personal fees from Novartis (executive committee, EVALUATE HF trial), Amgen (steering committee, GALACTIC HF trial), Boerhinger-Ingelheim/Eli Lilly (DSMB EMBRACE HF trial), and Windtree (DSMB SEISMiC trial) outside the submitted work; and serving on the Heart Failure Society of America Board of Directors, Abbott Adjudication Committee, and Quidel Adjudication Committee. Dr Claggett reported consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, and Rocket outside the submitted work. Dr de Boer reported grants from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals, Ionis Pharmaceuticals, Novo Nordisk, and Roche (to institution) and personal fees from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche (speaker fees) outside the submitted work. Dr Hernandez reported grants from AstraZeneca during the conduct of the study as well as grants from American Regent, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Cytokinetics, and Verily and personal fees from Bristol Myers Squibb outside the submitted work. Dr Inzucchi reported personal fees from AstraZeneca (serving on trial’s executive committee) during the conduct of the study as well as consultant and lecture fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck, Pfizer, and Bayer outside the submitted work. Dr Kosiborod reported personal fees from AstraZeneca (to institution) during the conduct of the study as well as personal fees paid to institution from Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Bayer, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, SC Pharmaceuticals, Structure Therapeutics, Vifor Pharma, Youngene Therapeutics, 35Pharma, Imbria Pharmaceuticals, Janssen, and Sanofi; grants to institution from AstraZeneca, Pfizer, and Boehringer Ingelheim; and other from AstraZeneca (data analytic center fees), Artera Health (stock options), and Saghmos Therapeutics (stock options) outside the submitted work. Dr Lam reported grants from NovoNordisk and Roche Diagnostics; consulting for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma, Echonous, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceuticals, Janssen, Medscape/WebMD, Merck, Novartis, NovoNordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, Recor Medical, Roche Diagnostics, Sanofi, and Siemens Healthcare; and serving as cofounder and nonexecutive director of Us2.ai outside the submitted work; in addition, Dr Lam had patents pending (PCT/SG2016/050217; method for diagnosis and prognosis of chronic heart failure) and issued (US Patent No. 10 702 247; automated clinical workflow that recognizes and analyses 2-dimensional and Doppler echo images for cardiac measurements and the diagnosis, prediction and prognosis of heart disease). Dr Martinez reported personal fees from AstraZeneca during the conduct of the study. Dr Shah reported personal fees from AstraZeneca (consulting fees for executive committee of the DELIVER trial) during the conduct of the study. Dr McCausland reported grants from National Institute of Diabetes and Digestive and Kidney Diseases, Lexicon, and Novartis and personal fees from GSK and Zydus outside the submitted work. Dr Petrie reported personal fees from AstraZeneca, Boehringer Ingelheim, NovoNordisk, Roche, Siemens, Takeda, New Amsterdam, Novartis, AbbVie, Pharmacosmos, and Vifor and grants from Boehringer Ingelheim, AstraZeneca, NovoNordisk, SQ Innovations, Roche, Novartis, and Pharmacosmos outside the submitted work. Dr Vaduganathan reported research grant support from 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 served on advisory boards or had speaker engagements or other support from AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics (clinical trial committees) outside the submitted work. Dr McMurray reported other from AstraZeneca (employer, Glasgow University, has been paid by AstraZeneca, which markets dapagliflozin, for time spent as principal/coprincipal investigator of the DAPA-HF, DELIVER, and DETERMINE trials and DAPA-Resist trial with dapagliflozin in heart failure and steering committee member for the DAPA-CKD trial with dapagliflozin in chronic kidney disease; these payments were made through a consultancy with Glasgow University and no personal payments were received in relation to this trial/this drug) during the conduct of the study and other from Amgen (employer, Glasgow University, has been paid by Amgen for time spent as steering committee member for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; Amgen has also paid for travel and accommodation for some of these meetings/activities; these payments were made through a consultancy with Glasgow University and no personal payments were received in relation to these trials/this drug); Bayer (employer, Glasgow University, has been paid by Bayer for time spent as coprincipal investigator of the FINEARTS trial with finerenone; these payments were made through a consultancy with Glasgow University and no personal payments were received in relation to these trials/drugs); Cardurion (employer, Glasgow University, has been paid by Cardurion for participation in a company advisory board about development in connection with drug development and design of clinical trials); Cytokinetics (employer, Glasgow University, has been paid by Cytokinetics for time spent as steering committee member for the GALACTIC-HF trial and meetings and other activities related to this trial; Cytokinetics has also paid for travel and accommodation for some of these meetings/activities; these payments were made through a consultancy with Glasgow University and no personal payments were received in relation to these trials/this drug); GSK (employer, Glasgow University, has been paid by GSK for time spent as steering committee member for the ASCEND-D and ASCEND-ND trials, using daprodustat, and meetings related to these trials; GSK has also paid for travel and accommodation for some of these meetings; these payments were made through a consultancy with Glasgow University and no personal payments were received in relation to these trials/drugs); KBP Biosciences (employer, Glasgow University, has been paid by KBP Biosciences for time spent scientific adviser to company to help guide clinical development in cardiorenal disease, inflammation, and infection); Novartis (employer, Glasgow University, has been paid by Novartis for time spent as coprincipal investigator for the PARAGON-HF trial and steering committee member for PARADISE-MI, PERSPECTIVE, and PARACHUTE-HF trials, all with sacubitril/valsartan, and meetings related to these trials; Novartis has also paid for travel and accommodation for some of these meetings; these payments were made through a consultancy with Glasgow University and no personal payments were received from Novartis in relation to these trials/drugs); serving on the data safety monitoring board for George Clinical; lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, Translational Medicine Academy; consulting fees from Alynylam Pharmaceuticals, Bayer, Bristol Myers Squibb, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; and serving as director at Global Clinical Trial Partners outside the submitted work. Dr Solomon reported grants from AstraZeneca (to institution) during the conduct of the study as well as grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI (to institution) and consulting fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Eli 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, and Valo outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Mode of Death Comparing Individuals With Heart Failure With Improved Ejection Fraction (HFimpEF) to Those With Left Ventricular Ejection Fraction (LVEF) Consistently Over 40%
CV indicates cardiovascular.
See this image and copyright information in PMC

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