Effect of dapagliflozin on cause-specific mortality in patients with heart failure across the spectrum of ejection fraction

Desai, A. S. et al. (2022) Effect of dapagliflozin on cause-specific mortality in patients with heart failure across the spectrum of ejection fraction. JAMA Cardiology, 7(12), pp. 1227-1234. (doi: 10.1001/jamacardio.2022.3736) (PMID:36189985) (PMCID:PMC9531084)

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

• Item Type: Articles
• Additional Information: The DAPA-HF and DELIVER trials were sponsored by AstraZeneca. In addition, this work was supported by grant RE/18/6/34217 from the British Heart Foundation Centre of Research Excellence (Drs Jhund and McMurray) and the Vera Melrose Heart Failure Research Fund.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lang, Professor Ninian and Connolly, Dr Eugene and Kondo, Dr Toru and Jhund, Professor Pardeep and McMurray, Professor John and Petrie, Professor Mark
• Authors: Desai, A. S., Jhund, P. S., Claggett, B. L., Vaduganathan, M., Miao, Z. M., Kondo, T., Barkoudah, E., Brahimi, A., Connolly, E., Finn, P., Lang, N. N., Mc Causland, F. R., McGrath, M., Petrie, M. C., McMurray, J. J.V., and Solomon, S. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: JAMA Cardiology
• Publisher: American Medical Association
• ISSN: 2380-6583
• ISSN (Online): 2380-6591
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in JAMA Cardiology 7(12):1227-1234
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
303944		BHF Centre of Excellence	Colin Berry	British Heart Foundation (BHF)	RE/18/6/34217	CAMS - Cardiovascular Science