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Randomized Controlled Trial
. 2025 Jul 1;10(7):678-685.
doi: 10.1001/jamacardio.2025.0860.

Mode of Death in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The FINEARTS-HF Randomized Clinical Trial

Akshay S Desai  1 , Pardeep S Jhund  2 , Muthiah Vaduganathan  1 , Brian L Claggett  1 , Jonathan W Cunningham  1 , Maria A Pabon  1 , Carolyn S P Lam  3 , Michele Senni  4 , Sanjiv Shah  5 , Adriaan A Voors  6 , Faiez Zannad  7 , Bertram Pitt  8 , Flaviana Amarante  9 , James Lay-Flurrie  10 , Markus F Scheerer  11 , Andrea Lage  9 , John J V McMurray  2 , Scott D Solomon  1
Affiliations
Randomized Controlled Trial

Mode of Death in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The FINEARTS-HF Randomized Clinical Trial

Akshay S Desai et al. JAMA Cardiol. .

Abstract

Importance: The mode of death in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) remains poorly understood and may vary by EF.

Objective: To evaluate the mode of death according to EF and the treatment effect of finerenone on cause-specific mortality in patients with HFmrEF/HFpEF.

Design, setting, and participants: This was a prespecified secondary analysis of the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial, which evaluated clinical outcomes in 6001 patients with HF and EF greater than or equal to 40% randomly assigned to finerenone or placebo. The mode of death in relation to baseline EF categories (<50%, ≥50-<60%, and ≥60%) was examined, and the effect of randomized treatment on cause-specific death in Cox regression models was assessed. Data analysis was conducted between September 2024 and January 2025.

Interventions: Finerenone vs placebo.

Main outcomes and measures: Mode of death as centrally adjudicated by a clinical end points committee.

Results: Of 1013 patients (16.9%; median [IQR] age, 76 [69-82] years; 594 male [58.6%]) who died during median (IQR) follow-up of 32 (23-36) months, mode of death was ascribed to cardiovascular causes in 502 (49.6%), noncardiovascular causes in 368 (36.3%), and undetermined cause in 143 (14.1%). Of cardiovascular deaths, 215 (42.8%) were due to sudden death, 163 (32.4%) to HF, 48 (9.6%) to stroke, 25 (5.0%) to myocardial infarction, and 51 (10.2%) to other cardiovascular causes. The proportion of all-cause, cardiovascular, and sudden death was higher in those with EF less than 50%. The proportion of deaths related to HF was similar across EF categories, and the proportion of deaths due to myocardial infarction, stroke, and other cardiovascular causes was low regardless of EF. Randomization to finerenone did not significantly reduce death or cause-specific death compared with placebo in any EF category.

Conclusions and relevance: Among patients with HFmrEF/HFpEF in the FINEARTS-HF randomized clinical trial, higher proportions of cardiovascular and overall mortality in those with EF less than 50% were related principally to higher proportions of sudden death. A clear treatment effect of finerenone on cardiovascular or cause-specific mortality was not identified, although the trial was likely underpowered for these outcomes.

Trial registration: ClinicalTrials.gov Identifier: NCT04435626.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Desai reported receiving grants from Bayer, Abbott, Alnylam, AstraZeneca, and Novartis and consulting fees from Bayer, Abbott, Alnylam, AstraZeneca, Avidity Biopharma, Axon Therapeutics, Biofourmis, Boston Scientific, Endotronix, GlaxoSmithKline, Medpace, Medtronic, Merck, New Amsterdam, Novartis, Parexel, Regeneron, Roche, River2Renal, scPharmaceuticals, Veristat, Verily, and Zydus outside the submitted work. Dr Jhund reported receiving trial remuneration from Bayer and AstraZeneca for working on the FINEARTS-HF trial during the conduct of the study; receiving trial remuneration from Novartis for working on the PARADIGM and PARAGON trials; receiving trial remuneration from Novo Nordisk for working clinical trials receiving grants from Boehringer Ingelheim, Roche Diagnostics, Analog Devices Inc, and AstraZeneca; and personal fees from ProAdwise outside the submitted work; and serving as director of GCTP Ltd. Dr Vaduganathan reported receiving grant support from American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; serving on advisory boards and/or having speaker engagements from Amgen, AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics clinical trial committees outside the submitted work. Dr Claggett reported receiving consulting fees from Alnylam, Cardior, Cardurion, Cytokinetics, CVRx, Intellia, Rocket, and Eli Lilly outside the submitted work. Dr Cunningham reported receiving personal fees from Occlutech, Us2.ai, Roche Diagnostics, and Edgewise Therapeutics outside the submitted work. Dr Pabon reported receiving travel fees from Bayer for the upcoming ACC 2025 not related to this study. Dr Lam reported receiving grants from National Medical Research Council of Singapore; research support from Novo Nordisk and Roche Diagnostics; consultant/advisory board/committee fees from Alnylam Pharma, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Corteria, CPC Clinical, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Quidel Corporation, Radcliffe Group Ltd., Roche, and Us2.ai; serving as cofounder/nonexecutive director of Us2.ai; and having a patent for PCT/SG2016/050217 pending and a patent for US Patent No. 10,702, 247 issued. Dr Senni reported receiving personal fees from Novartis, Bayer, Merck, MSD, Vifor, Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Cardurion, Amgen, and Abbott outside the submitted work. Dr Shah reported receiving consulting fees from Bayer during the conduct of the study. Dr Voors reported receiving financial support to institution from Merck and Bayer AG outside the submitted work. Dr Zannad reported receiving steering committee fees from Bayer and advisory, steering committee, and/or lecture fees from 89Bio Inc, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer Ingelheim, Cambrian, Cardior, Cellprothera, Cereno, Corteria, CVRx, CVCT, Lupin, Merck, Northsea, Otsuka, Owkin, Ribocure, Salubris, and Viatris outside the submitted work. Dr Pitt reported receiving consultant fees from AnaCardio, Bayer, Boehringer Ingelheim, and Lexicon; consultant fees and stock options from SCPharmaceuticals, SQ Innovations, G 3 Pharmaceuticals, Sarfez Pharmaceuticals, Cereno, KBP Biosciences, Prointel, and Sea Star; data safety monitoring board fees from Mineralis; and having a patent for US 9931412 issued and a patent pending for US 63/045,783. Dr Amarante reported being a full-time employee of sponsor Bayer AG. Dr Lay-Flurrie reported receiving full-time employee salary from Bayer during the conduct of the study. Dr Scheerer receiving an employee salary and stock options from Bayer AG and stock options from AstraZeneca, Novo Nordisk, and Eli Lilly outside the submitted work. Dr Lage reported being a full-time employee of Bayer. Dr McMurray reported receiving payments from Bayer, British Heart Foundation, National Institutes of Health—National Heart Lung and Blood Institute (NIH-NHLBI), Alynylam Pharmaceuticals, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, and Roche to Glasgow University during the conduct of the study; consultant fees from Alnylam Pharmaceuticals, AnaCardio, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, River BioMedics, Biohaven Pharmaceuticals, Chugai Pharmaceuticals, Protherics Medicine Developments Ltd., DalCor Pharmaceuticals; lecture fees from Alkem Metabolics, Astra Zeneca, Canadian Medical and Surgical Knowledge, Centrix Healthcare, Emcure Pharmaceuticals, Eris Lifesciences, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, Translational Medicine Academy, Regeneron, MCI India, Hilton Pharmaceuticals, IMEDIC Pharmaceuticals Micro Labs Ltd, At the Limits Ltd, ARMGO Pharmaceuticals; data safety monitoring board fees from WCG Clinical Services, and director fees from Global Clinical Trial Partners Ltd outside the submitted work. Dr Solomon reported receiving grants from Bayer, Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos/BridgeBio, Gossamer, GSK, Ionis, Lilly,NIH/NHLBI, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, and Us2.ai and personal fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, GSK, Intellia, Lilly, Novartis, Roche, Theracos, Quantum Genomics, 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 1.
Figure 1.. Adjudicated Mode of Death According to Left Ventricular Ejection Fraction (LVEF)
CV indicates cardiovascular; p-y, patient-year.
Figure 2.
Figure 2.. Variation in Incidence of Adjudicated Mode of Death by Continuous Left Ventricular Ejection Fraction (LVEF), N-Terminal Pro–Brain Natriuretic Peptide (NT-proBNP), Age, and Estimated Glomerular Filtration Rate (eGFR)
SI conversion factor: To convert NT-proBNP to nanograms per liter, multiply by 1. CV indicates cardiovascular.
Figure 3.
Figure 3.. Effect of Finerenone Compared With Placebo on Cause-Specific Mortality
CV indicates cardiovascular.
See this image and copyright information in PMC

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