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Background: Data on the effect of mineralocorticoid receptor antagonist therapy on HbA 1c levels and new-onset diabetes are conflicting. We aimed to examine the effect of oral finerenone, compared with placebo, on incident diabetes in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) trial., Methods: In this randomised, double-blind, placebo-controlled trial, 6001 participants with heart failure with New York Heart Association functional class II-IV, left ventricular ejection fraction 40% or higher, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomly assigned to finerenone or placebo, administered orally. Randomisation was performed with concealed allocation. The primary outcome of the trial was the composite of cardiovascular death and total (first and recurrent) heart failure events (ie, heart failure hospitalisation or urgent heart failure visit). In the present analysis, participants with diabetes at baseline (investigator-reported history of diabetes or baseline HbA 1c ≥6·5%) were excluded. New-onset diabetes was defined as a HbA 1c measurement of 6·5% or higher on two consecutive follow-up visits or new initiation of glucose-lowering therapy. The full-analysis set comprised all participants randomly assigned to study treatment, analysed according to their treatment assignment irrespective of the treatment received (ie, intention to treat). The safety analysis set comprised participants randomly assigned to study treatment who took at least one dose of the investigational product, analysed according to the treatment actually received. This trial is registered with ClinicalTrials.gov, NCT04435626, and is closed to new participants., Findings: Between Sept 14, 2020, and Jan 10, 2023, 6001 participants were recruited and randomly assigned to finerenone or placebo. 3222 (53·7%) participants did not have diabetes at baseline and comprised the study population. During a median duration of follow-up of 31·3 months (IQR 21·5-36·3), 115 (7·2%) participants in the finerenone group and 147 (9·1%) in the placebo group developed new-onset diabetes, corresponding to a rate of 3·0 events per 100 person-years (95% CI 2·5-3·6) in the finerenone group and 3·9 events per 100 person-years (3·3-4·6) in the placebo group. Compared with placebo, finerenone significantly reduced the hazard of new-onset diabetes by 24% (hazard ratio [HR] 0·76 [95% CI 0·59-0·97], p=0·026). Fine-Gray competing risk analysis, accounting for the competing risk of death, yielded a similar finding (subdistribution HR 0·75 [0·59-0·96], p=0·024). Results were similar in sensitivity analyses, in which the definition of new-onset diabetes was expanded to include initiation of SGLT2 inhibitor treatment with diabetes as indication, restricted to HbA 1c measurements only, and restricted to new initiation of glucose-lowering drugs only (excluding SGLT2 inhibitor treatment). Findings were similar when participants treated with glucose-lowering drugs at baseline were excluded (n=15). The effect of finerenone, compared with placebo, on new-onset diabetes was consistent across key participant subgroups. Seven participants had an adverse event of new diabetes not captured by any of the definitions above., Interpretation: In participants with heart failure with mildly reduced or preserved ejection fraction without diabetes, oral finerenone reduced the hazard of new-onset diabetes, representing a meaningful additional clinical benefit of this treatment in these individuals., Funding: Bayer., Competing Interests: Declaration of interests JHB reports advisory board honoraria from AstraZeneca and Bayer; consultant honoraria from Novartis and AstraZeneca; and travel grants from AstraZeneca. PSJ reports speakers' fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices, and Roche; remuneration to employer for clinical trial work from AstraZeneca, Bayer, Novartis, and Novo Nordisk; and directorship at Global Clinical Trial Partners. BLC reports personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and participation on a data safety monitoring board for Novo Nordisk. ASD reports institutional research grants from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River 2 Renal, Roche, Veristat, Verily, and Zydus. PV, PK, PS, and FA are employees of Bayer. CSPL reports research support from Novo Nordisk and Roche; consulting fees from Alleviant, Allysta, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia, Ionis, Janssen, Medscape, Merck, Novartis, Novo Nordisk, ProSciento, Quidel, Radcliffe Group, Recardio, Recor Medical, Roche, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and being a cofounder and non-executive director of Us2.ai. MS reports participation on advisory boards, consultancy, and honoraria for Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. SJS reports research grants from the National Institutes of Health, the American Heart Association, AstraZeneca, Corvia, and Pfizer; and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. AAV reports consultancy fees and research support to employer from Adrenomed, AnaCardio, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche, and SalubrisBio. FZ reports personal fees from 89bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno, CellProthera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche, NorthSea, and UsA2; stock options at G3 Pharmaceuticals; equities at Cereno, CardioRenal, and Eshmoun Clinical Research; and being the founder of Cardiovascular Clinical Trialists. BP reports consultancy for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP, Sarfez Pharmaceuticals, SQ Innovation, G3 Pharmaceuticals, SeaStar Medical, Vifor, ProIntel, and Brainstorm Medical; stock or stock options for KBP Biosciences, Sarfez Pharmaceuticals, SQ Innovation, Sea Star Medical, Vifor, ProIntel, and Brainstorm Medical; and patents US 9931412 (site specific delivery of eplerenone to the myocardium) and US pending 63/045,783 (histone modulating agents for the prevention and treatment of organ failure). MV reports research grant support from, participation on advisory boards for, or speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Bristol Myers Squibb, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche, Sanofi, and Tricog Health; and participation on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. SDS reports research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, the National Institutes of Health National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and consultancy for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, DiNAQOR, Tremeau, CellProthera, Moderna, American Regent, Sarepta, Lexicon, AnaCardio, Akros, and Valo. JVVM reports institutional payments, consultancy fees, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, Novartis, the British Heart Foundation, the National Institutes of Health National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovation, and Catalyze Group; personal consultancy fees from Alnylam, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis, Novartis, Regeneron, and River 2 Renal; personal 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, JB Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and the Translational Medicine Academy; participation on a data safety monitoring board for WIRB-Copernicus Group; and directorship of Global Clinical Trial Partners. ADH declares no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims: Large-scale, real-world data on early initiation of sacubitril/valsartan in patients newly diagnosed (de novo) with HF with reduced ejection fraction (HFrEF) are limited. We examined the effectiveness of sacubitril/valsartan versus angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) on all-cause and cause-specific hospitalizations among patients with de novo HFrEF from the Optum® dataset in the United States., Methods: This retrospective cohort study included adult patients with de novo HFrEF (diagnosed ≤30 days) with left ventricular ejection fraction (LVEF) ≤40% who were first prescribed with sacubitril/valsartan or ACEi/ARB from 1 January 2016 to 31 March 2020. The primary endpoint (all-cause hospitalization) and secondary endpoints were analysed in propensity score-matched cohorts., Results: A cohort of 3290 patients with de novo HFrEF who were prescribed with sacubitril/valsartan and a propensity-matched cohort of 6580 patients who were prescribed with ACEi/ARB were analysed. Overall, the mean (SD) age of patients was 63 (14) years, 34% were women, and baseline characteristics were balanced across treatment groups. Hypertension (67%), diabetes (33%) and chronic kidney disease (28%) were highly prevalent comorbidities. Patients in the sacubitril/valsartan cohort when compared with the ACEi/ARB cohort had lower annual rates of all-cause hospitalizations [incidence rate ratio (IRR): 0.81, 95% confidence interval (CI): 0.75-0.89, P < 0.001], cardiovascular (CV) hospitalizations (IRR: 0.80, 95% CI: 0.73-0.87, P < 0.001) and HF hospitalizations (IRR: 0.86, 95% CI: 0.78-0.95, P = 0.002)., Conclusions: Among patients with de novo HFrEF, sacubitril/valsartan (compared with that of ACEi/ARB) was associated with fewer all-cause, CV and HF hospitalizations. These findings are consistent with clinical trial evidence suggesting potential benefits of early initiation of sacubitril/valsartan in patients with HFrEF, including those soon after diagnosis., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Aims: An expansion of fat mass is an integral feature of patients with heart failure and preserved ejection fraction (HFpEF). While body mass index (BMI) is the most common anthropometric measure, a measure of central adiposity-the waist-to-height ratio (WHtR)-focuses on body fat content and distribution; is not distorted by bone or muscle mass, sex, or ethnicity; and may be particularly relevant in HFpEF., Methods: The PARAGON-HF trial randomized 4796 patients with heart failure and ejection fraction ≥45% to valsartan or sacubitril/valsartan. The current work characterizes the association of BMI and WHtR with clinical features, outcomes, and the response to neprilysin inhibition., Results: About half (49%) of the participants were considered obese by BMI (≥30 kg/m2), but nearly every patient (96%) had central adiposity (WHtR ≥0.5). Among patients who were not obese (BMI <30 kg/m2), 860 (37%) had marked central adiposity (WHtR ≥0.6). Higher BMI and WHtR were both associated with higher risk of total heart failure hospitalizations, but as compared with BMI, WHtR was linearly associated with heart failure outcomes and identified a higher proportion of patients who had a particularly elevated risk (i.e., 30% or greater). An obesity-survival paradox (i.e., improved outcomes in those with greater adiposity) was apparent with BMI in unadjusted analyses, but it was not observed with WHtR. Although neprilysin inhibition appeared to have greater effects on heart failure outcomes in patients with higher BMI and WHtR, analyses of interaction with obesity metrics did not show significant heterogeneity across the range of values for adiposity., Conclusions: In PARAGON-HF, in contrast with BMI, nearly every patient with HFpEF had central adiposity (as assessed by WHtR), and the risks of adverse heart failure events were more robustly related to WHtR. These data challenge the current reliance on BMI as an appropriate metric of adiposity, and they suggest that-rather than obesity-related HFpEF being regarded as a select HFpEF subgroup-central adiposity is a ubiquitous feature of HFpEF., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The sodium-glucose cotransporter 2 inhibitor canagliflozin reduces the risk of heart failure (HF) hospitalization or cardiovascular death and chronic kidney disease (CKD) progression among patients with type 2 diabetes at high cardiovascular risk or with CKD. Patients with type 2 diabetes commonly have coexisting HF or CKD that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized., Methods and Results: In this participant-level pooled analysis of the CREDENCE and CANVAS trials (not including CANVAS-R), 1454/8731 (16.7%) patients were treated with loop diuretics at baseline. Over a median on-treatment follow-up of 2.2 years, 1264 patients (14.5%) required oral loop diuretic intensification, of whom 981 (77.6%) required initiation of oral loop diuretics and 283 (22.4%) required oral loop diuretic dose increase. Patients requiring oral loop diuretic intensification experienced rates of subsequent HF hospitalization, CKD progression and mortality that were 29.5-, 5.0-, and 3.5-fold higher, respectively, than those not requiring oral loop diuretic intensification. Treatment with canagliflozin reduced the need for oral loop diuretic intensification by 41% (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.53-0.66) including both new diuretic initiation (HR 0.65; 95% CI 0.57-0.74) and diuretic dose increase (HR 0.42; 95% CI 0.33-0.54). Inclusion of oral diuretic intensification in an expanded HF composite outcome inclusive of cardiovascular death and HF hospitalization approximately double the number of events, with similar observed treatment effect (HR 0.64; 95% CI 0.58-0.70)., Conclusion: Among high-risk patients with type 2 diabetes, new oral loop diuretic intensification was frequent and portended adverse prognostic significance. Treatment with canagliflozin significantly reduced the need for loop diuretic intensification., Clinical Trial Registration: CANVAS (Canagliflozin Cardiovascular Assessment Study), ClinicalTrials.gov NCT01032629; CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), ClinicalTrials.gov NCT02065791., (© 2025 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: An initial decline in estimated glomerular filtration rate (eGFR) often leads to reluctance to continue life-saving therapies in patients with heart failure (HF)., Objectives: The goal of this study was to describe the association between initial decline in eGFR and subsequent clinical outcomes in patients randomized to placebo or finerenone., Methods: In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), we examined the association between initial decline in eGFR (≥15%) from randomization to 1 month and subsequent outcomes in patients assigned to finerenone or placebo. The primary outcome was the composite of total HF events and cardiovascular death., Results: Among 5,587 patients with an eGFR measurement at both baseline and 1 month, 1,018 (18.2%) experienced a ≥15% decline in eGFR. The proportion of patients experiencing a ≥15% decline in eGFR was 23.0% with finerenone and 13.4% with placebo (OR: 1.95; 95% CI: 1.69-2.24; P < 0.001). After adjustment, an eGFR decline was associated with a higher risk of the primary outcome in patients assigned to placebo (adjusted rate ratio: 1.50; 95% CI: 1.20-1.89) but not in those assigned to finerenone (adjusted rate ratio: 1.07; 95% CI: 0.84-1.35; P interaction  = 0.04). By contrast, the efficacy of finerenone was consistent across the range of change in eGFR from baseline to 1 month (P interaction  = 0.50 for percent change in eGFR), and safety, including hyperkalemia, was similar regardless of an early eGFR decline., Conclusions: Although an initial decline in eGFR was associated with worse outcomes in patients assigned to placebo, this relationship was not as strong in those treated with finerenone. An early decline in eGFR can be anticipated with finerenone and should not automatically lead to the discontinuation of this disease-modifying therapy (FINEARTS-HF Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [NCT04435626]; A Multicenter, Randomized, Double-Bline, Parallel-Group, Placebo-Controlled Study to Evaluate the efficacy and safety of finerenone on morbidity and mortality in participants With Heart Failure [NYHA II-IV] and left ventricular ejection fraction ≥40% [EudraCT 2020-000306-29])., Competing Interests: Funding Support and Author Disclosures The FINEARTS-HF trial was sponsored by Bayer. Dr Matsumoto has received research grants and personal fees from Abbott, Bayer Pharma, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Novartis, Ono Pharma, Orbus Neich, Otsuka Pharma, and the Uehara Memorial Foundation. Dr Jhund has received speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and he has served as Director GCTP Ltd. Dr Bauersachs has received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, Bristol Myers Squibb, Amgen, Corvia, Norgine, Edwards, and Roche not related to this paper; and has received research support for the department from Zoll, CVRx, Abiomed, Norgine, Roche, not related to this paper. Dr Claggett has received consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, New Amsterdam, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, scPharmaceuticals, Veristat, Verily, and Zydus. Drs Brinker, Schloemer, Viswanathan, Mares, and Scalise are employees of Bayer. Dr Lam has received research support from Novo Nordisk, and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is cofounder and nonexecutive director of Us2.ai. Dr Saraiva has served on advisory boards for and received consulting fees and honoraria from Bayer, Boehringer Ingelheim, Eli Lilly, Hypera, Medtronic, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Viatris. Dr Senni has served on advisory boards and received consulting fees and honoraria from Novartis, Abbott, Merck, Merck Sharp & Dohme, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Troughton has received grants and personal fees from Bayer during the conduct of the study; and has received grants and personal fees from Merck and Roche Diagnostics outside the submitted work. Dr Udell has received personal fees from Amgen, AstraZeneca, Eli Lilly and Company, Novavax, Novo Nordisk, and Sanofi; has received grants and personal fees from Boehringer Ingelheim; and has received grants from Novartis, outside the submitted work. Dr Voors’ employer has received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, EliLilly, Merck, Moderna, Novartis, Novo Nordisk, Roche diagnostics, and SalubrisBio. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; has stock options at G3Pharmaceutical; has equities at Cereno, Cardiorenal, and Eshmoun Clinical research; and is the founder of Cardiovascular Clinical Trialists. Dr Pitt has received consulting fees from Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; has stock/stock options with KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star medical, Vifor, Prointel, and Brainstorm Medical; has U.S. Patent 9931412 (site specific delivery of eplerenone to the myocardium); and has U.S. Patent pending 63/045,783 (histone-modulating agents for the prevention and treatment of organ failure). Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Bristol Myers Squibb, 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; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GlaxoSmithKline, Ionis, Lilly, MyoKardia, NIH/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has received consulting fees from Abbott, Action, Akros, Alexion, 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, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr McMurray has received payments through Glasgow University from work on clinical trials; and has received consulting fees and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline and Novartis, British Heart Foundation, National Institute for Health-National Heart, Lung, and Blood Institute (NIH-NHLBI), Boehringer Ingelheim, SQ Innovations, and Catalyze Group; has received consulting fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; has received lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, JB Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; has participated on the Data Safety Monitoring Board for WIRB-Copernicus Group Clinical Inc; and is a Director of Global Clinical Trial Partners Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Finerenone has kidney-protective effects in patients with chronic kidney disease with type 2 diabetes, but effects on kidney outcomes in patients with heart failure with and without diabetes and/or chronic kidney disease are not known., Objectives: The purpose of this study was to examine the effects of finerenone on kidney outcomes in FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure), a randomized trial of finerenone vs placebo among patients with heart failure with mildly reduced or preserved ejection fraction., Methods: We explored the effects of finerenone on the secondary outcome of a sustained ≥50% estimated glomerular filtration rate (eGFR) decline or kidney failure (sustained eGFR decline <15 mL/min/1.73 m 2 ; initiation of maintenance dialysis; renal transplantation). In this prespecified analysis, we also report effects of finerenone on: 1) sustained ≥57% eGFR decline or kidney failure; 2) eGFR slope; and 3) changes in urine albumin/creatinine ratio (UACR)., Results: Among 6,001 participants, mean baseline eGFR was 62 ± 20 mL/min/1.73 m 2 ; 48% had eGFR <60 mL/min/1.73 m 2 . Overall, 5,797 had baseline UACR data (median: 18 mg/g [Q1-Q3: 7-67 mg/g]). Over 2.6 years median follow-up, the incidence of the composite kidney outcome (≥50% eGFR decline or kidney failure) was numerically, but nonsignificantly, higher for finerenone vs placebo (75 vs 55 events; HR: 1.33; 95% CI: 0.94-1.89). Similar results were observed for the composite of ≥57% eGFR decline or kidney failure (41 vs 31 events; HR: 1.28; 95% CI: 0.80-2.05), although the overall event frequency was relatively low. During the first 3 months, finerenone led to an acute decline in eGFR of -2.9 mL/min/1.73 m 2 (95% CI: -3.4 to -2.4 mL/min/1.73 m 2 ) but did not alter chronic (from 3 months) eGFR slope (+0.2 mL/min/1.73 m 2 per year; 95% CI: -0.1 to 0.4 mL/min/1.73 m 2 per year), vs placebo. The difference in total slope was -0.7 mL/min/1.73 m 2 per year (95% CI: -0.9 to -0.4 mL/min/1.73 m 2 per year.). Finerenone reduced UACR by 30% (95% CI: 25%-34%) over 6 months vs placebo, an effect that persisted throughout follow-up. Finerenone reduced the risk of new-onset of microalbuminuria and macroalbuminuria by 24% (HR: 0.76; 95% CI: 0.68-0.83) and 38% (HR: 0.62; 95% CI: 0.53-0.73), respectively., Conclusions: In FINEARTS-HF, a population at low risk of adverse kidney outcomes, finerenone did not significantly modify the kidney composite outcomes. Finerenone led to a greater reduction in initial eGFR, but did not result in a significant difference in chronic eGFR slope vs placebo. Finerenone led to early and sustained reductions in albuminuria and reduced the risk of new-onset micro- and macroalbuminuria. (FINEARTS-HF [Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenon on Morbidity (Events Indicating Disease Worsening) & Mortality (Death Rate) in Participants with Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40%]; NCT04435626)., Competing Interests: Funding Support and Author Disclosures FINEARTS-HF was sponsored by Bayer. FINEARTS-HF was designed by the academic members of the executive committee in collaboration with representatives from Bayer. The sponsor, Bayer, was responsible for study supervision, site monitoring, and data collection. Primary data analysis was performed by Bayer and independent academic statisticians at the Brigham and Women’s Hospital, Boston, Massachusetts, USA. The present analyses were conducted by an independent academic group at Brigham and Women’s Hospital. All authors participated in the decision to submit the manuscript for publication with support from the study sponsor. Dr Mc Causland has received research funding from the National Institute of Diabetes and Digestive and Kidney Diseases, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon paid directly to his institution; has received consulting fees from GlaxoSmithKline and Zydus Therapeutics; and has received expert witness fees from Rubin-Anders Scientific. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Bristol Myers Squibb, 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; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. Dr Jhund has received speakers’ fees from AstraZeneca, Novartis, Alkem Laboratories, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and he is Director of GCTP Ltd. Drs Brinker, Perkins, Scheerer, and Schloemer are full-time employees of Bayer. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and non-executive director of Us2.ai. Dr Senni has served on advisory boards, been a consultant, or received honoraria from Novartis, Abbott, Merck, Merck Sharp and Dohme, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voor’s employer has received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, EliLilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, NovoNordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; has stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, Eshmoun Clinical research; and is the founder of Cardiovascular Clinical Trialists. Dr Pitt has served as a consultant for Bayer, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lexicon, Anacardia, and G3 Pharmaceuticals; has served as a consultant and received stock options or stocks from Sea Star Medical, Vifor, scPharmaceuticals, SQinnovations, KBP Biosciences, Sarfez, Cereno Scientific, Prointel, and Brainstorm Medical; holds a U.S. Patent (9931412-site specific delivery of Eplerenone to the myocardium); and has a U.S. Patent pending (63/045,783 HistoneModulating agents for the prevention and treatment of organ damage). Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, and Novartis; has received personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp, British Heart Foundation, National Institute for Health–National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, Catalyze Group; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, Translational Medicine Academy; has served on the Data Safety Monitoring Board fromWIRB-Copernicus Group Clinical Inc; and is a director of Global Clinical Trial Partners Ltd. Dr Solomon has received research grants from Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos/Bridgebio, Gossamer, GlaxoSmithKline, Ionis, Intellia, Lilly, NIH/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, GlaxoSmithKline, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure (HF) are limited by symptoms and have impaired quality of life. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient-reported outcome measure that enables evaluation of the effect of HF and the impact of new therapies on health status in patients with HF., Objectives: This prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) assessed the efficacy and safety of finerenone according to baseline KCCQ Total Symptom Score (TSS) and the effect of finerenone on KCCQ-TSS., Methods: FINEARTS-HF tested the efficacy of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone, compared with placebo, in patients with HF with mildly reduced ejection fraction/preserved ejection fraction. The primary endpoint was the composite of cardiovascular death and total worsening HF events. The KCCQ was completed by patients at randomization and at 6, 9, and 12 months after randomization. Change in KCCQ-TSS was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles at baseline. The association between KCCQ tertile and clinical outcomes was evaluated using semiparametric proportional-rates models for total events and Cox models for time-to-first-event data, and the effects of finerenone vs placebo on the primary endpoint were assessed across tertiles of KCCQ-TSS., Results: Of the 6,001 participants in FINEARTS-HF, 5,986 (99.8%) had baseline KCCQ-TSS recorded (median score 69.8 of a possible 100; higher score = better health status). Lower (worse) KCCQ-TSS was associated with a higher risk of the primary endpoint. Finerenone, compared with placebo, reduced the risk of the primary endpoint across the range of KCCQ-TSS: tertile 1 (score 0-<57): RR: 0.82 (95% CI: 0.68-1.00); tertile 2 (57-<81): 0.88 (95% CI: 0.70-1.11); tertile 3 (81-100): 0.88 (95% CI: 0.69-1.14) (P interaction  = 0.89). Compared with placebo, finerenone significantly improved KCCQ-TSS from baseline with a mean difference at 12 months of 1.62 points (95% CI: 0.69-2.56 points) (P < 0.001). Numerically fewer finerenone-treated patients experienced clinically meaningful deterioration, and more had improvements in KCCQ-TSS., Conclusions: Finerenone significantly reduced HF events and improved health status in patients with HF and mildly reduced ejection fraction/preserved ejection fraction across the spectrum of KCCQ-TSS at baseline. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; EudraCT 2020-000306-29)., Competing Interests: Funding Support and Author Disclosures The FINEARTS-HF trial was funded by Bayer. Dr Yang has received Global CardioVascular Clinical Trialists (CVCT) Young Trialist Grant and travel grants from AstraZeneca and Bayer. Dr Atherton has received other support from Bayer, during the conduct of the study; and has received other support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Novo Nordisk, Vifor Pharma, and Merck Sharp and Dome, outside of the submitted work. Dr Chiang has received personal fees from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Menarini, Merck Sharp and Dohme, Novartis, Pfizer, and Sanofi. Dr Chopra has received modest speaker fees from Boehringer, AstraZeneca, Novartis, Pfizer, Novo Nordisk, Glenmark, Sun, Mankind, Lupin, Alembic, JB, Reddy’s, Intas, Eris, and Cipla, outside of the submitted work. Dr Comin-Colet has received personal fees from Bayer, during the conduct of the study; has received grants from Novartis, Vifor Pharma, AstraZeneca, and Orion Pharma; and has received personal fees from Bayer, Boehringer Ingelheim, Vifor Pharma, Novartis, AstraZeneca, and Orion Pharma, outside the submitted work. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca and Vifor; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Saraiva has received grants or fees for working on clinical trials, consultancy, advisory board or steering committee membership, and other activities from AstraZeneca, Novo Nordisk, Bayer, Boehringer Ingelheim, Novartis, Merck Sharp and Dohme, and Janssen. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and non-executive director of Us2.ai. Dr Senni has served on advisory boards for, served as a consultant for, and received honoraria from Novartis, Abbott, Merck, Merck Sharp and Dohme, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from National Institutes of Health (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), AHA (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voors’ employer has received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, EliLilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; has stock options at G3Pharmaceutical; has equities at Cereno, Cardiorenal, and Eshmoun Clinical research; and is the founder of Cardiovascular Clinical Trialists. Dr Pitt is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star medical, Vifor Prointel, and Brainstorm Medical; has stock/stock options in KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star medical, Vifor Prointel, and Brainstorm Medical; and has U.S. Patent 9931412-site specific delivery of eplerenone to the myocardium, U.S. Patent pending 63/045,783 Histone modulating agents for the prevention and treatment of organ failure. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with 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; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Drs Jhund and McMurray are supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund. Dr Jhund has received speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and is Director of GCTP Ltd. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alexion, 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, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr McMurray has received payments through Glasgow University from work on clinical trials, as well as consulting fees and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, British Heart Foundation, National Institute for Health–National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; has received personal consultancy fees from Alnylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, Translational Medicine Academy; has served on the Data Safety Monitoring Board for WIRB-Copernicus Group Clinical Inc; and is a director of Global Clinical Trial Partners Ltd. Drs. Kolkhof, Viswanathan, Lage, and Rohwedder are employees of Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures FINEARTS-HF was funded by Bayer AG. Dr Vaduganathan has received research grant support, served on Advisory Boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Bristol Myers Squibb, 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; and has participated on Clinical Trial Committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and has served on a Data Safety Monitoring Board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Laboratories, ProAdWise Communications, and Sun Pharmaceuticals; has received Advisory Board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and he has served as director of GCTP Ltd. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharmaceuticals, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, ProSciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and nonexecutive director of Us2.ai. Dr Senni has served on the Advisory Boards of and has received consulting fees or honoraria from Novartis, Abbott, Merck, Merck Sharp & Dohme, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), the American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voor’s employer has received consulting fees and/or research support from Adrenomed, AnaCardio, AstraZeneca, Bayer AG, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, CellProthera, CEVA, Inventiva, KBP Biosciences, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, NorthSea, and USa2; holds stock options at G3Pharmaceutical; holds equities at Cereno, CardioRenal, and Eshmoun Clinical Research; and is the founder of Cardiovascular Clinical Trialists. Dr Pitt has served as a consultant for Bayer, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lexicon, Anacardia, and G3 Pharmaceuticvals; has served as a consultant and received stock options or stocks from Sea Star Medical, Vifor, scPharmaceuticals, SQinnovations, KBP Biosciences, Sarfez, Cereno Scientific, Prointel, and Brainstorm Medical; holds a U.S. Patent (9931412-site specific delivery of Eplerenone to the myocardium); and has a U.S. Patent pending (63/045,783 Histone Modulating agents for the prevention and treatment of organ damage). Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting fees, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, and Novartis; has received personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp, British Heart Foundation, National Institutes of Health/National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; has served on Data Safety Monitoring Board WIRB-Copernicus Group Clinical Inc; and is a director of Global Clinical Trial Partners Ltd. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and has consulted for Abbott, Action, Akros, Alexion, 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, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, DiNAQOR, Tremeau, CellProthera, Moderna, American Regent, Sarepta, Lexicon, AnaCardio, Akros, and Valo.

Background: Patients with heart failure (HF) and a recent worsening heart failure (WHF) event are known to be at high risk of recurrent hospitalization and death, regardless of ejection fraction., Objectives: This study examined the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in relation to the recency of a WHF event., Methods: FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. In this prespecified analysis, we assessed the risk of cardiovascular (CV) events and response to finerenone vs placebo in relation to the time from WHF to randomization (during or within 7 days, 7 days to 3 months, >3 months, or no prior WHF). The primary outcome was a composite of total (first and recurrent) WHF events and CV death, analyzed using a proportional rates method., Results: Of 6,001 patients validly randomized to finerenone or placebo, 1,219 (20.3%) were enrolled during (749 [12.5%]) or within 7 days (470 [7.8%]), 2,028 (33.8%) between 7 days and 3 months, and 937 (15.6%) >3 months from a WHF event; 1,817 (30.3%) had no prior history of WHF. Rates of the primary composite outcome varied inversely with time since WHF, with >2-fold higher risk in those enrolled during or within 7 days of WHF compared with those enrolled >3 months from WHF or without prior WHF (risk ratio [RR]: 2.13; 95% CI: 1.82-2.55). Compared to placebo, finerenone appeared to lower the risk of the primary composite to a greater extent in those enrolled within 7 days of WHF (RR: 0.74; 95% CI: 0.57-0.95) or between 7 days and 3 months of WHF (RR: 0.79; 95% CI: 0.64-0.97) than in those >3 months from WHF or without prior WHF (RR: 0.99; 95% CI: 0.81-1.21); however, no definitive treatment-by-time interaction could be confirmed (P = 0.07). Greater absolute risk reductions with finerenone were accordingly seen in those with recent WHF (P trend  = 0.011). The risk of adverse events including hyperkalemia and worsening renal function among patients assigned to finerenone was not increased in those with recent WHF., Conclusions: Compared with those without recent WHF, patients with HF and mildly reduced or preserved ejection fraction who have experienced a recent WHF event are at higher risk for recurrent HF events and CV death; a possible signal of enhanced absolute treatment benefit with finerenone in this population requires further confirmation in future studies. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; A study to gather information on the influence of study drug finerenone on the number of deaths and hospitalizations in participants with heart failure EudraCT 2020-000306-29)., Competing Interests: Funding Support and Author Disclosures The FINEARTS-HF trial was funded by Bayer AG. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Bristol Myers Squibb, 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; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and has served on a data safety monitoring board for Novo Nordisk. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and he is Director of GCTP Ltd. Dr Cunningham has received personal consulting fees from Roche Diagnostics, Occlutech, KCK, and Edgewise Therapeutics. Mr Lay-Flurrie is a full-time employee of Bayer PLC, Research and Development, Pharmaceuticals. Drs Borentain, Viswanathan, Rohwedder, and Amarante are employees of Bayer AG. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and nonexecutive director of Us2.ai. Dr Senni has served on advisory boards for and received consultancy and honoraria from Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from National Institutes of Health (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voors’ employer has received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, Bristol Myers Squibb, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; has stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical research; and is the founder of Cardiovascular Clinical Trialists. Dr Pitt is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP Biosciences, Sarfez Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star Medical, Vifor Prointel, and Brainstorm Medical; has stock/stock options in KBP Biosciences, Sarfez Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star Medical, Vifor Prointel, and Brainstorm Medical; and holds U.S. Patent 9931412, site specific delivery of eplerenone to the myocardium, and U.S. Patent pending 63/045,783 Histone modulating agents for the prevention and treatment of organ failure. Dr Kosiborod has received grants, personal fees, and other from AstraZeneca and Vifor Pharma; has received grants and personal fees from Boehringer Ingelheim and Pfizer; has received personal fees from 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, Bayer, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Regeneron, Sanofi, scPharmaceuticals, Structure Therapeutics, and Youngene Therapeutics; and other from Artera Health, Saghmos Therapeutics, outside of the submitted work. Dr McMurray has received payments through Glasgow University for work on clinical trials; has consulted for and received grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, and Novartis; and has received personal consultancy fees from Alnylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp, British Heart Foundation, National Institute for Health, National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, and the Catalyze Group; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; has served on the Data Safety Monitoring Board of WIRB-Copernicus Group Clinical Inc; and is a director of Global Clinical Trial Partners Ltd. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health, National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alexion, 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, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Kulac has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is associated with excessive adipocyte-derived aldosterone secretion, independent of the classical renin-angiotensin-aldosterone cascade, and mineralocorticoid receptor antagonists may be more effective in patients with heart failure (HF) and obesity., Objectives: This study sought to examine the effects of the nonsteroidal mineralocorticoid receptor antagonist finerenone compared with placebo, according to body mass index (BMI) in FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure)., Methods: A total of 6,001 patients with HF with NYHA functional class II, III, and IV, a left ventricular ejection fraction of ≥40%, evidence of structural heart disease, and elevated natriuretic peptide levels were randomized to finerenone or placebo. BMI (kg/m 2 ) was examined using World Health Organization categories, namely, underweight/normal weight (<25.0 kg/m 2 ; n = 1,306); overweight (25.0-29.9 kg/m 2 ; n = 1,990); obesity class I (30.0-34.9 kg/m 2 ; n = 1,546); obesity class II (35.0-39.9 kg/m 2 ; n = 751); and obesity class III (≥40 kg/m 2 ; n = 395). The primary outcome was cardiovascular death and total worsening HF events., Results: Data on baseline BMI were available for 5,988 patients (median: 29.2 kg/m 2 ; Q1-Q3: 25.5-33.6 kg/m 2 ). Compared with patients who were underweight/normal weight, those with obesity class II or III had a higher risk of the primary outcome (underweight/normal weight, reference; overweight, unadjusted rate ratio: 0.96 [95% CI: 0.81-1.15]; obesity class I: 1.04 [95% CI: 0.86-1.26]; obesity class II-III: 1.26 [95% CI: 1.03-1.54]). The effect of finerenone on the primary outcome did not vary by baseline BMI (underweight/normal weight, rate ratio: 0.80 [95% CI: 0.62-1.04]; overweight: 0.91 [95% CI: 0.72-1.15]; obesity class I: 0.92 [95% CI: 0.72-1.19]; obesity class II-III: 0.67 [95% CI: 0.50-0.89]; P interaction  = 0.32). However, when BMI was examined as a continuous variable, the beneficial effect of finerenone seemed to be greater in those with a higher BMI (P interaction  = 0.005). A similar pattern was observed for total worsening HF events. Consistent effects across baseline BMI were observed for cardiovascular and all-cause death and improvement in the Kansas City Cardiomyopathy Questionnaire scores., Conclusions: In patients with HF with mildly reduced/preserved ejection fraction, the beneficial effects of finerenone on clinical events and symptoms were consistent, irrespective of BMI at baseline, possibly with a greater effect on the primary outcome in patients with higher BMI. (FINEARTS-HF [FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure]; NCT04435626)., Competing Interests: Funding Support and Author Disclosures FINEARTS-HF was funded by Bayer AG. The Steering Committees of the trial designed and oversaw their conduct in collaboration with the Sponsor. The primary analyses, interpretation of the data, and initial manuscript drafting were conducted independently by the academic team. Dr Butt has received advisory board honoraria from AstraZeneca and Bayer; has received consultant honoraria from Novartis and AstraZeneca; and has received travel grants from AstraZeneca. Dr Jhund has received speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, Roche Diagnostics; his employer the University of Glasgow has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and he is a director at GCTP Ltd. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket; and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. Drs Viswanathan, Lage, Scheerer, and Lay-Flurrie are full-time employees of Bayer. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and, Us2.ai; and is a co-founder and nonexecutive director of Us2.ai. Dr Senni has served on advisory boards for, as a consultant for, and has received honoraria from Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from the NIH (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), AHA (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voors’ employer received consultancy fees and/or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, BMS, Boehringer Ingelheim, Corteria, EliLilly, Merck, Moderna, Novartis, Novo Nordisk, Roche diagnostics, and SalubrisBio. Dr Bauersachs received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, Norgine, Edwards, and Roche not related to this paper; and has received research support for the department from Zoll, CVRx, Abiomed, Norgine, and Roche, not related to this paper. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, NovoNordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, USa2; has stock options at G3Pharmaceutical; has equity in Cereno, Cardiorenal, and Eshmoun Clinical research; and is the founder of Cardiovascular Clinical Trialists. Dr Pitt is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Myers Squibb, KBP Biosciences∗, Sarfez Pharmaceuticals∗, Pharmaceuticals∗, SQinnovations∗, G3 Pharmaceuticals, Sea Star medical∗, Vifor∗ Prointel∗, and Brainstorm Medical; has stock options in KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, Sea Star medical, Vifor, Prointel, and Brainstorm Medical; and has U.S. Patent 9931412-site specific delivery of eplerenone to the myocardium, and U.S. Patent pending 63/045,783 Histone modulating agents for the prevention and treatment of organ failure. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with 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; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr McMurray has received payments through Glasgow University from work on clinical trials; has receviedconsulting and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK and Novartis, British Heart Foundation, National Institute for Health – National Heart, Lung, and Blood Institute (NIH-NHLBI), Boehringer Ingelheim, SQ Innovations, and Catalyze Group; has receivedpersonal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; has received personal lecture fees from Abbott, Alkem Metabolics, Astra Zeneca, Blue Ocean Scientific Solutions Ltd., Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd., Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; and data safety monitoring board membership for WIRB-Copernicus Group Clinical Inc; andis a director of Global Clinical Trial Partners Ltd.All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known., Methods: FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity on the basis of baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during-trial use of SGLT2i in time-varying analyses., Results: Among 6001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6 years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio, 0.83 [95% CI, 0.60-1.16]) and without an SGLT2i at baseline (rate ratio, 0.85 [95% CI, 0.74-0.98]; P interaction =0.76). In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% versus 20.1%; hazard ratio, 0.86 [95% CI, 0.76-0.97]). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary end point., Conclusions: The treatment benefits of the nonsteroidal mineralocorticoid receptor antagonist finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a nonsteroidal mineralocorticoid receptor antagonist may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626., Competing Interests: Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with 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, and participates on clinical trial committees for studies sponsored by Amgen, AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket, and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer, as well as personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. Dr Jhund reports speaker fees from AstraZeneca, Novartis, Alkem Laboratories, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics. Dr Jhund is Director of GCTP Ltd. Dr Jhund’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Henderson reports no financial conflicts of interest. Drs. Brinker, Viswanathan, Scheerer, and Lage and J. Lay-Flurrie are full-time employees of Bayer. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and nonexecutive director of Us2.ai. Dr Senni has served on advisory boards, provided consultancy, and received honoraria from Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, X01 HL169712, R01 HL140731, and R01 HL149423), American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer, and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voor’s employer received consultancy fees or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, BMS, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; having stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and being the founder of Cardiovascular Clinical Trialists. Dr Pitt has served as a consultant for Bayer, AstraZeneca, Bristol Meyers Squibb, Boehringer Ingelheim, Lexicon, Anacardia, and G3 Pharmaceuticals; has served as a consultant and received stock options or stocks from Sea Star Medical, Vifor, scPharmaceuticals, SQinnovations, KBP Biosciences, Sarfez, Cereno Scientific, Prointel, and Brainstorm Medical; and holds a US patent (9931412: site-specific delivery of eplerenone to the myocardium) and has a US patent pending (63/045,783: histone modulating agents for the prevention and treatment of organ damage). Dr McMurray reports payments through Glasgow University from work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, and Novartis; personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp, British Heart Foundation, National Institutes of Health–National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; data safety monitoring board participation for WIRB-Copernicus Group Clinical Inc; and is a director of Global Clinical Trial Partners Ltd. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai, and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo.

Background: The importance of nutritional status is underappreciated in patients with heart failure (HF). This study aimed to describe the range of the prognostic nutrition index (PNI), and the clinical characteristics and outcomes according to PNI, in patients with HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). The primary outcome was the composite of HF hospitalization or cardiovascular death., Methods and Results: Individual patient data from the PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in HF) trials were used to examine patient characteristics and outcomes according to quartiles of PNI. Cox regression was used to analyze clinical outcomes, and multivariable fractional polynomial interaction analysis to examine the effects of sacubitril-valsartan, according to PNI. Patients with lower PNI (poorer nutrition) were older, frailer, and had more comorbidities and worse HF status, with greater congestion. Patients with lower PNI had biomarker abnormalities indicating inflammation, bone marrow suppression, and increased collagen turnover, among other physiologic perturbations. Lower PNI was associated with worse outcomes; that is, the rate of the primary end point among patients in the first quartile was 11.31 (10.20-12.54) compared with 7.09 (6.17-8.14) per 100 person-years in the fourth quartile. These associations persisted after adjustment for other prognostic variables. PNI did not modify the effects of sacubitril-valsartan in HFrEF although sacubitril/valsartan seemed to have a greater benefit in patients with HFpEF with a higher PNI., Conclusions: Nutritional status, assessed using PNI, is an independent predictor of poor outcomes in HF. Evaluation of nutritional status in clinical practice, the causes of undernutrition, and whether undernutrition should be a therapeutic target, are all worthy of further investigation in HF.

Background: The effects of treatments for heart failure (HF) may vary among patients according to left ventricular ejection fraction (LVEF). In FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure), the nonsteroidal mineralocorticoid receptor antagonist finerenone reduced the risk of cardiovascular death and total worsening HF events in patients with HF with mildly reduced or preserved ejection fraction. We examined the effect of finerenone according to LVEF in FINEARTS-HF., Methods: FINEARTS-HF was a randomized, placebo-controlled trial examining the efficacy and safety of finerenone in patients with HF and LVEF ≥40%. The treatment effect of finerenone was examined in prespecified analyses according to LVEF categories (<50%, ≥50% to <60%, and ≥60%) and with LVEF as a continuous variable. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death., Results: Baseline LVEF data were available for 5993 of the 6001 participants in FINEARTS-HF. Mean and median LVEF were 53±8% and 53% (interquartile range, 46%-58%), respectively. LVEF was <50% in 2172 (36%), between 50% and <60% in 2674 (45%), and ≥60% in 1147 (19%). Patients with higher LVEF were older, were more commonly female, were less likely to have a history of coronary artery disease, and more frequently had a history of hypertension and chronic kidney disease compared with those with a lower LVEF. Finerenone reduced the risk of cardiovascular death and total HF events consistently across LVEF categories (LVEF <50% rate ratio, 0.84 [95% CI, 0.68-1.03]; LVEF ≥50% to <60% rate ratio, 0.80 [0.66-0.97]; and LVEF ≥60% rate ratio, 0.94 [0.70-1.25]; P interaction =0.70). There was no modification of the benefit of finerenone across the range of LVEF when analyzed as a continuous variable ( P interaction =0.28). There was a similar consistent effect of finerenone on reducing the total number of worsening HF events (continuous P interaction =0.26)., Conclusions: In patients with HF with mildly reduced or preserved ejection fraction, finerenone reduced the risk of cardiovascular death and worsening HF events, irrespective of LVEF., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626. URL: https://eudract.ema.europa.eu; Unique identifier: 2020-000306-29., Competing Interests: Dr Docherty reports that his employer, the University of Glasgow, has been remunerated by AstraZeneca for his work on clinical trials, and he has received speaker fees from AstraZeneca, Boehringer Ingelheim, Pharmacosomos, and Translational Medicine Academy; has served on advisory boards or performed consultancy for FIRE-1, Us2.ai, and Bayer AG; holds stock in Us2.ai; has served on a Clinical Endpoint Committee for Bayer AG; and has received research grant support (paid to his institution) from AstraZeneca, Roche, Novartis, and Boehringer Ingelheim. Dr Jhund reports speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics. Dr Jhund is Director of GCTP Ltd. Dr Jhund’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket, and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer, as well as personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. K. Mueller and Drs Viswanathan and Scalise are employees of Bayer. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and nonexecutive director of Us2.ai. Dr Senni has served on advisory boards, performed consultancy, and received honoraria for Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer, and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voors’ employer received consultancy fees or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, BMS, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, NovoNordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; having stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and being the founder of Cardiovascular Clinical Trialists. Dr Pitt is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Meyers Squibb, KBP Biosciences (stock or stock options), Sarfez Pharmaceuticals (stock or stock options), SQinnovations (stock or stock options), G3 Pharmaceuticals, Sea Star Medical (stock or stock options), Vifor (stock or stock options), Prointel (stock or stock options), and Brainstorm Medical (stock or stock options); US patent 9931412 (site-specific delivery of eplerenone to the myocardium); and US patent pending 63/045,783 (histone modulating agents for the prevention and treatment of organ failure). Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with 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, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.ai, and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr McMurray reports payments through Glasgow University from work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, Novartis, British Heart Foundation, National Institutes of Health–National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; and personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, and Sun Pharmaceuticals.

Importance: Sex is associated with the clinical presentation, outcomes, and response to treatment in patients with heart failure (HF). However, little is known about the safety and efficacy of treatment with finerenone according to sex., Objective: To estimate the efficacy and safety of finerenone compared with placebo in both women and men., Design, Setting, and Participants: Prespecified analyses were conducted in the phase 3 randomized clinical trial Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF). The trial was conducted across 653 sites in 37 countries. Participants were adults aged 40 years and older with symptomatic HF and left ventricular ejection fraction (LVEF) of 40% or greater randomized between September 2020 and January 2023., Intervention: Finerenone (titrated to 20 mg or 40 mg) or placebo., Main Outcomes and Measures: The primary outcome was a composite of cardiovascular death and total (first and recurrent) HF events (unplanned HF hospitalizations or urgent HF visits)., Results: A total of 6001 patients were randomized in FINEARTS-HF, of whom 2732 were women (45.5%), with a mean (SD) age of 73.6 (9.1) years. Women had higher rates of any obesity, higher LVEF (54.6 [7.6%] vs 50.9 [7.6] for men), lower mean (SD) estimated glomerular filtration rate than men (59.7 [19.1] vs 64.1 [20.0] for men; P<.001) , worse New York Heart Association functional class, and lower Kansas City Cardiomyopathy Questionnaire-Total Symptom Scores (KCCQ-TSS) (mean [SD] 62.3 [24.0] vs 71.0 [23.1]). The incident rate of the primary outcome was slightly lower in women (15.7; 95% CI, 14.3-17.3) than in men (16.8; 95% CI, 15.4-18.3) per 100 person-years. Compared with placebo, finerenone reduced the risk of the primary end point similarly in women and men: rate ratio 0.78 (95% CI, 0.65-0.95) in women and 0.88 (95% CI, 0.74-1.04) in men (P = .41 for interaction). Consistent effects were observed for the components of the primary outcome and all-cause mortality. The mean increase (improvement) in KCCQ-TSS from baseline to 12 months was greater with finerenone, regardless of sex (P = .73 for interaction). Finerenone had similar tolerability in women and men., Conclusions and Relevance: In FINEARTS-HF, finerenone reduced the risk of the primary end point similarly in women and men with heart failure with mildly reduced or preserved ejection fraction. Finerenone had similar tolerability in women and men., Trial Registration: ClinicalTrials.gov Identifier: NCT04435626.

Background: Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF)., Objectives: The authors aimed to examine the safety and efficacy of sacubitril/valsartan among patients with HF by self-reported race., Methods: PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) were global, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor (RASi) (enalapril or valsartan, respectively) in patients with HF and left ventricular ejection fraction ≤40% (PARADIGM-HF) or left ventricular ejection fraction ≥45% (PARAGON-HF). Patients with self-reported race were categorized as White, Asian, or Black. We assessed the composite of first HF hospitalization or cardiovascular death, its components, and angioedema across races., Results: Among 12,097 participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Over a median follow-up of 2.5 years, Black (adjusted HR: 1.68; 95% CI: 1.42-1.98) and Asian patients (adjusted HR: 1.32; 95% CI: 1.18-1.47) experienced higher risks of the primary outcome compared with White patients. Treatment effects of sacubitril/valsartan vs RASi on the primary endpoint were consistent among White (HR: 0.84; 95% CI: 0.77-0.91), Asian (HR: 0.92; 95% CI: 0.78-1.10), and Black patients (HR: 0.79; 95% CI: 0.58-1.07; P interaction  = 0.58). Rates of severe angioedema were higher with sacubitril/valsartan vs RASi (White: 0.2% vs 0.1%; Black: 1.5% vs 0.0%; Asian: 0.1% vs 0.1%)., Conclusions: In a pooled experience of 2 global trials, Black and Asian patients exhibited a higher risk of cardiovascular events than White patients. The benefits of sacubitril/valsartan were consistent across races. Risks of severe angioedema were low but numerically higher with sacubitril/valsartan. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255; Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., Competing Interests: Funding Support and Author Disclosures The PARADIGM-HF and PARAGON-HF trials were sponsored by Novartis. Dr Lu has received research funding from the Gottfried und Julia Bangerter-Rhyner Foundation, the SICPA Foundation, and the Société Académique Vaudoise. Dr Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. Dr Packer has received consulting fees from 89bio, AbbVie, Actavis, Alderlyx, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra. Dr Pfeffer has received the following research grant support Lexicon and Novartis, paid to his institution; has served as a consultant to Alexion, Alnylam, Apnimed, AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, Intellia, National Heart, Lung, and Blood Institute—Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (Master Protocol Committee), Novartis, and Novo Nordisk; and has equity in DalCor. Dr Lewis has received personal fees from Amgen and Dal-Cor. Dr Lam has received grants from Novo Nordisk and Roche Diagnostics; has served as a consultant for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb (BMS), CardioRenal, Cytokinetics, Darma, Echonous, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceuticals, Janssen, Medscape/WebMD, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, Recor Medical, Roche Diagnostics, Sanofi, and Siemens Healthcare; has served as cofounder and nonexecutive director of Us2.ai outside the submitted work; and has patents pending (PCT/SG2016/050217; method for diagnosis and prognosis of chronic heart failure) and issued (U.S. 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 Rouleau has served as a Data Monitoring Committee member; and has received consulting fees from Alexion, Intellia, BMS, AstraZeneca, Bayer, and Novartis. Dr Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Lefkowitz is an employee of Novartis Pharmaceuticals Corporation. Dr Desai has received research grant support from Abbott, AstraZeneca, Alnylam, Bayer, and Novartis; and has received consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Axon Therapeutics, Avidity Biopharma, Bayer, Biofourmis, GlaxoSmithKline, Merck, Novartis, Parexel, Regeneron, River2Renal, Roche, Verily, Veristat, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; has served as the director of Global Clinical Trial Partners; and his employer the University of Glasgow has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis and Novo Nordisk. Dr McMurray has received grants, paid to his employer, from AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study; grants paid to his employer from Novartis, Amgen, BMS, Bayer, Abb-vie, Dal-Cor, Kidney Research UK, and Cardurion; and grants from British Heart Foundation. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, 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, BMS, 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, and PureTech Health. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with 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; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Pabon has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: N-terminal pro-B-type natriuretic peptides (NT-proBNPs) are guideline-recommended biomarkers for risk stratification in patients with heart failure. However, NT-proBNP levels are often elevated in chronic kidney disease, introducing uncertainty about their prognostic relevance in persons across a broad range of estimated glomerular filtration rate (eGFR)., Objectives: The aim of this study was to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function., Methods: A pooled analysis was conducted of participants with NT-proBNP and eGFR measured at baseline in the I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction), TOPCAT (Americas region) (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function), PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trials. The relationship between NT-proBNP and eGFR was assessed using piecewise linear regression. Using multivariable Cox and Poisson regression models, the association of NT-proBNP with outcomes across a range of eGFR was evaluated. The primary outcome was hospitalization for heart failure or cardiovascular death., Results: Among 14,831 participants (mean age: 72.1 years; 50.3% female; mean eGFR: 63.3 mL/min/1.73 m 2 , and median NT-proBNP: 840 pg/mL) followed up for a median 33.5 months, there were 3,092 primary outcomes. NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73 m 2 lower eGFR in patients with baseline eGFR ≥60, 45-<60, and <45 mL/min/1.73 m 2 , respectively (P for nonlinearity < 0.001). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR: 1.37; 95% CI: 1.34-1.41), consistent across different eGFR categories (P for interaction = 0.42). For the same incidence of the primary outcome, NT-proBNP levels were approximately 2.5- to 3.5-fold lower in patients with eGFR <45 mL/min/1.73 m 2 , compared with patients with eGFR ≥60 mL/min/1.73 m 2 . Similar patterns were observed across all outcomes studied, including cardiovascular and noncardiovascular death., Conclusions: The same NT-proBNP concentration predicts a substantially higher absolute risk of adverse outcomes for people with heart failure and reduced kidney function, compared with those with preserved kidney function. These data call into question proposals for higher NT-proBNP references ranges in people with CKD, and suggest that reduced kidney function per se should not be a reason to disregard higher NT-proBNP levels., Competing Interests: Funding Support and Author Disclosures Dr Neuen is supported by an Australian National Health and Medical Research Council Emerging Leader Investigator Grant (grant number 2026621) and a Ramaciotti Foundation Health Investment Grant (grant number 2023HIG69). The funders had no role in the writing of the manuscript or decision to submit for publication. Dr Neuen has received fees for travel support, advisory boards, and scientific presentations from AstraZeneca, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, the Limbic, Janssen, Medscape, Novo Nordisk, and Travere Therapeutics; and has served on clinical trial committees for studies sponsored by AstraZeneca, Bayer, and CSL Behring. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with 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; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Alnylam, Cardior, Cardurion, Corvia, CVRx, Cytokinetics, Intellia, Rocket, and Valo. Dr Beldhuis is supported by the Junior clinical scientist grant by the Dutch Heart Foundation; her employer is supported by an unrestricted medical grant by Novartis. Dr Myhre has served on advisory boards or had speaker engagements with Amarin, AmGen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Novartis, Novo Nordisk, Pharmacosmos, Roche, Sanofi, US2.ai, and Vifor. Dr Desai has received honoraria for consulting or speaking from Abbott, AstraZeneca, Alnylam, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, GlaxoSmithKline, Medpace, Medtronic, Merck, New Amsterdam Pharma, Novartis, Parexel, Regeneron, River2Renal, Roche, scPharmaceuticals, Verily, Veristat, and Zydus; and has received institutional research grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer. Dr Mc Causland has received research funding from the National Institute of Diabetes and Digestive and Kidney Diseases, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon, which is paid directly to his institution; and he has received consulting fees from GlaxoSmithKline and Zydus Therapeutics. Dr McGrath has received research funding from Lexicon Pharmaceuticals and has served as a consultant to Alexion. Dr Anand has received consultancy fees from Amgen, ARCA, AstraZeneca, Boehringer Ingelheim, Boston Scientific, LivaNova, Novartis, Rockwell Medical, and Zensun. Dr Zile has received research funding from Novartis; and has served as a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronix, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Pfeffer has received research grant support (via institution) from Lexicon and Novartis; has been a consultant to Alnylam Pharmaceuticals, Apnimed, AstraZeneca, Boehringer Ingelheim, Eli Lilly Alliance, DalCor, Intellia, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, and Novo Nordisk; and holds equity in DalCor. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of Continuing Medical Education, Hikma Pharmaceuticals, Imagica health, Intas Pharma, JB Chemicals and Pharma, Lupin Pharma, Medscape or Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners. 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/NHLBI, 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, CellPro-Thera, Moderna, American Regent, and Sarepta. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Influenza vaccination in patients with acute myocardial infarction (AMI) reduces major adverse cardiac events and is strongly recommended in clinical practice guidelines. Effective strategies to improve vaccination are needed in these high-risk patients., Objective: To evaluate whether electronically delivered behavioral nudges improve influenza vaccine uptake in patients with AMI across 3 nationwide implementation randomized clinical trials (RCTs)., Design, Setting, and Participants: Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU), Nationwide Utilization of Danish Government Electronic Letter System for Confirming the Effectiveness of Behavioral Nudges in Increasing Influenza Vaccine Uptake Among Older Adults (NUDGE-FLU-2), and Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake Among Adults With Chronic Disease (NUDGE-FLU-CHRONIC) were RCTs conducted during the 2022 to 2023 and 2023 to 2024 influenza seasons in Denmark. Participants were randomized to either usual care or various behaviorally informed, electronically delivered, letter-based nudges. In a prespecified participant-level pooled meta-analysis, interaction of AMI status on the effects of letter-based nudges vs usual care was examined. Pooled treatment effects were estimated using binomial regression models with identity link, adjustment for trial, and 2-way clustered SEs at the household and participant levels. Effect modification by recency of AMI as a continuous variable was assessed using restricted cubic spline modeling in NUDGE-FLU-CHRONIC., Interventions: Behaviorally informed, electronically delivered, letter-based nudges or usual care., Main Outcome and Measures: The primary end point was influenza vaccination receipt., Results: Of 2 146 124 individual randomizations (mean [SD] age, 71.1 [11.6] years; 1 114 725 female [51.9%]) across all 3 trials, 59 458 (2.8%) had a history of AMI. Improvement in vaccine uptake was similar in patients with vs without a history of AMI who received any nudge letter compared with usual care (+1.81 vs +1.32 percentage points; P for interaction by AMI status = .09). A letter highlighting the cardiovascular benefits of vaccination (ie, cardiovascular-gain frame) resulted in larger improvements in vaccine uptake among patients with (vs without) a history of AMI (+3.91 vs +2.03 percentage points; P for interaction by AMI status = .002). Among patients with AMI, the benefits of the cardiovascular-gain frame letter were more pronounced in those not vaccinated in the prior season (+13.7 vs +1.48 percentage points; P for interaction <.001). Among younger participants with chronic disease, the cardiovascular-gain frame letter was particularly effective in patients with more recent AMI (P for interaction by continuous recency of AMI <.001)., Conclusions and Relevance: Across 3 nationwide RCTs of Danish citizens, messaging emphasizing the cardiovascular benefits of vaccination improved influenza vaccination uptake, with greater benefits observed in patients with a history of AMI. This low-cost, scalable implementation strategy should be considered to encourage influenza vaccination in high-risk patients., Trial Registration: ClinicalTrials.gov Identifiers: NCT05542004, NCT06030726, NCT06030739.

Background: Lower estimated glomerular filtration rate (eGFR) may be one of the major reasons for hesitation or failure to initiate potentially beneficial therapies in patients with heart failure (HF)., Objectives: This study sought to assess if the effects of sacubitril/valsartan (vs valsartan) on cardiovascular outcomes differ according to baseline kidney function in patients with HF with preserved ejection fraction., Methods: The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial was global clinical trial of 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF) ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the effect of treatment on cardiovascular outcomes using Cox regression models, stratified by region, and assessed for differential treatment effects according to the baseline eGFR and ejection fraction., Results: At randomization, mean eGFR was 67 ± 19 mL/min/1.73 m 2 ; 1,955 (41%) participants had an eGFR <60 mL/min/1.73 m 2 . Compared with valsartan, sacubitril/valsartan reduced the primary cardiovascular outcome (cardiovascular death and total HF hospitalizations) to a greater extent among those with lower baseline eGFR (P interaction = 0.07 for continuous eGFR), and was most pronounced for those with eGFR ≤45 mL/min/1.73 m 2 (RR: 0.69; 95% CI: 0.51-0.94). The influence of eGFR on the treatment effect for cardiovascular death was nonlinear, with the most pronounced treatment effect for those with baseline eGFR <45 mL/min/1.73 m 2 (HR: 0.65; 95% CI: 0.43-0.97). In further subgroup analyses according to LVEF and eGFR, the treatment effect for the primary outcome was most pronounced among those with LVEF ≤57% and eGFR ≤45 mL/min/1.73 m 2 (HR: 0.66; 95% CI: 0.45-0.97)., Conclusions: In the PARAGON-HF trial, the benefits of sacubitril/valsartan to reduce the frequency of HF hospitalizations and cardiovascular death were most apparent in patients with lower baseline eGFR and lower ejection fraction. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., Competing Interests: Funding Support and Author Disclosures Dr Mc Causland has received research funding from the National Institute of Diabetes and Digestive and Kidney Diseases, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon paid directly to his institution; expert witness fees from Rubin-Anders Scientific; and consulting fees from GlaxoSmithKline and Zydus Therapeutics. Dr Vaduganathan has received research grant support from or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexi-con Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi; had speaker engagements with Novartis and Roche Diagnostics; and participated in clinical trial committees for studies sponsored by Bayer AG, Galmed, Occlutech, Novartis, and Impulse Dynamics. Dr Claggett has performed statistical consulting for Alnylam, Cardurion, Corvia, CVRX, Cytokinetics, Intellia, and Rocket. Dr Gori has reported that he has no relationships relevant to the contents of this paper to disclose. Dr Jhund has received consulting fees, advisory board fees, and lecture fees from Novartis; advisory board fees from Cytokinetics; and grant support from Boehringer Ingelheim. Dr McGrath has received research support from Lexicon paid directly to her institution. Dr Neuen has received fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Alexion, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, Janssen, the limbic, and Medscape, with all honoraria paid to the George Institute for Global Health. Dr Packer has received consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson and Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr Pfeffer has received research grant support from Lexicon, Novartis; has received consulting fees from Alnylam, Apnimed, AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, Intellia, the National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, and Novo Nordisk; and owns stock options in DalCor. Dr Rouleau has received grants and consulting fees from Novartis and consulting fees from Abbott, AstraZeneca, MyoKardia, and Sanofi. Dr Senni has received consultancy fees from Novartis, Merck, Vifor Pharma, Abbott, Boehringer Ingelheim, Bioventrix, Servier, and Novo Nordisk. Dr Swedberg has received honoraria from AstraZeneca, Boehringer Mannheim, and Novartis. Dr Zannad has received steering committee or advisory board fees from Amgen, AZ, Bayer, BI, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, NN, and Vifor Fresenius. Dr Zile has received research funding from Novartis; and served as a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Lefkowitz is an employee of Novartis. Dr McMurray has received payments to his employer, Glasgow University, for work on clinical trials, consulting, lecturing, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; personal lecture fees from Abbott, Hikma, Sun Pharmaceuticals, Servier, and Theracos; and personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, and Servier. Dr Solomon has received research grants from Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos/Bridgebio, Gossamer, GlaxoSmithKline, Ionis, Intellia, Lilly, NIH/NHLBI, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, GlaxoSmithKline, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Treatment with finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), improved outcomes in patients with heart failure with mildly reduced or preserved ejection fraction in FINEARTS-HF, but was associated with increased levels of serum potassium in follow-up., Objective: To investigate the frequency and predictors of serum potassium level greater than 5.5 mmol/L and less than 3.5 mmol/L and examine the treatment effect associated with finerenone, relative to placebo, on clinical outcomes based on postrandomization potassium levels., Design, Setting, and Participants: Secondary analysis of the FINEARTS-HF multicenter, randomized clinical trial, performed between September 14, 2020, and January 10, 2023, with a median follow-up of 32 months (final date of follow-up: June 14, 2024). Patients with heart failure and left ventricular ejection fraction greater than or equal to 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides were included., Intervention: Participants received finerenone or placebo., Main Outcomes and Measures: The primary outcome was a composite of total worsening heart failure events or cardiovascular death., Results: A total of 6001 participants were included (3003 randomized to receive finerenone and 2998 randomized to receive placebo). The increase in serum potassium was greater in the finerenone group than the placebo group at 1 month (median [IQR] difference, 0.19 [0.17-0.21] mmol/L) and 3 months (median [IQR] difference, 0.23 [0.21-0.25] mmol/L), which persisted for the remainder of trial follow-up. Finerenone increased the risks of potassium level increasing to greater than 5.5 mmol/L (hazard ratio [HR], 2.16 [95% CI, 1.83-2.56]; P < .001) and decreased the risks for potassium level decreasing to less than 3.5 mmol/L (HR, 0.46 [95% CI, 0.38-0.56]; P < .001). Both low (< 3.5 mmol/L; HR, 2.49 [95% CI, 1.8-3.43]) and high (>5.5 mmol/L; HR, 1.64 [95% CI, 1.04-2.58]) potassium levels were associated with higher subsequent risks of the primary outcome in both treatment groups. Nevertheless, the risk of the primary outcome was generally lower in patients treated with finerenone compared with placebo, even in those whose potassium level increased to greater than 5.5 mmol/L., Conclusions and Relevance: In patients with heart failure with mildly reduced or preserved ejection fraction, finerenone resulted in more frequent hyperkalemia and less frequent hypokalemia. However, with protocol-directed surveillance and dose adjustment, clinical benefit associated with finerenone relative to placebo was maintained even in those whose potassium level increased to greater than 5.5 mmol/L., Trial Registration: ClinicalTrials.gov Identifier: NCT04435626.