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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.

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: NT-proBNP and hs-cTnT are associated with cardiovascular outcomes and are recommended for measurement in type 2 diabetes (T2D). However, the effects of an intensive lifestyle intervention (ILI) targeting weight loss on cardiac biomarkers and the prognostic association of changes in these biomarkers with risk of adverse cardiovascular outcomes in T2D are not well-established., Objectives: To evaluate the effects of an ILI on cardiac biomarkers and the association of changes in cardiac biomarkers with risk of cardiovascular outcomes in T2D., Methods: Participants of the LookAHEAD trial underwent NT-proBNP and hs-cTnT measurement at baseline (N=3,984), 1- and 4-years. The effects of the ILI (vs. diabetes support and education [DSE]) on cardiac biomarkers were assessed using adjusted linear mixed-effect models and summarized as geometric mean ratios (GMR). Associations of longitudinal changes in cardiac biomarkers with risk of cardiovascular outcomes were assessed using adjusted Cox models., Results: Average baseline NT-proBNP and hs-cTnT was 77 and 10.7 ng/L, respectively. The ILI (vs. DSE) led to an increase in NT-proBNP at 1-year (GMR[95% CI]: 1.14[1.08-1.20]), but this difference was attenuated by 4-years (GMR[95% CI]: 1.01[0.96-1.07]). The ILI (vs. DSE) led to lower hs-cTnT at 1-year (GMR[95% CI]: 0.94[0.91-0.97]) and 4-years (GMR[95% CI]: 0.93 [0.90-0.96]). Participants with meaningful weight loss by 1-year (≥5% vs. <5%) had a significant increase in NT-proBNP in the short-term (year-1) which attenuated in the long-term follow-up (year-4). Meaningful 1-year weight loss was significantly associated with reduction in hs-cTnT in the long-term. In adjusted Cox-models, increase in NT-proBNP was significantly associated with higher risk of the composite ASCVD outcome and HF independent of baseline measure of the cardiac biomarker and changes in risk factors. In contrast, longitudinal increase in hs-cTnT was significantly associated with higher risk of the composite ASCVD outcome but not HF in the most adjusted model., Conclusions: Among adults with T2D, an ILI led to a significant reduction in hs-cTnT on follow-up but a transient increase in NT-proBNP levels at 1-year that attenuated over time. Longitudinal assessment of NT-proBNP and hs-cTnT provide prognostic information for ASCVD risk while only changes in NT-proBNP predicted HF risk., (Copyright © 2024. Published by Elsevier Inc.)

Background: Finerenone improves outcomes in patients with heart failure and mildly reduced or preserved ejection fraction. It is important to understand the efficacy and safety of finerenone in these patients according to age., Methods: The aim of this analysis was to evaluate the interaction between age and the efficacy and safety of finerenone in the FINEARTS-HF trial (Finerenone Trial to Investigate Efficacy and Safety Compared to Placebo in Patients With Heart Failure). A total of 6001 patients aged 40 to 97 years were stratified by quartile (Q1-Q4) of baseline age: Q1, 40 to 66 years (n=1581); Q2, 67 to 73 years (n=1587); Q3, 74 to 79 years (n=1421); and Q4, ≥80 years (n=1412). FINEARTS-HF evaluated the impact of age on the efficacy of finerenone with respect to the primary composite outcome of cardiovascular death and total (first and recurrent) heart failure events, including heart failure hospitalization or urgent heart failure event, along with secondary efficacy and safety outcomes., Results: The incidence of primary outcomes increased with age. Finerenone reduced the risk of the primary outcome consistently across all age categories: rate ratio in Q1, 0.70 (95% CI, 0.53-0.92); Q2, 0.83 (95% CI, 0.64-1.07); Q3, 0.98 (95% CI, 0.76-1.26); and Q4, 0.85 (95% CI, 0.67-1.07); P interaction =0.27. Similarly, a consistent effect was observed for the components of the primary outcome. The mean increase in Kansas City Cardiomyopathy Questionnaire-total symptom score from baseline to 12 months was greater with finerenone than placebo, with a consistent effect across all age categories: mean placebo-corrected change in Q1, 2.87 (95% CI, 1.09-4.66); Q2, 1.24 (95% CI, -0.59 to 3.07); Q3, 0.94 (-0.98 to 2.86); and Q4, 1.24 (-0.90 to 3.38); P interaction =0.50. Adverse events were similar across all age categories. The odds of experiencing hypotension, elevated creatinine, or hyperkalemia (increased) or hypokalemia (decreased) related to finerenone did not differ by age., Conclusions: In the FINEARTS-HF trial, finerenone reduced the primary outcome and components of the primary outcome and improved symptoms across a wide age spectrum. In addition, finerenone was safe and well-tolerated, irrespective of age., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT04435626 and EudraCT 2020-000306-29., Competing Interests: Dr Chimura received research grants and personal fees from Otsuka Pharma, Daiwa Foundation, and the Japan Research Foundation for Clinical Pharmacology. Dr Petrie reports, outside of the submitted work, grants or contracts from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; consulting fees from Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, Abbvie, Bayer, Horizon Therapeutics, Foundry, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences; and is Director of Global Clinical Trials Partners. Dr Schou reports other from Novo Nordisk, Novartis, AstraZeneca, and Boehringer outside the submitted work and reports personal fees from Bayer during the conduct of the study and personal fees from Alleviant, AstraZeneca, Boehringer Ingelheim, Edwards Lifesciences, Janssen, Novartis, Novo Nordisk, and Rivus outside the study. Dr Martinez reports personal fees from Bayer, during the conduct of the study. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb (BMS), 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. Drs Kolkhof, Lage, and Rohwedder and K. Mueller are employees of Bayer. Dr Viswanathan is a full-time employee of Bayer Pharmaceuticals. Dr Lam has received research support from NovoNordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, BMS, 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, consultancy and honoraria for Novartis, Abbott, Merck, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from the National Institutes of Health (NIH; U54 HL160273, X01 HL169712, R01 HL140731, and R01 HL149423), the American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer; and received consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, BMS, 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 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, Astra Zeneca, Boehringer Ingelheim, Lexicon, BMS, KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; stock/stock options for KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQinnovations, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; and 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 Jhund reports speakers’ 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’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and is the director of GCTP Ltd. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, the NIH/National Heart, Lung, and Blood Institute (NHLBI), Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline (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, and Novartis, the British Heart Foundation, the NIH/NHLBI, 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; 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, JB Chemicals and 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 for WIRB-Copernicus Group Clinical Inc. He is a director of Global Clinical Trial Partners Ltd. All other authors report no conflicts.

Background: Anemia is one of the most frequent comorbidities in patients with heart failure (HF), which potentially can interfere with the effect of guideline-recommended HF medical therapy and can be associated with the use of neurohormonal blockers., Aim: The aim of this analysis was to determine the prevalence and changes of anemia status in the STRONG-HF study, its association with clinical endpoints, and possible interaction of the presence of anemia with the efficacy and safety of high-intensity HF treatment., Methods: The design and main results of the study have been previously described. Patients were randomized within 2 days prior to anticipated hospital discharge after HF worsening in a 1:1 fashion to either high-intensity care (HIC) or usual care (UC). Baseline characteristics, clinical and safety outcomes, and treatment effect of HIC vs. UC on the primary and secondary outcomes were compared in groups based on baseline anemia. In addition, dynamics of hemoglobin during the study follow-up and predictors of incident anemia at 90 days were investigated., Results: The proportion of anemia in 1077 STRONG-HF patients at enrollment was 27.2%, while at 90 days, it changed to 32.1%. The primary composite outcome occurred in 18.2% of patients without baseline anemia, and 22.5% of patients with baseline anemia (unadjusted HR 1.27; 95% CI 0.90-1.80), a difference that did not reach statistical significance. However, patients with baseline anemia had significantly less improvement of EQ-VAS questionnaire values from baseline to day 90 (adjusted LS-Mean difference -2.34 (-4.37, -0.31), P = 0.02). During the study, anemia developed in 19.4 and 14.6% in HIC and UC groups, respectively. The opposite phenomenon-recovery of anemia-occurred in 27.6 and 28.8% in HIC and UC groups (P = 0.1379). The predictors of incident anemia at 90 days were male sex, geographical region other than Europe, ischemic etiology, higher glucose, and elevated uric acid at baseline. The percentages of optimal doses of renin-angiotensin system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists were not different between anemic and non-anemic patients. High-intensity care strategy did not increase rate of incident anemia at 90 days and reduced the rate of primary and secondary endpoints regardless of baseline hemoglobin., Conclusion: Hemoglobin level and status of anemia have a dynamic nature in the acute HF patients in the post-discharge period dependent on multiple factors. High-intensity HF treatment is safe and beneficial regardless of baseline hemoglobin level and presence of anemia. The improvement of quality of life is significantly lower in anemic HF patients implying specific attention to correction of this condition., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Sacubitril/valsartan is indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalizations in patients with chronic HF. However, many of these patients are older and have multiple comorbidities that increase the risk of hospitalization for causes other than HF., Objective: To assess the effects of sacubitril/valsartan on hospitalizations of any cause across the spectrum of left ventricular ejection fraction (LVEF)., Design, Setting, and Participants: This post hoc, participant-level, pooled analysis of the PARADIGM-HF (in patients with an LVEF ≤40%) and PARAGON-HF (in patients with an LVEF ≥45%) randomized clinical trials was conducted from February 5, 2024, to April 5, 2024. Participants with chronic HF, New York Heart Association classes II through IV symptoms, and elevated natriuretic peptides were randomized to treatment with either sacubitril/valsartan or a renin-angiotensin system inhibitor (RASi)-enalapril in the PARADIGM-HF trial or valsartan in the PARAGON-HF trial., Intervention: Sacubitril/valsartan vs RASi (enalapril or valsartan)., Main Outcomes and Measures: The effects of sacubitril/valsartan on time to first investigator-reported all-cause and cause-specific hospitalizations were examined using Cox proportional hazards models, stratified by geographic region and trial. Effect modification by LVEF as a continuous function was examined., Results: Among 13 194 participants in the PARADIGM-HF and PARAGON-HF trials, mean (SD) patient age was 67 (11) years, 8883 patients (67.3%) were male, and mean (SD) LVEF was 40% (15%). Sacubitril/valsartan significantly reduced the risk of all-cause hospitalization (ACH) compared with RASi over a median (IQR) follow-up period of 2.5 (1.8-3.1) years (hazard ratio [HR], 0.92; 95% CI, 0.88-0.97; P = .002). The incidence rate of first ACH was 25 (95% CI, 24-26) per 100 patient-years in the sacubitril/valsartan arm and 27 (95% CI, 26-28) per 100 patient-years in the RASi arm. The absolute risk reduction (ARR) was 2.1 per 100 patient-years, corresponding to a number needed to treat (NNT) of 48 patient-years of treatment exposure to prevent 1 ACH. Reductions in overall hospitalizations seemed primarily driven by lower rates of cardiac and pulmonary hospitalizations with sacubitril/valsartan. Patients in the 2 treatment arms had similar rates of composite noncardiac hospitalizations. Treatment heterogeneity on ACH by LVEF was observed (P for interaction = .03), with benefits most apparent in patients with an LVEF less than 60% (HR, 0.91; 95% CI, 0.86-0.96), but not in patients with an LVEF of 60% or more (HR, 0.97; 95% CI, 0.86-1.09)., Conclusions and Relevance: In this post hoc pooled analysis of 13 194 patients with chronic HF in the PARADIGM-HF and PARAGON-HF randomized clinical trials, sacubitril/valsartan significantly reduced hospitalization for any reason, with benefits most apparent in patients with an LVEF below normal. This reduction appeared to be principally driven by lower rates of cardiac and pulmonary hospitalizations., Trial Registrations: ClinicalTrials.gov Identifiers: NCT01035255 (PARADIGM-HF) and NCT01920711 (PARAGON-HF).

Background: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk., Methods: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years., Conclusion: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter., Trial Registration: ClinicalTrials.gov NCT05757869., Competing Interests: Disclosures SSJ reports consulting fees from Bristol Myers Squibb, ARTIS Ventures, and Broadview Ventures outside of the submitted work. KWM’s financial disclosures can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey. KSP is a member of The Thrombosis Research Institute which has received institutional research grant support from Anthos Therapeutics and Bayer Pharmaceuticals. She has received honoraria from Element Science and Artivion, Inc. WS has received honoraria (>10K USD) from Daiichi Sankyo, Nippon Boehringer Ingelheim, and Pfizer Japan, and research grants (>50K USD) from Daiichi Sankyo and Nippon Boehringer Ingelheim. CTR reports Research Grants through Institution from: Athos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis. Honoraria for scientific ad boards and consulting from: Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen and Pfizer. He is a member of The TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from: Abbott, Abiomed, Inc, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc, Janssen Research & Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, Saghmos Therapeutics, Inc, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc, Zora Biosciences. PRK reports consultancy from Anthos, J&J, BMS and Bayer. GS has received research grants from Amarin, AstraZeneca, and Sanofi; has participated in clinical trials, consulting, or speaking for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Idorsia, Janssen, Novartis, Novo Nordisk, PhaseBio, Pfizer, and Sanofi; is a Senior Associate Editor at Circulation; and serves as the CMO for Bioquantis. RM reports institutional research payments from: Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi; consultant to Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Esperion Science/Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, Ltd., IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Radcliffe and honoararia from AMA and ACC. SCJ has received research support from Jansen, BMS, and AstraZeneca. GJH reports personal honoraria outside the submitted work from the American Heart Association (Associate Editor, Circulation), Bristol Myers Squibb (Steering Committee, AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention) and Janssen (Co-chair, Executive Committee, Librexia Stroke trial of milvexian for secondary stroke prevention). RAH has received research grants/contracts from NHLBI (ISCHEMIA), Duke/PCORI (ADAPTABLE), Janssen (Factor Xia inhibitor), CSL (HDL), Baim Institute, UColorado, Harvard (BWH), and Merck; has served as a consultant/advisor for NHLBI (COVID/CONNECTS), Atropos Health, Bitterroot Bio, Bristol Myers Squibb, Bridge Bio, Chiesi, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, and WebMD; and serves on the Board of Directors for AHA and Cytokinetics. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from Novo Nordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, 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 serves as Co-founder and nonexecutive director of Us2.ai. The remaining authors report no relevant disclosures or competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy., Methods: The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo., Conclusion: VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF., (© 2024 Bayer AG, Merck Sharp & Dohme LLC and The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Outcomes of hospitalized patients with heart failure (HF) and characteristics of advanced HF stage may vary across left ventricular ejection fraction (LVEF) and world regions., Objectives: This study sought to analyze characteristics of hospitalized advanced HF patients across LVEF spectrum, world regions, and country income., Methods: Among 18,553 hospitalized patients with acute HF (7,902 new-onset HF and 10,651 decompensated chronic HF) enrolled in the global registry REPORT-HF (International Registry to Assess Medical Practice With Longitudinal Observation for Treatment of Heart Failure), we analyzed characteristics and outcomes of patients with advanced HF, defined as previously diagnosed HF; severe symptoms before current admission (NYHA functional class III/IV); and ≥1 HF-related hospitalization in the preceding 12 months, excluding the current. Differences among hospitalized advanced HF subgroups stratified by LVEF, world region, and country income were examined., Results: Among 6,999 patients with decompensated chronic HF and available previous NYHA functional class and HF hospitalization status, 3,397 (48.5%; 18.3% of the total population) had advanced HF. Of these, 44.5% had severely reduced (≤30%), 34.9% mildly/moderately reduced (31%-49%), and 20.7% preserved (≥50%) LVEF. Patients from Eastern Europe had the lowest 1-year mortality (23%), whereas those from Southeast Asia had the highest (37%). Patients from lower-middle-income countries were younger, with shorter HF duration and lower comorbidity prevalence, received fewer beta-blockers and HF-devices, and had higher 1-year mortality (34%) than upper-middle- (26%) or high-income countries (27%; P = 0.018). Adjusted 1-year mortality risk did not differ among LVEF subgroups (all P > 0.05), nor did 1-year HF hospitalization rate (P = 0.56)., Conclusions: Hospitalized patients with advanced HF and preserved LVEF had similarly adverse outcomes as those with reduced LVEF. Patients from lower-middle-income countries had less implementation of HF therapies and higher 1-year mortality., Competing Interests: Funding Support and Author Disclosures Novartis Pharma AG sponsored REPORT-HF. The Steering Committee was responsible for the trial design and supervised patient recruitment and clinical management of the trial. Novartis Pharma AG oversaw data collection and management. The Steering Committee oversaw the analysis and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. The corresponding author had full access to all the data of the study and had final responsibility for the decision for manuscript submission. Dr Bistola has received honoraria for lectures or Advisory Boards from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Roche Diagnostics. Dr Farmakis has received lecture honoraria, consulting or Advisory Board fees and/or grants from AstraZeneca, Bayer, Boehringer Ingelheim, Leo, Myocardial Solutions, Novartis, Remedica, Roche Diagnostics, and Viatris, all outside the present work. Dr Tromp is supported by the National University of Singapore Start-up grant, the tier 1 grant from the Ministry of Education, and the Clinician Scientist–Individual Research Grant New Investigator Grant from the National Medical Research Council; has received research support from AstraZeneca and consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche Diagnostics and Us2.ai; and owns patent US-10702247-B2 unrelated to the present work. Dr Angermann has been a member of the Executive Committee of International Registry to Assess Medical Practice With Longitudinal Observation for Treatment of Heart Failure (REPORT-HF) and has received speaker honoraria, personal fees, and publication support from Novartis in the context of REPORT-HF; has received grant support from the German Ministry for Education and Research (grants 01GI0205 and 01GI1202A); and grant support, personal fees, and/or nonfinancial support from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly Company, Medtronic, Novo Nordisk, ResMed, Thermo Fisher, and Vifor, all outside of the submitted work. Dr Dahlström has received research grants from Pfizer, AstraZeneca, Vifor Pharma, Boehringer Ingelheim, Boston Scientific, and Roche Diagnostics and honoraria/consultancies from AstraZeneca, Pfizer, and Amgen, all outside the submitted work. Dr Ghadanfar is a former employee of Novartis Pharma AG and owns Novartis shares. Dr Schweizer is an employee of Novartis Pharma AG and owns Novartis shares. Dr Collins has received research support from the National Institutes of Health, Patient-Centered Outcomes Research Institute, U.S. Department of Defense, and Beckman Coulter and consulting fees from Abbott, Redesign Health, and Reprieve Cardiovascular, Inc. Dr Lam has been supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, 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 serves as cofounder and nonexecutive director of Us2.ai. Dr Filippatos has received lecture fees and/or Advisory and/or Trial Committee membership from Bayer, Boehringer Ingelheim, Servier, Novartis, Impulse Dynamics, Vifor, Medtronic, Cardior, and Novo Nordisk and research grants from the European Union. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed., Methods: In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed., Results: Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia., Conclusions: In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Finerenone has kidney protective effects in patients with chronic kidney disease (CKD) with type 2 diabetes, but effects on kidney outcomes in patients with heart failure (HF) with and without diabetes and/or CKD are not known., Objectives: Examine the effects of finerenone on kidney outcomes in FINEARTS-HF, a randomized trial of finerenone vs. placebo among patients with HF with mildly reduced or preserved ejection fraction., Methods: We explored the effects of finerenone on the secondary outcome of a sustained ≥50% eGFR decline or kidney failure (sustained eGFR decline <15 mL/min/1.73 m 2 ; initiation of maintenance dialysis; renal transplant). In this prespecified analysis, we also report effects of finerenone on: 1) sustained ≥57% eGFR decline or kidney failure; 2) eGFR slope; 3) changes in urine albumin/creatinine ratio (UACR)., Results: Among 6,001 participants, mean baseline eGFR was 62 ±20mL/min/1.73m 2 ; 48% had eGFR <60mL/min/1.73m 2 . Overall, 5,797 had baseline UACR data (median 18 [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 non-significantly, 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), though 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/1.73m 2 (95%CI -3.4, -2.4) but did not alter chronic (from 3 months) eGFR slope (+0.2 mL/min/1.73m 2 /year; 95%CI -0.1, +0.4), vs. placebo. The difference in total slope was -0.7 (95%CI -0.9 to -0.4) mL/min/1.73 m 2 /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 micro- 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The VICTORIA trial demonstrated a significant reduction in the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death with vericiguat relative to placebo in high-risk HF. This study aimed to contextualize treatment effects of vericiguat in populations with varying risk profiles simulated from the PARADIGM-HF and DAPA-HF trials., Methods: Subgroups of VICTORIA participants (n = 5050) were generated to simulate PARADIGM-HF and DAPA-HF trial populations. The PARADIGM-HF-eligible population excluded participants not meeting left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and minimal dose criteria and those with high predicted probability of run-in failure. The DAPA-HF-eligible population excluded those not meeting LVEF and eGFR criteria or with recent (<30 days) HF hospitalization. The time-to-first-event analysis was performed using an unadjusted Cox proportional hazards model., Results: A total of 1982 (39.2%) and 2543 (50.4%) VICTORIA participants were respectively deemed eligible for PARADIGM-HF and DAPA-HF. Vericiguat was associated with numerically larger reductions in the primary outcome of HF hospitalization or cardiovascular death in populations simulated from PARADIGM-HF [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.72-0.99] and DAPA-HF (HR 0.82, 95% CI 0.71-0.94) compared with the overall VICTORIA trial (HR 0.90). Significant reduction in HF hospitalization with vericiguat was also observed in the DAPA-HF-eligible population (HR 0.83, 95%CI 0.73-0.95) and with a nominal reduction in the PARADIGM-HF-eligible population (HR 0.86, 95% CI 0.74-1.01)., Conclusions: A trend towards enhanced efficacy of vericiguat in populations simulated from PARADIGM-HF and DAPA-HF was observed. These findings support further exploration of vericiguat in lower-risk HF populations as is being investigated in the ongoing VICTOR (a study of vericiguat in participants with chronic heart failure with reduced ejection fraction) trial., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood., Methods: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide)., Results: At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death., Conclusions: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

Aims: Abnormalities in specific echocardiographic parameters and cardiac biomarkers have been reported among individuals with diabetes. However, a comprehensive characterization of diabetic cardiomyopathy (DbCM), a subclinical stage of myocardial abnormalities that precede the development of clinical heart failure (HF), is lacking. In this study, we developed and validated a machine learning-based clustering approach to identify the high-risk DbCM phenotype based on echocardiographic and cardiac biomarker parameters., Methods and Results: Among individuals with diabetes from the Atherosclerosis Risk in Communities (ARIC) cohort who were free of cardiovascular disease and other potential aetiologies of cardiomyopathy (training, n = 1199), unsupervised hierarchical clustering was performed using echocardiographic parameters and cardiac biomarkers of neurohormonal stress and chronic myocardial injury (total 25 variables). The high-risk DbCM phenotype was identified based on the incidence of HF on follow-up. A deep neural network (DeepNN) classifier was developed to predict DbCM in the ARIC training cohort and validated in an external community-based cohort (Cardiovascular Health Study [CHS]; n = 802) and an electronic health record (EHR) cohort (n = 5071). Clustering identified three phenogroups in the derivation cohort. Phenogroup-3 (n = 324, 27% of the cohort) had significantly higher 5-year HF incidence than other phenogroups (12.1% vs. 4.6% [phenogroup 2] vs. 3.1% [phenogroup 1]) and was identified as the high-risk DbCM phenotype. The key echocardiographic predictors of high-risk DbCM phenotype were higher NT-proBNP levels, increased left ventricular mass and left atrial size, and worse diastolic function. In the CHS and University of Texas (UT) Southwestern EHR validation cohorts, the DeepNN classifier identified 16% and 29% of participants with DbCM, respectively. Participants with (vs. without) high-risk DbCM phenotype in the external validation cohorts had a significantly higher incidence of HF (hazard ratio [95% confidence interval] 1.61 [1.18-2.19] in CHS and 1.34 [1.08-1.65] in the UT Southwestern EHR cohort)., Conclusion: Machine learning-based techniques may identify 16% to 29% of individuals with diabetes as having a high-risk DbCM phenotype who may benefit from more aggressive implementation of HF preventive strategies., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Renal dysfunction is common and associated with a poor prognosis in patients with heart failure. However, the association of cardiac structure and function with decline in kidney function in this population is unknown. We aimed to assess the association between individual measures of cardiac structure and function with changes in renal function and renal outcomes in patients with heart failure with preserved ejection fraction., Methods: Patients enrolled in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction) echocardiographic substudy were included. The association between each echocardiographic parameter (expressed in standardized units) and changes over time in estimated glomerular filtration rate was calculated with repeated-measures mixed-effect models. Multivariable Cox proportional hazards models were used to identify individual cardiac parameters associated with the composite renal outcome (≥50% decline in estimated glomerular filtration rate relative to baseline, development of end-stage renal disease, or death attributable to renal causes), after adjusting for covariates., Results: Among 1097 patients (mean age 74±8 years and 53% women), over a median follow-up of 2.9 years, 28 composite renal events (0.9 per 100 person-years) occurred. Higher left ventricular (LV) mass index and higher E/average e' ratio were associated with significantly more profound annual decline in estimated glomerular filtration rate (for both, -0.4 [95% CI, -0.7 to -0.1] mL/min/1.73 m 2 /y per 1 higher SD). Higher LV mass index, LV end-diastolic volume index, right ventricular end-diastolic area, and a lower right ventricular fractional area change were each associated with a significantly higher risk for the composite renal outcome., Conclusions: In the PARAGON-HF echocardiographic substudy, higher LV mass and filling pressures were independently associated with more profound kidney function decline, and higher LV mass and volume, as well as impaired right ventricular structure and function, were each associated with renal events. Assessing these parameters may help identify patients with heart failure with preserved ejection fraction at higher risk for adverse renal events and indicate potential therapeutic targets., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711., Competing Interests: Dr Lu received research funding from the Gottfried und Julia Bangerter-Rhyner Foundation, the SICPA (Société industrielle et commerciale de produits alimentaires) Foundation, and the Société Académique Vaudoise. Dr Chatur is supported by the Canadian Arthur J.E. Child’s Cardiology Fellowship. Dr Mc Causland reports grant funding from the National Institutes of Health (NIH), Satellite Healthcare, Fifth Eye, Lexicon, and Novartis paid directly to his institution; consulting fees from GlaxoSmithKline (GSK) and Zydus Therapeutics; and expert witness fees from Rubin-Anders Scientific. Dr Shah reports consulting fees from Philips Ultrasound and research funds from Novartis through Brigham and Women’s Hospital. He was supported by NIH/National Heart, Lung, and Blood Institute (NHLBI) grant K24HL152008. Dr Cikes reports Investigator-Initiated Research Grants to institution: Novartis, Abbott, and Pfizer; Clinical Study Contracts with institution: NovoNordisk and CorVia; advisory role and speaker honoraria, travel grants from Abbott, Abiomed, Amgen, Amicus Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Livanova, Krka Pharma, Novartis, NovoNordisk, Pfizer, Pulsify Medical, Roche, Swixx, Takeda, Teva Pharmaceutical Industries, and Viatris. Dr Claggett reports personal consulting from Alnylam, Cardurion, Corvia, Cytokinetics, CVRX, Intellia, and Rocket. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee (SC)/Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, 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 serves as cofounder and nonexecutive director of Us2.ai. Dr O’Meara reports grants/research support from the Montreal Heart Institute’s Carolyn & Richard J. Renaud Chair for Research in Heart Failure, with fees paid through her institution for this Chair and for the following: Canadian Heart Function Alliance (CHFA) Team Grant, funded by the Canadian Institutes of Health Research (SC member), and involvement in the following trials as a SC member for DAPA ACT HF-TIMI 68 (Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure–Thrombolysis in Myocardial Infarction 68; TIMI [Thrombolysis in Myocardial Infarction] group and AZ) and GARDEN-HF (A Study of Ponsegromab in People With Heart Failure; TIMI group and Pfizer), for HEART-FID (Ferric Carboxymaltose in Heart Failure With Iron Deficiency; SC member, American Regent), CARDINAL-HF (Effectiveness of CRD-740 in Heart Failure; SC member, Cardurion), and HERMES (Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation; National Lead Investigator Novo Nordisk); reports consulting fees from Astra Zeneca, Boerhinger Ingelheim, GSK, Novartis, and Novo Nordisk; speaker fees from Astra Zeneca, Boerhinger Ingelheim, GSK, Novartis, Novo Nordisk, Pfizer, and other fees from Cytokinetics (Heart Failure Patient Steering Committee), industry partners for Canadian Heart Function Alliance Network. Dr Wang is supported by the Scott Schoen and Nancy Adams First.In.Women Cardiovascular Fellowship, Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, and the American College of Cardiology/Association of Black Cardiologists Merck Research Fellowship Award. Dr McMurray reports payments through Glasgow University from work on clinical trials, consulting and other activities from: Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; personal consultancy fees from: Alnylam Pharma, Bayer, Bristol Myers Squibb (BMS), George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; reports the following lecture fees: Abbott, Alkem Metabolics, Astra Zeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of Continuing Medical Education, Hikma Pharmaceuticals, Imagica health, Intas Pharma, J.B. Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, Translational Medicine Academy. He is a director of Global Clinical Trial Partners Ltd. Dr Pfeffer reports research grant support (via institution): Lexicon and Novartis. He is a consultant to Alnylam, AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, Lexicon, NHLBI Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (Master Protocol Committee), Novartis, Novo Nordisk, and Sanofi, and has equity in DalCor. Dr Hegde reports fees paid to the institution for core laboratory services for BMS and Cytokinetics. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Cytokinetics, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/NHLBI, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, Us2.ai, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Skali reports research support or consulting fees from: ABT Associates, Astellas Pharma, Emmi Solutions, and Hikma Pharmaceuticals. The other authors report no conflicts.

This Series paper provides an overview of digital tools in heart failure care, encompassing screening, early diagnosis, treatment initiation and optimisation, and monitoring, and the implications these tools could have for research. The current medical environment favours the implementation of digital tools in heart failure due to rapid advancements in technology and computing power, unprecedented global connectivity, and the paradigm shift towards digitisation. Despite available effective therapies for heart failure, substantial inadequacies in managing the condition have hindered improvements in patient outcomes, particularly in low-income and middle-income countries. As digital health tools continue to evolve and exert a growing influence on both clinical care and research, establishing clinical frameworks and supportive ecosystems that enable their effective use on a global scale is crucial., Competing Interests: Declaration of interests PLM has received research grants from AstraZeneca and received speaker or consulting honoraria from Amarin, AmGen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Novo Nordisk, Orion Pharma, Pharmacosmos, Vifor, and Us2.ai. JT is supported by the National University of Singapore Start-up Grant, the tier 1 grant from the Ministry of Education, and the Clinician Scientist-Individual Research Grant New Investigator Grant from the National Medical Research Council; has received research support from AstraZeneca and consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche Diagnostics, and Us2.ai; is a patent holder of US-10702247-B2; and has stock options in Us2.ai. KFD has received speaker's honoraria from AstraZeneca, Pharmacosmos, Radcliffe Cardiology, Boehringer Ingelheim, and Fire1; has served on an advisory board for Us2.ai and Bayer and a clinical endpoint committee for Bayer; and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and AstraZeneca (paid to his institution). His employer, the University of Glasgow, has been remunerated by AstraZeneca for work relating to clinical trials. WO has consulted for Us2.ai, is a patent holder of US-10702247-B2, and has stock options in Us2.ai. DTSW is a consultant for AbbVie, Carl Zeiss, Alcon, Novartis, Bayer, Genentech/Roche, and Ocutrx and is a patent holder for EyRIS and for three AI image analysis methodologies or systems. CMG has received funding from CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson Corporation, and the Spontaneous Coronary Artery Dissection Alliance; has provided consulting services to Adaptimmune, Angel/Avertix Medical, AstraZenca, Bayer Corporation, Bioclinica, Boston Clinical Research Institute, Boston Scientific, Bristol Myers Squibb, Caladrius Biosciences, Cardiovascular Research Foundation, CeleCor Therapeutics, CSL Behring, Cytokinetics, Daiichi Sankyo, Duke Clinical Research Institute, Esperion, EXCITE International ($0 received), Fortress Biotech, Gilead Sciences, Inari, Janssen Pharmaceuticals, Johnson & Johnson Corporation, MashUp MD, MD Magazine, Merck, Microport, Micodrop, Miracor, MjHealth, Novartis, NovoNordisk, the Pulmonary Embolism Response Team Consortium, Pfizer, PhaseBio, PHRI, PLxPharma, Revance Therapeutics, the Society for Cardiovascular Angiography & Interventions, Solstic Health/New Amsterdam Pharma, Somahlution/Marizyme, Vectura, Web MD, and Woman As One; holds equity in Absolutys, nference, Dyad Medical, and Fortress Biotech; and has received royalties as a contributor to UpToDate in Cardiovascular Medicine. CPSL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board, Steering Committee, or Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; serves as Cofounder and Non-executive Director of Us2.ai; and has the following patents issued or pending: PCT/SG2016/050217 (for a method for diagnosis and prognosis of chronic heart failure) and US Patent number 10702247 (for an automated clinical workflow that recognises and analyses two-dimensional and Doppler echo images for cardiac measurements and the diagnosis, prediction, and prognosis of heart disease)., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Type 2 diabetes mellitus (T2DM) significantly worsens heart failure (HF) prognosis., Objectives: This study sought to investigate the impact of T2DM on outcomes in patients enrolled in VICTORIA and assess the efficacy of vericiguat in patients with and without T2DM., Methods: Patients with HF with reduced ejection fraction were randomized to receive vericiguat or placebo in addition to standard therapy. The primary outcome was a composite of cardiovascular death or first heart failure hospitalization (HFH). A Cox proportional hazards model was used to calculate HRs and 95% CIs to assess if the effect of vericiguat differed by history of T2DM., Results: Of 5,050 patients enrolled, 3,683 (72.9%) had glycosylated hemoglobin (HbA 1c ) measured at baseline. Of these, 2,270 (61.6%) had T2DM, 741 (20.1%) had pre-T2DM, 449 (12.2%) did not have T2DM, and 178 (4.8%) had undiagnosed T2DM. The risks of the primary outcome, HFH, and all-cause and cardiovascular mortality were high across all categories. The efficacy of vericiguat on the primary outcome did not differ in patients stratified by T2DM by history (HR: 0.92; 95% CI: 0.81-1.04), T2DM measured by HbA 1c (HR: 0.77; 95% CI: 0.49-1.20), and pre-T2DM measured by HbA 1c (HR: 0.88; 95% CI: 0.68-1.13) and in those with normoglycemia (HR: 1.02: 95% CI: 0.75-1.39; P for interaction = 0.752). No significant differences were observed in subgroups with respect to the efficacy of vericiguat on HFH and all-cause or cardiovascular death., Conclusions: In this post hoc analysis of VICTORIA, vericiguat compared with placebo significantly reduced the risk of cardiovascular death or HFH in patients with worsening HF with reduced ejection fraction regardless of T2DM status. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [Mk-1242-001] [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures VICTORIA was funded by Bayer and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA. Dr Khan has served as an Advisory Board Member for Bayer. Dr Butler has received consulting fees from Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor. Dr Roessig has been an employee of Bayer AG. Dr Blaustein has been an employee of Merck & Co, Inc. Dr Lam has received research grants from Bayer, National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; has received consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd, and Corpus; has patent PCT/SG2016/050217 pending and patent 16/216929 pending; and is cofounder and nonexecutive director of eKo.ai. Dr Voors has received research grants from Boehringer Ingelheim and Roche Diagnostics and consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, MyoKardia, Novartis, Servier, and Roche Diagnostics. Dr Ponikowski has received research grants, has received consulting fees, and has served on the Speakers Bureau for Bayer, MSD, Servier, Novartis, Vifor Pharma Ltd, BMS, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuardSolution, and Berlin Chemie. Dr Anstrom has received research grants from Merck and the National Institutes of Health. Dr Armstrong has received consulting fees from Merck, Bayer, Boehringer Ingelheim, and Novo Nordisk and research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly, and CSL Limited. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Reverse ventricular remodelling, defined as a decrease in left ventricular end-systolic volume indexed to body surface area (LVESVI) or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying pathophysiological mechanisms remain unclear., Methods and Results: We evaluated paired core-lab assessed echocardiograms and measurements of 92 biomarkers at baseline and 8 months thereafter in 419 participants with HFrEF. Reverse ventricular remodelling was defined as a >5% LVEF increase or >15% LVESVI relative decrease between baseline and 8 months. We evaluated the association between baseline biomarkers and their changes with reverse ventricular remodelling in the prospectively randomized controlled VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial. Of 419 patients (median age 66 [interquartile range 57-74] years, 27.4% women), 206 (49.2%) had reverse ventricular remodelling (either a 5% LVEF increase or a 15% LVESVI decrease). There were no differences in baseline biomarker concentrations between patients with versus those without reverse ventricular remodelling on follow-up. However, in patients with reverse ventricular remodelling there were significant decreases in biomarkers relating to inflammation and cardiac metabolism; particularly the tumour necrosis factor superfamily member 13B (ratio 0.82, 95% confidence interval [CI] 0.77-0.88), growth differentiation factor-15 (ratio 0.74, 95% CI 0.66-0.84), and insulin-like growth factor binding protein 7 (ratio 0.80, 95% CI 0.73-0.88)., Conclusions: Reverse ventricular remodelling in patients with HFrEF is associated with a decrease of biomarkers related to inflammation and cardiac metabolism., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Multimorbidity frequently occurs in patients with acute heart failure (AHF). The co-occurrence of comorbidities often follows specific patterns., Objectives: This study investigated multimorbidity subtypes and their associations with clinical outcomes., Methods: From the prospective RELAX-AHF-2 (Relaxin for the Treatment of Acute Heart Failure-2) trial, 6,545 patients (26% with HF with preserved ejection fraction, defined as LVEF ≥50%) were classified into multimorbidity groups using latent class analysis. The association between subgroups and clinical outcomes was examined. Validation of these findings was conducted in the RELAX-AHF trial, which comprised 1,161 patients., Results: Five distinct multimorbidity groups emerged: 1) diabetes and chronic kidney disease (CKD) (often male, high prevalence of CKD and diabetes mellitus); 2) ischemic (ischemic HF); 3) elderly/atrial fibrillation (AF) (oldest, high prevalence of AF); 4) metabolic (obese, hypertensive, more often HF with preserved ejection fraction); and 5) young (fewest comorbidities). After adjusting for confounders, patients in the diabetes and CKD (HR: 1.80; 95% CI: 1.50-2.20), elderly/AF (HR: 1.42; 95% CI: 1.20-1.70), and metabolic (HR: 1.40; 95% CI: 1.20-1.80) groups had higher rates of the composite outcome than patients in the young group, primarily driven by differences in rehospitalization. Treatment allocation (placebo or serelaxin) modified these associations (P interaction  <0.001). Serelaxin-treated patients in the young group were associated with a lower risk for all-cause mortality (HR: 0.59; 95% CI: 0.40-0.90). Similarly, patients from the RELAX-AHF trial clustered in 5 multimorbidity groups. The clinical characteristics and associations with outcomes could also be validated., Conclusions: Comorbidities naturally clustered into 5 mutually exclusive groups in RELAX-AHF-2, showing variations in clinical outcomes. These data emphasize that the specific combination of comorbidities can influence adverse outcomes and treatment responses in patients with AHF., Competing Interests: Funding Support and Author Disclosures This study was funded by the PROMINENT project (funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement number 754425). Dr Tromp is supported by the National University of Singapore Start-up grant, the tier 1 grant from the ministry of education, and the CS-IRG New Investigator Grant from the National Medical Research Council; has received consulting or speaker fees from Daiichi Sankyo, Boehringer Ingelheim, Roche Diagnostics, and Us2.ai; and owns patent US-10702247-B2 unrelated to the present work. Drs Cotter and Davison are employees of Momentum Research, Inc, which has received grants from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics Inc, Corteria Pharmaceuticals, Roche Diagnostics Inc, Sanofi, Windtree Therapeutics Inc, and XyloCor Therapeutics. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree Therapeutics, and Whiteswell; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Gimpelewicz is an employee of Novartis. Dr Greenberg is a consultant for or on the advisory board of AstraZeneca, Bayer, Ionis, Merck, Mesoblast, and Tenaya; and has been on the Data Safety Monitoring Board of ACI, Axon, AstraZeneca, Bayer, Cytokinetics, Boehringer Ingelheim, EBR Systems, Faraday, Inventiva, Impulse Dynamics, Ionis, Salubris, Vifor, Viking, and Windtree. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, ProSciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and nonexecutive director of Us2.ai. Dr Voors has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, MyoKardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr Metra received personal fees of minimal amounts in the last 3 years from Actelion, Amgen, LivaNova, and Vifor pharma as a member of Executive or Data Monitoring Committees of sponsored clinical trials; and from AstraZeneca, Abbott Vascular, Bayer, Boehringer Ingelheim, and Edwards Therapeutics for participation on advisory boards and/or speeches at sponsored meetings. Dr Teerlink has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. Dr van der Meer received grant support and/or consultancy fees from Novartis, Pharma Nord, Pfizer, Ionis, Astra Zeneca, Vifor Pharma, Pharmacosmos, BridgeBio, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Electronic health records (EHR) linked to Digital Imaging and Communications in Medicine (DICOM), biological specimens, and deep learning (DL) algorithms could potentially improve patient care through automated case detection and surveillance. We hypothesized that by applying keyword searches to routinely stored EHR, in conjunction with AI-powered automated reading of DICOM echocardiography images and analysing biomarkers from routinely stored plasma samples, we were able to identify heart failure (HF) patients., Methods and Results: We used EHR data between 1993 and 2021 from Tayside and Fife (~20% of the Scottish population). We implemented a keyword search strategy complemented by filtering based on International Classification of Diseases (ICD) codes and prescription data to EHR data set. We then applied DL for the automated interpretation of echocardiographic DICOM images. These methods were then integrated with the analysis of routinely stored plasma samples to identify and categorize patients into HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), and controls without HF. The final diagnosis was verified through a manual review of medical records, measured natriuretic peptides in stored blood samples, and by comparing clinical outcomes among groups. In our study, we selected the patient cohort through an algorithmic workflow. This process started with 60 850 EHR data and resulted in a final cohort of 578 patients, divided into 186 controls, 236 with HFpEF, and 156 with HFrEF, after excluding individuals with mismatched data or significant valvular heart disease. The analysis of baseline characteristics revealed that compared with controls, patients with HFrEF and HFpEF were generally older, had higher BMI, and showed a greater prevalence of co-morbidities such as diabetes, COPD, and CKD. Echocardiographic analysis, enhanced by DL, provided high coverage, and detailed insights into cardiac function, showing significant differences in parameters such as left ventricular diameter, ejection fraction, and myocardial strain among the groups. Clinical outcomes highlighted a higher risk of hospitalization and mortality for HF patients compared with controls, with particularly elevated risk ratios for both HFrEF and HFpEF groups. The concordance between the algorithmic selection of patients and manual validation demonstrated high accuracy, supporting the effectiveness of our approach in identifying and classifying HF subtypes, which could significantly impact future HF diagnosis and management strategies., Conclusions: Our study highlights the feasibility of combining keyword searches in EHR, DL automated echocardiographic interpretation, and biobank resources to identify HF subtypes., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The effect of treatments for heart failure may vary among patients according to left ventricular ejection fraction (LVEF). In the FINEARTS-HF, the nonsteroidal MRA finerenone reduced the risk of cardiovascular death and total worsening heart failure events in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). 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 heart failure and LVEF &#x226540%. 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% (IQR 46% -58%), respectively. LVEF was <50% in 2172 (36), between 50 to <60% in 2674 (45%), and ≥60% in 1147 (19%). Patients with a higher LVEF were older, 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 to those with a lower LVEF. Finerenone reduced the risk of cardiovascular death and total heart failure events consistently across LVEF categories: LVEF <50% rate ratio (RR) = 0.84 (95% CI 0.68, 1.03), LVEF ≥50 to <60% RR = 0.80 (0.66, 0.97) and LVEF ≥60% RR = 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 heart failure events (continuous p interaction = 0.26)., Conclusions: In patients with HFmrEF/HFpEF, finerenone reduced the risk of cardiovascular death and worsening heart failure events, irrespective of LVEF.

Aims: To estimate the incidence of major adverse cardiovascular events (MACE), expanded MACE, and MACE or Death across Fibrosis- 4 score (FIB-4) categories in people with type 2 diabetes and to determine whether efpeglenatide's effect varies with increasing FIB-4 severity., Materials and Methods: AMPLITUDE-O trial data were used to estimate the relationship of FIB-4 score categories to the hazard of MACE, expanded MACE, and MACE or death. Interactions on these outcomes between baseline FIB-4 score, and between FIB-4 score and efpeglenatide were also assessed., Results: Baseline FIB-4 score was available for 4059 participants (99.6%) allowing subdivision of the population in tertiles. During a median follow-up of 1.8 years, numerical increases in the incidence of all 3 outcomes did not change significantly across tertiles of FIB-4 score (P for trend ≥ 0.25) with negligible relationship of the score to incident outcomes (MACE HR, per 1 SD higher score, 95% CI: 1.00, 0.89-1.13). Efpeglenatide's effect on all MACE outcomes did not vary across FIB-4 tertiles (all interaction p values ≥ 0.64)., Conclusions: In high-risk people with type 2 diabetes, the degree of liver fibrosis, as estimated by FIB-4 score, was not related to incident cardiovascular outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of FIB-4 category., (© 2024. The Author(s).)

Background: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. The sodium glucose-co-transporter-2 inhibitors (SGLT2i) and the non-steroidal mineralocorticoid receptor antagonist (MRA) 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 was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction (LVEF) ≥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 based on 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 6,001 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% confidence interval 0.60 to 1.16) and without an SGLT2i at baseline (rate ratio 0.85; 95% confidence interval 0.74 to 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% vs. 20.1%; hazard ratio 0.86; confidence interval 0.76 to 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 endpoint., Conclusions: The treatment benefits of the non-steroidal MRA finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a non-steroidal MRA may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction.

Importance: People living with heart failure (HF) with mildly reduced or preserved ejection fraction have substantially curtailed life expectancy free from clinical events compared with their peers of comparable age. The nonsteroidal mineralocorticoid receptor antagonist, finerenone, was recently shown to reduce risks of cardiovascular events in this population over a median follow-up of 2.6 years; as patients with HF typically continue treatment beyond this time frame, estimating the potential long-term benefits of finerenone could inform shared clinical decision-making., Objective: To estimate the projected long-term treatment effects of finerenone in patients with HF with mildly reduced or preserved ejection fraction if treated over a patient's lifetime., Design, Setting, and Participants: Prespecified analyses were conducted of the FINEARTS-HF trial, a phase 3 randomized clinical trial conducted across 653 sites in 37 countries. Adults 40 years and older with symptomatic HF and left ventricular ejection fraction of 40% or greater were randomized from September 2020 to January 2023. Median (IQR) follow-up was 2.6 (1.9-3.0) years., Interventions: Finerenone (titrated to either 20 mg or 40 mg) or placebo., Main Outcomes and Measures: The primary composite outcome was time to cardiovascular death or worsening HF event. The long-term gains in survival free from a primary end point with finerenone were iteratively estimated with age-based Kaplan-Meier curves using age at randomization rather than time from randomization. Differences in areas under the survival curves between the finerenone and placebo arms represented event-free survival gains., Results: Among 6001 participants (median [IQR] age, 73 [66-79] years; 3269 male [54.5%]), mean survival free from the primary end point for a 55-year-old participant was 13.6 years (95% CI, 11.9-15.2 years) with finerenone and 10.5 years (95% CI, 6.8-11.3 years) with placebo, representing a gain in event-free survival of 3.1 years (95% CI, 0.8-5.4 years; P = .007). Mean event-free survival for a 65-year-old participant was 11.0 years (95% CI, 10.1-11.9 years) with finerenone and 8.9 years (95% CI, 8.1-9.8 years) with placebo, representing a gain of 2.0 years (95% CI, 0.8-3.3 years; P = .001). Projected mean event-free survival was numerically greater with finerenone than with placebo for every starting age between 50 to 80 years. Lifetime gains in event-free survival were observed even among individuals already treated with a sodium-glucose cotransporter 2 inhibitor (65-year-old participant: 3.1 years; 95% CI, 0.1-6.0 years; P = .04)., Conclusions and Relevance: In this prespecified secondary analysis of the FINEARTS-HF randomized clinical trial, long-term treatment with finerenone was estimated to extend event-free survival by up to 3 years among people with HF with mildly reduced or preserved ejection fraction., Trial Registration: ClinicalTrials.gov Identifier: NCT04435626.

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 © 2024. Published by Elsevier Inc.)

Background: Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisations and death in patients with heart failure and reduced ejection fraction (HFrEF), but the benefit in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or heart failure and preserved ejection fraction (HFpEF) is unclear. We evaluated the effect of MRAs in four trials that enrolled patients with heart failure across the range of ejection fraction., Methods: This is a prespecified, individual patient level meta-analysis of the RALES (spironolactone) and EMPHASIS-HF (eplerenone) trials, which enrolled patients with HFrEF, and of the TOPCAT (spironolactone) and FINEARTS-HF (finerenone) trials, which enrolled patients with HFmrEF or HFpEF. The primary outcome of this meta-analysis was a composite of time to first hospitalisation for heart failure or cardiovascular death. We also estimated the effect of MRAs on components of this composite, total (first or repeat) heart failure hospitalisations (with and without cardiovascular deaths), and all-cause death. Safety outcomes were also assessed, including serum creatinine, estimated glomerular filtration rate, serum potassium, and systolic blood pressure. An interaction between trials and treatment was tested to examine the heterogeneity of effect in these populations. This study is registered with PROSPERO, CRD42024541487., Findings: 13 846 patients were included in the four trials. MRAs reduced the risk of cardiovascular death or heart failure hospitalisation (hazard ratio 0·77 [95% CI 0·72-0·83]). There was a statistically significant interaction by trials and treatment (p for interaction=0·0012) due to the greater efficacy in HFrEF (0·66 [0·59-0·73]) compared with HFmrEF or HFpEF (0·87 [0·79-0·95]). We observed significant reductions in heart failure hospitalisation in the HFrEF trials (0·63 [0·55-0·72]) and the HFmrEF or HFpEF trials (0·82 [0·74-0·91]). The same pattern was observed for total heart failure hospitalisations with or without cardiovascular death. Cardiovascular death was reduced in the HFrEF trials (0·72 [0·63-0·82]) but not in the HFmrEF or HFpEF trials (0·92 [0·80-1·05]). All-cause death was also reduced in the HFrEF trials (0·73 [0·65-0·83]) but not in the HFmrEF or HFpEF trials (0·94 [0·85-1·03]). With an MRA, the risk of hyperkalaemia was doubled compared with placebo (odds ratio 2·27 [95% CI 2·02-2·56]), but the incidence of serious hyperkalaemia (serum potassium >6·0 mmol/L) was low (2·9% vs 1·4%); the risk of hypokalaemia (potassium <3·5 mmol/L) was halved (0·51 [0·45-0·57]; 7% vs 14%)., Interpretation: Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF., Funding: None., Competing Interests: Declaration of interests PSJ reports speakers 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, and Roche Diagnostics; and is a director of Global Clinical Trial Partners. PSJ's employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer, Novartis, and Novo Nordisk. BLC has received personal consulting fees from Alnylam, Bristol Myers Squibb (BMS), Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket, and has served on a data safety monitoring board for Novo Nordisk. MV has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, 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, Occlutech, and Impulse Dynamics. ASD has received institutional research grants (to Brigham and Women's Hospital) 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, River2Renal, Roche, Veristat, Verily, and Zydus. CSPL has received research support from NovoNordisk and Roche Diagnostics; consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, BMS, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and non-executive Director of Us2.ai. BP is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, BMS, KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQ Innovation, G3 Pharmaceuticals, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; and holds stock or stock options in KBP Biosciences, Sarfez Pharmaceuticals, SQ Innovation, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical. He holds US Patent 9931412 on site specific delivery of eplerenone to the myocardium, and US Patent pending 63/045,783 on histone modulating agents for the prevention and treatment of organ failure. MS has served on advisory boards for and has received consultancy fees and honoraria from Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. SJS has received research grants from the US National Institutes of Health (NIH; U54 HL160273, X01 HL169712, R01 HL140731, and R01 HL149423), the 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, BMS, 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's employer received consultancy fees or research support from Adrenomed, Anacardio, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. FZ 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; stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and being the founder of Cardiovascular Clinical Trialists. SDS has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/National Heart, Lung, and Blood Institute (NHLBI), Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai, and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-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. JJVM reports payments through the University of Glasgow for 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, British Heart Foundation, NIH/NHLBI, Boehringer Ingelheim, SQ Innovation, and Catalyze Group; 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, J B Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; served on a data safety monitoring board for WIRB-Copernicus Group Clinical; and is a director of Global Clinical Trial Partners. All other authors declare no competing interests., (Copyright © 2024 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: Patients with heart failure (HF) with improved ejection fraction (HFimpEF) may face residual risks of clinical events that are comparable to those experienced by patients with HF whose left ventricular ejection fraction (LVEF) has consistently been above 40%. However, little is known about the clinical course of patients with HFimpEF during hospitalization for HF., Methods and Results: DELIVER randomized patients with HF and LVEF >40% to dapagliflozin or placebo, including HFimpEF (LVEF previously ≤40%). We evaluated all HF hospitalizations adjudicated by the clinical endpoints committee with available data for determination of in-hospital course. Complicated hospitalization was defined as any hospitalization requiring intensive care unit stay, intravenous vasopressors/inotropes/vasodilators, invasive or non-invasive ventilation, mechanical fluid removal, ultrafiltration, or mechanical circulatory support. LVEF changes were extracted using a validated GPT-3.5, a large language model, via a secure private endpoint. Of the 6263 patients enrolled in DELIVER, 1151 (18%) had HFimpEF. During a median follow-up of 2.3 years, there were 224 total HF hospitalizations in 144 patients with HFimpEF and 985 in 603 patients with LVEF consistently >40%. Patients with HFimpEF experienced higher rates of complicated HF hospitalization as compared with patients with LVEF consistently >40% (39% vs. 27%; p < 0.001). Among those who experienced a first HF hospitalization, there was no significant difference in length of stay or in-hospital mortality between patients with HFimpEF versus LVEF consistently >40%. In a subset of participants who had at least one LVEF measurement available during HF hospitalization, 66% of those with HFimpEF and 29% of patients with LVEF consistently >40% experienced a reduction in their LVEF to ≤40% from the time of enrolment (p < 0.001). In the entire DELIVER cohort, dapagliflozin reduced total uncomplicated and complicated HF hospitalizations, irrespective of HFimpEF status (p interaction ≥0.30)., Conclusions: Among patients hospitalized for HF in DELIVER, those with HFimpEF experienced a more adverse in-hospital clinical course, necessitating higher resource utilization beyond standard diuretic therapy compared with patients with HF and LVEF consistently >40%, but had similar in-hospital mortality. Treatment benefits of dapagliflozin were not modified by hospitalization type., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Cardiovascular-kidney-metabolic syndrome is an emerging entity that connects cardiovascular diseases, chronic kidney disease and diabetes. The non-steroidal mineralocorticoid receptor antagonist finerenone has been studied in three prospective randomized clinical trials of patients with cardiovascular-kidney-metabolic syndrome: FIDELIO-DKD, FIGARO-DKD and FINEARTS-HF. In light of the strong epidemiological overlap and shared mechanistic drivers of clinical outcomes across cardiovascular-kidney-metabolic syndrome, we summarize the efficacy and safety of finerenone on cardiovascular, kidney and mortality outcomes in this pre-specified participant-level pooled analysis. The three trials included 18,991 participants (mean age 67 ± 10 years; 35% women). During 2.9 years of median follow-up, the primary outcome of cardiovascular death occurred in 421 (4.4%) participants assigned to finerenone and 471 (5.0%) participants assigned to placebo (hazard ratio (HR): 0.89; 95% confidence interval (CI): 0.78-1.01; P = 0.076). Death from any cause occurred in 1,042 (11.0%) participants in the finerenone arm and in 1,136 (12.0%) participants in the placebo arm (HR: 0.91; 95% CI: 0.84-0.99; P = 0.027). Finerenone further reduced the risk of hospitalization from heart failure (HR: 0.83; 95% CI: 0.75-0.92; P < 0.001) and the composite kidney outcome (HR: 0.80; 95% CI: 0.72-0.90; P < 0.001). While in this pooled analysis the reduction in cardiovascular death was not statistically significant, finerenone reduced the risks for deaths of any cause, cardiovascular events and kidney outcomes. PROSPERO identifier: CRD42024570467 ., (© 2024. The Author(s).)

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that may emerge from overlapping systemic processes associated with comorbidities. We assessed whether unique clusters of circulating proteins are associated with specific clinical characteristics and functional status at baseline and follow-up in a well-phenotyped cohort of patients with HFpEF., Methods: We evaluated 368 proteins associated with cardiovascular disease and inflammation in prerandomization blood samples from 763 VITALITY-HFpEF (Vericiguat to Improve Physical Functioning in Daily Living Activities of Patients With HFpEF) participants who had a left ventricular ejection fraction ≥45% and a heart failure decompensation event within 6 months. Proteins were clustered, and their associations with clinical characteristics, baseline, and 24-week functional outcomes (Kansas City Cardiomyopathy Questionnaire Physical Limitation Score, 6-minute walk distance [6MWD], and Fried frailty phenotype) were estimated with linear regression. Elastic net regression was used to derive a proteomic summary composite to predict changes in 24-week functional outcomes., Results: Four unique protein clusters were identified, containing 24, 66, 197, and 81 proteins. At baseline, 2 protein clusters with the hub proteins caspase-3 and Dickkopf-related protein 1 were associated with increased frailty, whereas the cluster with tumor necrosis factor receptor 1 as a hub protein was associated with lower Kansas City Cardiomyopathy Questionnaire Physical Limitation Score and shorter 6MWD. By contrast, the cluster with protein C as a hub protein was associated with less frailty and longer a 6MWD. The 24-week increase in 6MWD was negatively correlated with the protein cluster with caspase-3; the protein C cluster was correlated with less frailty at 24 weeks. The baseline proteomic summary composite predicted observed changes in Kansas City Cardiomyopathy Questionnaire Physical Limitation Score and 6MWD at 24 weeks (r=0.42 and 0.30; P <0.001 for both)., Conclusions: Proteomics differentiate specific baseline functional traits associated with HFpEF and may facilitate phenotyping in a heterogeneous disease. These proteins also provide insights into the diverse pathophysiology of HFpEF and which patients may improve functional status during follow-up., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03547583., Competing Interests: Dr deFilippi has received research funding to Inova from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics and consults for FujiRebio, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics. Dr P. Shah received National Institutes of Health (NIH) K23 Career Development Award 1K23HL143179; related grant support paid to institution from Merck, Bayer, and Roche; unrelated grant support from Abbott; related consulting for Merck; and unrelated consulting for Procyrion. Dr S.J. Shah has received research grants from Actelion, Corvia, and NIH; consulting fees/honoraria from Abbott, Amgen, Aria, AstraZeneca, Axon, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cariora, Cardiovascular Systems Inc, Cyclerion, Cytokinetics, Eisai, ekoi.ai, GlaxoSmithKline, Imara, Ionis, Ironwood, Janssen, Keyto, Lilly Medical, MyoKardia, Novartis, Pfizer, Prothena, Regeneron, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr Lam has received research grants from Bayer, National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd, and corpus; and patent PCT/SG2016/050217 pending, a patent 16/216929 pending and cofounder and nonexecutive director of eKo.ai. Dr Butler is a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Pfizer, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, scPharmaceuticals, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Roessig is an employee of Bayer AG. Dr O’Connor received research funding from Merck and consulting fees from Bayer, Dey Pharma LP, and Bristol Myers Squibb Foundation. Dr Westerhout received consulting fees from Bayer. Dr Armstrong received consulting fees from Merck, Bayer, Boehringer Ingelheim, and Novo Nordisk and research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly, and CSL Limited. The other author reports no conflicts.

Aims: Renin-angiotensin system inhibitors (RASi) have been shown to lower haemoglobin levels, potentially related to reductions in erythropoietin levels and haematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anaemia in patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF)., Methods and Results: PARAGON-HF was a global, multicentre randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction ≥45%. We evaluated haemoglobin trajectory and risks of incident anaemia and new iron therapy initiation during follow-up. Among 4795 participants, 1111 (23.2%) had anaemia at randomization and 5.6% were treated with iron at baseline. Over a median follow-up of 2.9 years, patients with anaemia were at significantly higher risk for total HF hospitalizations and cardiovascular death, compared with those without anaemia (21.6 vs. 11.5 per 100 patient-years; adjusted rate ratio 1.31; 95% confidence interval [CI] 1.12-1.54; p = 0.001). Sacubitril/valsartan slightly slowed the decline in haemoglobin levels by 0.1 g/dl (95% CI 0.0-0.2 g/dl; p = 0.005). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anaemia (30.3% vs. 37.6%; hazard ratio [HR] 0.76; 95% CI 0.68-0.85; p < 0.001) and starting iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI 0.67-0.97; p = 0.026). Treatment effects of sacubitril/valsartan versus valsartan on total HF hospitalizations and cardiovascular death were consistent among patients across the haemoglobin spectrum (p interaction  = 0.60)., Conclusions: Among patients with HFmrEF/HFpEF, treatment with sacubitril/valsartan resulted in modestly smaller declines in haemoglobin, lower rates of incident anaemia, and fewer new initiations of iron therapy compared with RASi., Clinical Trial Registration: ClinicalTrials.gov ID NCT01920711., (© 2024 European Society of Cardiology.)

Background: Patients recently hospitalized for heart failure (HF) are at a higher risk of adverse clinical outcomes, but they may experience a greater absolute and relative benefit from effective therapies than individuals who are considered more "stable.", Objectives: The authors examined the effects of dapagliflozin according to the timing of prior HF hospitalization in a patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure)., Methods: A total of 11,007 patients were randomized in DAPA-HF and DELIVER. The primary outcome was the composite of worsening HF or cardiovascular death., Results: In total, 12.4% were hospitalized for HF within 3 months of randomization, 14.2% between 3 and 12 months, and 16.8% more than 1 year before randomization, whereas 56.5% had not been hospitalized. The risk of the primary endpoint was inversely associated with time from prior HF hospitalization, and patients with a recent HF hospitalization had the highest risk. Compared with placebo, dapagliflozin reduced the risk of the primary outcome across HF hospitalization category (0-3 months, HR: 0.66 [95% CI: 0.55-0.81]; 3-12 months, HR: 0.73 [95% CI: 0.59-0.90]; >1 year, HR: 0.91 [95% CI: 0.74-1.12]; and no prior hospitalization, HR: 0.83 [95% CI: 0.73-0.94]; P interaction  = 0.09). The number of patients needed to treat with dapagliflozin to prevent 1 event over the median follow-up of 22 months was 13, 20, 23, and 28, respectively. The beneficial effect was consistent across the range of LVEF regardless of HF hospitalization category., Conclusions: The relative benefits of dapagliflozin were consistent across the range of LVEF regardless of the timing of the most recent HF hospitalization with a greater absolute benefit in patients with recent hospitalization., Competing Interests: Funding Support and Author Disclosures The DAPA-HF and DELIVER trials were funded by AstraZeneca. Profs McMurray and Jhund 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 Butt has received Advisory Board honoraria from Bayer; has received consultant honoraria from Novartis and AstraZeneca; and has received travel grants from AstraZeneca. Dr Jhund’s employer the University of Glasgow has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials; he has received personal fees from Novartis and Cytokinetics, and has received grants from Boehringer Ingelheim. Dr Docherty has received honoraria from AstraZeneca; and has received a research grant to his institution from Boehringer Ingelheim. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr Vaduganathan has received research grant support, has served on Advisory Boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Bachus is an employee and shareholder of AstraZeneca. Dr Hernandez has received research support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Novartis, Novo Nordisk and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, GlaxoSmithKline, Myokardia, Merck, Novartis, Novo Nordisk, and Vifor. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and nonexecutive director of Us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck, Pfizer, and Bayer; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer’s institution has received research grants and fees (outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside of the submitted work). Dr Kosiborod has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an Advisory Board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received grants and personal fees from AstraZeneca during the conduct of the study; has received personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; has received grants and personal fees from Alnylam and Novartis; and has received personal fees from Amgen outside the submitted work. Dr Køber has received compensation from Novartis for other services; has received compensation from Novo Nordisk for other services; and has received compensation from AstraZeneca for other services. Dr Ponikowski has received compensation from AstraZeneca for consultant services; has received compensation from Boehringer Ingelheim for consultant services; has received compensation from Servier for consultant services; has received compensation from AstraZeneca for other services; has received compensation from Pfizer for other services; has received compensation from Amgen for consultant services; has received compensation from Vifor Pharma for consultant services; has received compensation from Novartis for other services; and has received compensation from Abbott Vascular for other services. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, IONIS, Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; and has received consulting honoraria for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk. 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, NovoNordisk, 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. 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 Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals & Pharma Ltd, Lupin Pharma, Medscape/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 Ltd., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The primary aim was to evaluate the effect of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction (LVEF), given that prolongation of QRS duration is associated with less favourable ventricular remodelling with pharmacological therapy and worse outcomes., Methods and Results: A pooled analysis of the DAPA-HF and DELIVER trials, excluding patients with a paced rhythm and cardiac resynchronization therapy. Overall, 4008 patients had heart failure (HF) with reduced ejection fraction (HFrEF), and 5816 had HF with mildly reduced/preserved ejection fraction (HFmrEF/HFpEF). QRS duration was <120 ms in 7039 patients (71.7%), 120-149 ms in 1725 (17.6%), and ≥150 ms in 1060 patients (10.8%). The median follow-up time was 23 months. The rate of the primary composite outcome of cardiovascular death or worsening HF was 9.2 (95% confidence interval [CI] 8.7-9.7), 14.3 (13.0-15.7), and 15.9 (14.1-17.9) per 100 patient-years in the <120, 120-149, and ≥150 ms groups, respectively. This gradient in event rates was observed both in HFrEF and HFmrEF/HFpEF. Dapagliflozin, compared with placebo, reduced the risk of the primary outcome consistently across the QRS duration subgroups (hazard ratio [95% CI] 0.75 [0.67-0.85], 0.79 [0.65-0.96], and 0.89 [0.70-1.13] in the <120, 120-149, and ≥150 ms groups, respectively; p for interaction = 0.28). The effect of dapagliflozin on the primary outcome was consistent across the QRS duration regardless of HF phenotype that is, HFrEF or HFmrEF/HFpEF., Conclusions: Prolongation of QRS duration is associated with worse outcomes irrespective of HF phenotype. Dapagliflozin reduced the risk of the primary outcome, regardless of QRS duration, in DAPA-HF and DELIVER., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Competing Interests: Disclosures RA reports receiving grants from the Bristol Myers Squibb Pfizer alliance, serving as a consultant for Lexicon Pharmaceuticals and an unpaid research collaboration with Novartis, all outside the submitted work. BLC reports personal fees from Alnylam, personal fees from Cardior, Cardurion, Corvia, Cytokinetics, CVRx, Intellia, and Rocket, outside the submitted work. ASD 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. PSJ reports receiving speaker fees from Novartis and AstraZeneca, Alkem metabolomics, Sun Pharmaceuticals and ProAdWise Communications and his employer, University of Glasgow has been paid for his time working on clinical trials by Novartis, AstraZeneca, Bayer and NovoNordisk, and grants from Analog Devices Inc, Boehringer Ingelheim, and Roche Diagnostics outside the submitted work, Director GCTP Ltd. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics, has served as consultant to or on the advisory board/steering committee/ executive committee for 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, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai, and serves as cofounder and nonexecutive director of Us2.ai. BP has served as a consultant for Bayer, AstraZeneca, Bristol Meyers Squibb, Boehringer Ingelheim, Lexicon, Anacardia, and G3 Pharmaceuticvals and 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). MS reports personal fees from Novartis, Bayer, Vifor, Abbott, AstraZeneca, Merck, Boehringer Ingelheim, Novo Nordisk, MSD, and Cardurion outside the submitted work. SJS reports personal fees from Bayer during the conduct of the study. The employer of AAV 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, SalubrisBio. FZ reports steering committee fees during the conduct of the study, personal fees from Boehringer, BMS, CVRx, Cardior, Cereno, Cellprothera, Merck, Owkin, Roche, and Northsea outside the submitted work and stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, Eshmoun Clinical and is a researchr and founder of CVCT. JL-F is a full-time employee of Bayer and reports personal fees from Bayer outside the submitted work. PV reports that he is a full-time employee of Bayer Pharmaceuticals. JJVM reports payments to his employer, Glasgow University, from Bayer, time spent as coprincipal investigator of the FINEARTS trial with finerenone; other fees from AstraZeneca, Amgen, Cardurion, Cytokinetics, Glaxo Smith Kline, KBP Biosciences, Novartis, and personal fees from George Clinical PTY, Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, Translational Medicine Academy, Global Clinical Trial Partners , Alnylam Pharmaceuticals, Bayer, BMS, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal outside the submitted work. SDS has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Eli 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. MV 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, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health and participates in clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. JWO has nothing to disclose.

Background: Guideline-directed medical therapy (GDMT) decisions may be less affected by single patient variables such as blood pressure or kidney function and more by overall risk profile. In STRONG-HF (Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure), high-intensity care (HIC) in the form of rapid uptitration of heart failure (HF) GDMT was effective overall, but the safety, tolerability and efficacy of HIC across the spectrum of HF severity is unknown. Evaluating this with a simple risk-based framework offers an alternative and more clinically translatable approach than traditional subgroup analyses., Objectives: The authors sought to assess safety, tolerability, and efficacy of HIC according to the simple, powerful, and clinically translatable MAGGIC (Meta-Analysis Global Group in Chronic) HF risk score., Methods: In STRONG-HF, 1,078 patients with acute HF were randomized to HIC (uptitration of treatments to 100% of recommended doses within 2 weeks of discharge and 4 scheduled outpatient visits over the 2 months after discharge) vs usual care (UC). The primary endpoint was the composite of all-cause death or first HF rehospitalization at day 180. Baseline HF risk profile was determined by the previously validated MAGGIC risk score. Treatment effect was stratified according to MAGGIC risk score both as a categorical and continuous variable., Results: Among 1,062 patients (98.5%) with complete data for whom a MAGGIC score could be calculated at baseline, GDMT use at baseline was similar across MAGGIC tertiles. Overall GDMT prescriptions achieved for individual medication classes were higher in the HIC vs UC group and did not differ by MAGGIC risk score tertiles (interaction nonsignificant). The incidence of all-cause death or HF readmission at day 180 was, respectively, 16.3%, 18.9%, and 23.2% for MAGGIC risk score tertiles 1, 2, and 3. The HIC arm was at lower risk of all-cause death or HF readmission at day 180 (HR: 0.66; 95% CI: 0.50-0.86) and this finding was robust across MAGGIC risk score modeled as a categorical (HR: 0.51; 95% CI: 0.62-0.68 in tertiles 1, 2, and 3; interaction nonsignificant) for all comparisons and continuous (interaction nonsignificant) variable. The rate of adverse events was higher in the HIC group, but this observation did not differ based on MAGGIC risk score tertile (interaction nonsignificant)., Conclusions: HIC led to better use of GDMT and lower HF-related morbidity and mortality compared with UC, regardless of the underlying HF risk profile. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies [STRONG-HF]; NCT03412201)., Competing Interests: Funding Support and Author Disclosures Funding for the STRONG-HF study was through an unrestricted grant provided to the Heart Initiative by Roche Diagnostics International (Rotkreuz, Switzerland). The funder had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the manuscript for publication. Dr Ambrosy has received relevant research support through grants to his institution from the National Heart, Lung, and Blood Institute (K23HL150159), the American Heart Association (2nd Century Early Faculty Independence Award), The Permanente Medical Group, Northern California Community Benefits Programs, Garfield Memorial Fund, Abbott Laboratories, Amarin Pharma, Inc, Edwards Lifesciences LLC, Esperion Therapeutics, Inc, and Novartis. Dr Mebazaa has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and Merck Sharp & Dohme; is a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is coinventor of a patent on combination therapy for patients having acute or persistent dyspnoea. Drs Cotter, Davison, Edwards, Mebazaa, Novosadova, and Takagi are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Drs Cotter and Davison are directors of Heart Initiative, a nonprofit organization. Dr Adamo has received speaker fees from Abbott Vascular and Medtronic. Dr Celutkiene has received personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, and Pfizer. Dr Chioncel has received grants from Servier. Dr Cohen-Solal has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. Dr Damasceno works for the Faculty of Medicine, Eduardo Mondlane University (Maputo, Mozambique), which received research grants from the Heart Initiative for their participation in this study. Dr Diaz has received supporting fees for coordination of STRONG-HF trial activities. Dr Filippatos has received lecture fees or was a committee member for trials and registries sponsored by Bayer, Vifor, Boehringer Ingelheim, Medtronic, Servier, and Amgen. Dr Sliwa has received grants from Medtronic, Servier, and Amylam and honoraria from Merck Sharp & Dohme, Novartis, and Sanofi. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/ Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Redcardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as co-founder and nonexecutive director of Us2.ai. Dr Metra has received personal fees from Amgen, Livanova, and Vifor Pharma as a member of executive committees of sponsored clinical trials and from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Roche Diagnostics for participation to advisory boards or for speaking at sponsored meetings. Dr Pagnesi has received personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, and Vifor Pharma. Dr Pang has received grants or research contracts from American Heart Association, Roche, Siemens, Ortho Diagnostics, Abbott, Beckman Coulter, and Siemens; consulting fees from Roche; honoraria from WebMD; and he has financial interest in The Heart Course. Dr Voors has received consultancy fees or research support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Filippatos has received lecture fees and/or advisory and/or trial committee membership by Bayer, Boehringer Ingelheim, Servier, Novartis, Impulse Dynamics, Vifor, Medtronic, Cardior, Novo Nordisc and Research Grants from the European Union. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: In the absence of randomized trial evidence, we performed a large observational analysis of the association between beta-blocker (BB) use and clinical outcomes in patients with heart failure (HF) and mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF)., Methods and Results: We pooled individual patient data from four large HFmrEF/HFpEF trials (I-Preserve, TOPCAT, PARAGON-HF, and DELIVER). The primary outcome was the composite of cardiovascular death or HF hospitalization. Among the 16 951 patients included, the mean left ventricular ejection fraction (LVEF) was 56.8%, and 13 400 (79.1%) had HFpEF (LVEF ≥50%). Overall, 12 812 patients (75.6%) received a BB. The median bisoprolol-equivalent dose of BB was 5.0 (Q1-Q3: 2.5-5.0) mg with BB continuation rates of 93.1% at 2 years (in survivors). The unadjusted hazard ratio (HR) for the primary outcome did not differ between BB users and non-users (HR 0.98, 95% confidence interval [CI] 0.91-1.05), but the adjusted HR was lower in BB users than non-users (0.81, 95% CI 0.74-0.88), and this association was maintained across LVEF (p interaction  = 0.88). In subgroup analyses, the adjusted risk of the primary outcome was similar in BB users and non-users with or without a history of myocardial infarction, hypertension, or a baseline heart rate <70 bpm. By contrast, a better outcome with BB use was seen in patients with atrial fibrillation compared to those without atrial fibrillation (p intreraction  = 0.02)., Conclusions: In this observational analysis of non-randomized BB treatment, there was no suggestion that BB use was associated with worse HF outcomes in HFmrEF/HFpEF, even after extensive adjustment for other prognostic variables., (© 2024 European Society of Cardiology.)

Aims: Although the prevalence of heart failure (HF) increases markedly with advancing age, surprisingly little is known about HF in the very elderly. The aim of this study was to describe the clinical characteristics and outcomes of octogenarians with HF., Methods and Results: Individual participant meta-analysis of patients with HF and reduced, mildly reduced, and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF, respectively) enrolled in eight large randomized trials. Overall, the proportion of octogenarians was 1518 of 20 168 patients (7.5%) with HFrEF, 610 of 4609 (13.2%) with HFmrEF, and 3130 of 15 354 (20.4%) with HFpEF. Regardless of HF phenotype, octogenarian patients were more often female and had more comorbidities, more symptoms and signs of congestion, and worse health status (but not quality of life), in comparison to patients aged <80 years. The incidence (per 100 person-years) of the composite of cardiovascular death or HF hospitalization was 13.3 (95% confidence interval [CI] 12.7-14.0) in octogenarians versus 9.5 (95% CI 9.3-9.7) in non-octogenarians (adjusted hazard ratio [aHR] 1.40, 95% CI 1.32-1.48). Each component of the composite was more frequent in octogenarians with rates of cardiovascular mortality of 7.0 (95% CI 6.5-7.4) per 100 person-years versus 4.9 (95% CI 4.8-5.1) in non-octogenarians (aHR 1.60, 95% CI 1.48-1.72, p < 0.001). Octogenarians received less evidence-based therapy, especially mineralocorticoid receptor antagonists, than younger patients., Conclusion: Despite worse health status and higher hospitalization and mortality rates, octogenarians were undertreated compared to younger patients., (© 2024 European Society of Cardiology.)

Background: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension., Methods: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline., Results: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P =0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P =0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group., Conclusions: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points., Registration: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595., Competing Interests: Dr Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, AOP Health, Bayer, Ferrer, GossamerBio, Janssen, Keros, and MSD. Max Wissmüller has received lecture fees from Janssen. Hanno Leuchte has received fees for consultations and/or lectures from Acceleron, Jansse-Cilag, Bayer, Boehringer-Ingelheim, Ferrer, MSD, and Pfizer. Michael Halank has received fees for lectures and/or consultations from AstraZeneca, Janssen-Cilag, and MSD. In addition, he has received support for attending meetings and/or travel from AOP Health and Janssen-Cilag. Hans-Jürgen Seyfarth has received fees for lectures and/or consultations from Janssen-Cilag and MSD. Stephan Baldus has received fees for lectures and/or consultations from Abbott, Edwards, Jenavalve, AstraZeneca, Bayer, Daiicho Sankyo, and Amgen, as well as research grants from Abbott, AstraZeneca, and Daiichi Sankyo. Johann Bauersachs has received fees for lectures and/or consultations from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cardior, Corvia, CVRx, Edwards, Norgine, Novartis, Pfizer, Roche and Vifor. In addition, institutional grants have been provided by Abiomed, CVRx, Norgine, Roche, and Zoll. He holds patents for microRNA and downstream targets for diagnostics and therapeutic purposes (PCT/EP2007/008772 and PCT/EP2009/051986). Michael Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor, Servier and Vifor. Hossein-Ardeschir Ghofrani has received honoraria for consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly, and Novartis. He is member of the Advisory Board for Acceleron, Bayer HealthCare AG, Pfizer, GSK, Actelion, Lilly, Merck, Encysive, and Ergonex. He has also received governmental grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, State Government of Hessen, and the German Ministry for Education and Research. Stavros Konstantinides reports personal lecture/advisory fees and research grants to his institution from Bayer AG, Boston Scientific, Daiichi-Sankyo, LumiraDx, and Penumbra, as well as personal lecture/advisory fees from MSD and Pfizer–Bristol-Myers Squibb. Karen M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, Ferrer, GSK, Janssen, MSD, Pfizer, and United Therapeutics. Rolf Wachter has received fees for lectures and/or consultation from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Medtronic, Novartis, Pfizer, Pharmacosmo, Sciarc, Servier, and Vifor. His institution has received research grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Union, and Medtronic. Carolyn S.P. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corp, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and non–executive director of Us2.ai. Stephan Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Aerovate, AOP, AstraZeneca, Bayer, Boehringer-Ingelheim, Edwards, Ferrer, Gossamer, Janssen, MSD, and United Therapeutics. His institution has received research grants from Actelion, AstraZeneca, Bayer, Janssen, and Lempo. The other authors report no conflicts.

Direct oral anticoagulants have a dose-dependent increased bleeding risk which limits use in certain populations. Studies in both animals and humans with inherited variations in factor XI levels provide a theoretical basis for a drug target capable of addressing current unmet needs. Milvexian is an oral factor XIa inhibitor that has the potential to provide robust anticoagulant effect without increased bleeding compared with current standard of care. Several key studies in the preclinical, phase I, and phase II stages have reported promising safety data in venous thromboembolism and stroke prevention without compromising hemostasis. The planned phase III trials will examine the efficacy of milvexian for prevention of thrombotic events in patients with acute stroke, acute coronary syndrome, and atrial fibrillation., (© 2024. The Author(s).)

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and has a prevalence that is expected to rise with the growing ageing population. HFpEF is associated with significant morbidity and mortality. Specific HFpEF risk factors include age, diabetes, hypertension, obesity and atrial fibrillation. Haemodynamic contributions to HFpEF include changes in left ventricular structure, diastolic and systolic dysfunction, left atrial myopathy, pulmonary hypertension, right ventricular dysfunction, chronotropic incompetence, and vascular dysfunction. Inflammation, fibrosis, impaired nitric oxide signalling, sarcomere dysfunction, and mitochondrial and metabolic defects contribute to the cellular and molecular changes observed in HFpEF. HFpEF impacts multiple organ systems beyond the heart, including the skeletal muscle, peripheral vasculature, lungs, kidneys and brain. The diagnosis of HFpEF can be made in individuals with signs and symptoms of heart failure with abnormality in natriuretic peptide levels or evidence of cardiopulmonary congestion, facilitated by the use of HFpEF risk scores and additional imaging and testing with the exclusion of HFpEF mimics. Management includes initiation of guideline-directed medical therapy and management of comorbidities. Given the significant impact of HFpEF on quality of life, future research efforts should include a particular focus on how patients can live better with this disease., (© 2024. Springer Nature Limited.)

Aims: We investigated the prevalence, clinical characteristics, and prognosis of patients with heart failure (HF) with improved ejection fraction (HFimpEF)., Methods and Results: We used data from BIOSTAT-CHF including patients with a left ventricular ejection fraction (LVEF) ≤40% at baseline who had LVEF re-assessed at 9 months. HFimpEF was defined as a LVEF >40% and a LVEF ≥10% increase from baseline at 9 months. We validated findings in the ASIAN-HF registry. The primary outcome was a composite of time to HF rehospitalization or all-cause mortality. In BIOSTAT-CHF, about 20% of patients developed HFimpEF, that was associated with a lower primary event rate of all-cause mortality (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.28-0.97, p = 0.040) and the composite endpoint (HR 0.46, 95% CI 0.30-0.70, p < 0.001) compared with patients who remained in persistent HF with reduced ejection fraction (HFrEF). The findings were similar in the ASIAN-HF (HR 0.40, 95% CI 0.18-0.89, p = 0.024, and HR 0.29, 95% CI 0.17-0.48, p < 0.001). Five independently common predictors for HFimpEF in both BIOSTAT-CHF and ASIAN-HF were female sex, absence of ischaemic heart disease, higher LVEF, smaller left ventricular end-diastolic and end-systolic diameter at baseline. A predictive model combining only five predictors (absence of ischaemic heart disease and left bundle branch block, smaller left ventricular end-systolic and left atrial diameter, and higher platelet count) for HFimpEF in the BIOSTAT-CHF achieved an area under the curve of 0.772 and 0.688 in the ASIAN-HF (due to missing left atrial diameter and platelet count)., Conclusions: Approximately 20-30% of patients with HFrEF improved to HFimpEF within 1 year with better clinical outcomes. In addition, the predictive model with clinical predictors could more accurately predict HFimpEF in patients with HFrEF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Considering the high prevalence of mitral regurgitation (MR) and the highly subjective, variable MR severity reporting, an automated tool that could screen patients for clinically significant MR (≥ moderate) would streamline the diagnostic/therapeutic pathways and ultimately improve patient outcomes., Objectives: The authors aimed to develop and validate a fully automated machine learning (ML)-based echocardiography workflow for grading MR severity., Methods: ML algorithms were trained on echocardiograms from 2 observational cohorts and validated in patients from 2 additional independent studies. Multiparametric echocardiography core laboratory MR assessment served as ground truth. The machine was trained to measure 16 MR-related parameters. Multiple ML models were developed to find the optimal parameters and preferred ML model for MR severity grading., Results: The preferred ML model used 9 parameters. Image analysis was feasible in 99.3% of cases and took 80 ± 5 seconds per case. The accuracy for grading MR severity (none to severe) was 0.80, and for significant (moderate or severe) vs nonsignificant MR was 0.97 with a sensitivity of 0.96 and specificity of 0.98. The model performed similarly in cases of eccentric and central MR. Patients graded as having severe MR had higher 1-year mortality (adjusted HR: 5.20 [95% CI: 1.24-21.9]; P = 0.025 compared with mild)., Conclusions: An automated multiparametric ML model for grading MR severity is feasible, fast, highly accurate, and predicts 1-year mortality. Its implementation in clinical practice could improve patient care by facilitating referral to specialized clinics and access to evidence-based therapies while improving quality and efficiency in the echocardiography laboratory., Competing Interests: Funding Support and Author Disclosures Mr Jiang is an employee of Us2.ai. Mr Hummel is an employee of Us2.ai. Mr Frost is an employee of Us2.ai. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, 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; has served as cofounder and non-executive director of Us2.ai; has a patent pending (PCT/SG2016/050217; Method for diagnosis and prognosis of chronic heart failure); and holds U.S. Patent No. 10,702,247 for 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 Shah is supported by grants from the U.S. National Institutes of Health (National Heart, Lung, and Blood Institute; U54 HL160273, R01 HL140731, and R01 HL149423), AstraZeneca, Corvia Medical, and Pfizer; and has received consulting fees from Abbott, AstraZeneca, Alleviant, 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, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, Ultromics, and United Therapeutics. Dr Lund is supported by Karolinska Institutet, the Swedish Research Council (grant 523-2014-2336), the Swedish Heart Lung Foundation (grants 20150557, 20190310), and the Stockholm County Council (grants 20170112, 20190525); and unrelated to the present work, Dr Lund has received grants, consulting, and honoraria from Abbot, Alleviant, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Edwards, Merck/Merck Sharp & Dohme, Novartis, Novo Nordisk, Owkin, Pharmacosmos, Vifor Pharma; and has stock ownership in AnaCardio. Dr Stone has received Speaker or other honoraria from Cook, Terumo, QOOL Therapeutics, and Orchestra Biomed; is a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, Cardiomech; and has equity/options from Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix. Dr Swaminathan has received consulting fees from US2.ai. Dr Weissman is the Associate Director of an academic core laboratory with research institutional grants/agreements (MedStar Health) with Us2.ai, Ultromics, TOMTEC, GE, Caption Health, egnite, Abbott, Edwards, Medtronic, Boston Scientific, Corcym, Ancora Heart, Neovasc, InnovHeart, and Polares Medical. Dr Asch is the director of an academic core laboratory with research institutional grants/agreements (MedStar Health) with Us2.ai, Ultromics, TOMTEC, GE, Caption Health, egnite, Abbott, Edwards, Medtronic, Boston Scientific, Corcym, Ancora Heart, Neovasc, InnovHeart, Polares Medical, and Foldax; and is on the Scientific Advisory Board (unpaid) for Us2.ai, Ultromics, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Persons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown., Methods: In this prespecified subgroup analysis of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) trial, 685 participants with asymptomatic DbCM underwent baseline echocardiography data, laboratory investigations, and functional assessments. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test., Results: The median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/E', or right ventricular systolic pressure. In contrast, NT-proBNP was significantly correlated with overall Kansas City Cardiomyopathy Questionnaire score (rho = - 0.10; p = 0.007), the Physical Activity Scale in the Elderly (rho = - 0.12; p = 0.004), duration of cardiopulmonary exercise testing (rho = - 0.28; p < 0.001), peak VO 2 (rho = - 0.26; p < 0.001), and ratio of minute ventilation/carbon dioxide production (rho = 0.12; p = 0.002). After adjustment for known confounders, the correlation with Physical Activity Scale in the Elderly and overall Kansas City Cardiomyopathy Questionnaire score was no longer significant., Conclusion: Among patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals., Trial Registration: ARISE-HF, NCT04083339 Date Registered August 23, 2019., (© 2024. The Author(s).)

Aims: Compared to heart failure (HF) with reduced ejection fraction, HF with preserved ejection fraction (HFpEF), and HF with mildly reduced ejection fraction (HFmrEF) are increasing in prevalence, yet little is known about the geographic variation in patient characteristics, treatments and outcomes among these two HF phenotypes. The aim of this study was to investigate geographic differences in HFpEF and HFmrEF., Methods and Results: We conducted an individual patient analysis of five clinical trials enrolling patients with HFpEF or HFmrEF from North America (NA), Latin America (LA), Western Europe (WE), Central/Eastern Europe and Russia (CEER), and Asia-Pacific (AP). We compared regions using descriptive statistics and multivariable regression models. Among the 19 959 patients included, 4066 (23.1%) had HFmrEF and 15 353 (76.9%) HFpEF. Regardless of HF phenotype, patients from WE were oldest, and those in CEER youngest. LA had the largest portion of females and NA most black patients. Obesity and diabetes were most prevalent in NA and hypertension and coronary heart disease most common in CEER. Self-reported health status varied strikingly and was the worst in NA and best in AP. Among patients with HFmrEF, rates of the primary composite endpoint (cardiovascular death or HF hospitalization) were: NA 12.56 per 100 patient-years (/100py), AP 11.67/100py, CEER 10.12/100py, LA 8.90/100py, and WE 8.43/100py, driven by differences in the rate of HF hospitalization. The corresponding values in HFpEF were 11.47/100py, 7.80/100py, 5.47/100py, 5.92/100py, and 7.80/100py, respectively., Conclusions: There is substantial geographic variation in patient characteristics, treatment and outcomes among patients with HFpEF and HFmrEF. These findings have implications for interpretation and generalizability of trial results, design and conduct of future trials, and optimization of care for these patients., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)