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Background: Optimal medical therapy (OMT) scoring may stratify clinical risk in real-world chronic heart failure with reduced ejection fraction (HFrEF) by integrating use and dosing of guideline-directed medical therapy (GDMT) for HFrEF., Objectives: The purpose of this study was to characterize patients and associated long-term clinical outcomes by OMT score-derived treatment groups., Methods: CHAMP-HF (Change the Management of Patients with Heart Failure) included U.S. outpatients with chronic HFrEF receiving ≥1 GDMT. OMT subgroups were defined as suboptimal (score <3), acceptable (score = 3), and optimal (score ≥4) by baseline use and dose of GDMT, as proposed by the HF Collaboratory consortium. Cox proportional hazard analyses were used to assess for all-cause and cardiovascular death across subgroups, after adjusting for demographic and clinical covariates., Results: The authors studied 4,582 participants enrolled in CHAMP-HF with available 2-year follow-up. Median age was 68 years, 1,327 (29%) were women, and 2,842 (62%) were White, non-Hispanic. Median OMT score across the population was 4 (Q1-Q3: 2-5), and 1,628 (35%) had suboptimal, 665 (14%) had acceptable, and 2,289 (50%) had optimal therapy. Participants with optimal treatment were younger, had higher annual household income, and were enrolled from practices with dedicated HF clinics (all P < 0.001) than participants with acceptable or suboptimal treatment. Participants with optimal treatment had lower all-cause death (adjusted HR: 0.77; 95% CI: 0.64-0.92) and cardiovascular death (adjusted HR: 0.79; 95% CI: 0.65-0.96) than those with suboptimal treatment., Conclusions: Across a large cohort of chronic ambulatory HFrEF, OMT scores stratified risk of all-cause and cardiovascular death., Competing Interests: Funding Support and Author Disclosures CHAMP-HF was supported by Novartis Pharmaceuticals. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Rao has received salary support by a National Institutes of Health training grant (5T32HL069749-18). Dr Spertus has provided consultative services on patient-reported outcomes and evidence evaluation to Abbott, Alnylam, AstraZeneca, Bayer, Janssen, Bristol Meyers Squibb, Edwards, Terumo, Cytokinetics, and Imbria; holds research grants from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the American College of Cardiology Foundation, Bristol Meyers Squibb, Cytokinetics, Imbria, and Janssen; owns the copyright to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire; and serves on the Board of Directors for Blue Cross Blue Shield of Kansas City. Dr Butler is a consultant to 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, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr DeVore has received research funding through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent Inc, the National Heart, Lung, and Blood Institute, Novartis, and PCORI; he provides consulting services for Amgen, AstraZeneca, Bayer, CareDx, InnaMed, LivaNova, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, Story Health, and Zoll; and has received nonfinancial support from Abbott for educational activities. 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: 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.)

Background: In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction., Objectives: This study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization., Methods: The treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro-B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported., Results: There were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro-B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo., Conclusions: Additional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures The VICTORIA trial was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Company, Inc, and Bayer AG. Dr Mentz has received research support and honoraria from Bayer and Merck Sharp & Dohme Corporation, a subsidiary of Merck & Company, Inc. 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 Chiang has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, and Sanofi. Dr Ezekowitz has received research grants and consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and received honoraria from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr Hilkert is an employee of Merck & Company, Inc. Dr Lam has received research grants from Bayer, the 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, and Radcliffe Group Ltd, Corpus; has a patent pending (PCT/SG2016/050217 & 16/216929); and is a co-founder and nonexecutive director of eKo.ai. Dr O’Connor has received research funding from Merck and consulting fees from Bayer, Dey LP, and the Bristol Myers Squibb Foundation. Dr Pieske has received research support from Boston Scientific and honoraria from Bayer, MSD, Novartis, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, BMS, Edwards Lifesciences, and Boston Scientific. Dr Ponikowski has received research grants, consulting fees, and Speakers Bureau for Bayer, MSD, Servier, Novartis, Vifor Pharma Ltd, BMS, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuard Solutions, and Berlin-Chemie. Dr Roessig is an employee of Bayer AG. Dr Voors has received research support and honoraria from AstraZeneca, BMS, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Anstrom has received research grants from Merck and the National Institutes of Health. Dr Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche & Développement, Boehringer Ingelheim, and CSL Limited; and has received consulting fees from Merck, Bayer, AstraZeneca, and Novartis. 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: Although beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF., Objectives: This study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF., Methods: In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction (LVEF) >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF., Results: Overall, beta-blockers were used in 5,177 patients (83%), with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR: 0.70; 95% CI: 0.60-0.83). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR: 0.82; 95% CI: 0.72-0.94) and in patients not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03; P interaction  = 0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use., Conclusions: In patients with HFmrEF or HFpEF who were enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DELIVER trial was funded by AstraZeneca. Dr Peikert has received a research grant from the German Research Foundation. Dr Bart has received research grant support (paid to institution) from AstraZeneca, Cardurion, and Daxor; and has participated in clinical trial committees for studies sponsored by Daxor and Nuwellis. Dr Vaduganathan has received research grant support, 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 Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, and Rocket. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35 Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received institutional research grants from Abbott, AstraZeneca, Alnylam, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, AstraZeneca, Alnylam, Avidity, Axon Therapeutics, Bayer, Biofourmis, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, River2Renal, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; has received personal fees from Roche and Intas Pharma; has served as Director of Global Clinical Trial Partners (GCTP); and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Lam has received supported from 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, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and us2.ai; and has served as 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, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic 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, Eidos, Intercept, Merck, and Novartis. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Eli Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Petersson is an employee and shareholder of AstraZeneca. Dr Langkilde is an employee and shareholder of AstraZeneca. 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 consulting fees from Alnylam Pharma, Bayer, Bristol-Myers Squibb, George Clinical PTY, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals and Pharma, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, Translational Medicine Academy; and has served as a director of Global Clinical Trial Partners. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli 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 served as a consultant for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. Dr Vardeny has received research support from AstraZeneca, Bayer, and Cardurion; and has received personal consulting fees from Cardior. Mr Kulac has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cardio-renal-metabolic (CRM) conditions are individually common among patients with heart failure (HF), but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied., Objectives: This study aims to evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF., Methods: In this post hoc analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status., Results: Among 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher body mass index, longer-duration HF, worse health status, and lower left ventricular ejection fraction. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR: 2.16 [95% CI: 1.72-2.72]; P < 0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (P interaction  = 0.773) and by the number of CRM conditions (P interaction  = 0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated 2-year numbers needed to treat with dapagliflozin to prevent 1 primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum., Conclusions: CRM multimorbidity was common and associated with adverse outcomes among patients with HF and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin was safe and effective across the CRM spectrum, with greater absolute benefits among those with highest CRM overlap (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures DELIVER was sponsored by AstraZeneca. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr Desai has received institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Regeneron, River2Renal Roche, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk; and is the Director of Global Clinical Trial Partners (GCTP). Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; and has received consulting fees from Alnylam, AstraZeneca, Amgen, Bayer, Boehringer-Ingelheim, Cytokinetics, Esperion, Eli Lilly, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Pharmacosmos, Novo Nordisk, Sanofi, and Vifor. Dr Lam has received support from 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 and 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 Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grant support from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche; and has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. Dr Hernandez has received research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic; and has received verily consulting fees from Amgen, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Cytokinetics, Merck, Novartis, and NovoNordisk. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. Drs Petersson and Langkilde are employees of AstraZeneca. Dr McMurray has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca. 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, CellProThera, Moderna, American Regent, and Sarepta. Dr Vaduganathan has received research grant support, 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. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure (HF) have a high burden of multimorbidity, often necessitating numerous medications. There may be clinical concern about introducing another medication, especially among individuals with polypharmacy., Objectives: This study examined the efficacy and safety of addition of dapagliflozin according to the number of concomitant medications in HF with mildly reduced or preserved ejection fraction., Methods: In this post hoc analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, 6,263 participants with symptomatic HF with left ventricular ejection fraction >40% were randomized to dapagliflozin or placebo. Baseline medication use (including vitamins and supplements) was collected. Efficacy and safety outcomes were assessed by medication use categories ("nonpolypharmacy": <5 medications; "polypharmacy": 5 to 9 medications; and "hyperpolypharmacy": ≥10 medications) and continuously. The primary outcome was worsening HF or cardiovascular death., Results: Overall, 3,795 (60.6%) patients met polypharmacy and 1,886 (30.1%) met hyperpolypharmacy criteria. Higher numbers of medications were strongly associated with higher comorbidity burden and increased rates of the primary outcome. Compared with placebo, dapagliflozin similarly reduced the risk of the primary outcome irrespective of polypharmacy status (nonpolypharmacy HR: 0.88 [95% CI: 0.58-1.34]; polypharmacy HR: 0.88 [95% CI: 0.75-1.03]; hyperpolypharmacy HR: 0.73 [95% CI: 0.60-0.88]; P interaction  = 0.30). Similarly, benefits with dapagliflozin were consistent across the spectrum of total medication use (P interaction  = 0.06). Although adverse events increased with higher number of medications, they were not more frequent with dapagliflozin, regardless of polypharmacy status., Conclusions: In the DELIVER trial, dapagliflozin safely reduced worsening HF or cardiovascular death across a broad range of baseline medication use, including among individuals with polypharmacy (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding support and author disclosures The DELIVER trial was funded by AstraZeneca. Dr Peikert has received a research grant from the German Research Foundation. Dr Goyal has received consulting fees from Sensorum Health. Dr Vaduganathan has received research grant support; has served on advisory boards or has 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 Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, and Intellia, Rocket. Dr Vardeny has received institutional research support from AstraZeneca, Bayer, and Cardurion; and has served as a consultant or advisory board member for AstraZeneca, Cardior, Cytokinetics, and Sanofi-Pasteur. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35 Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received institutional research grants from Abbott, AstraZeneca, Alnylam, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, AstraZeneca, Alnylam, Avidity, Axon Therapeutics, Bayer, Biofourmis, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, River2Renal, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; and personal fees from Roche and Intas Pharma; has served as Director of Global Clinical Trial Partners (GCTP); and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk. 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 and 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 has served as 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, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic 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, Eidos, Intercept, Merck, and Novartis. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Eli Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Drs Petersson and Langkilde are employees and shareholders of AstraZeneca. Dr McMurray has received 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, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; personal lecture fees from 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, Translational Medicine Academy; and he is a director of Global Clinical Trial Partners Ltd. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, 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, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Background: Initiation of evidence-based medications for patients with heart failure with reduced ejection fraction (HFrEF) during hospitalization in contemporary practice is unknown., Objectives: This study characterized opportunities for and achievement of heart failure (HF) medication initiation., Methods: Using the GWTG-HF (Get With The Guidelines-Heart Failure) Registry 2017-2020, which collected data on contraindications and prescribing for 7 evidence-based HF-related medications, we assessed the number of medications for which each patient with HFrEF was eligible, use before admission, and prescribed at discharge. Multivariable logistic regression identified factors associated with medication initiation., Results: Among 50,170 patients from 160 sites, patients were eligible for mean number of 3.9 ± 1.1 evidence-based medications with 2.1 ± 1.3 used before admission and 3.0 ± 1.0 prescribed on discharge. The number of patients receiving all indicated medications increased from admission (14.9%) to discharge (32.8%), a mean net gain of 0.9 ± 1.3 medications over a mean of 5.6 ± 5.3 days. In multivariable analysis, factors associated with lower odds of HF medication initiation included older age, female sex, medical pre-existing conditions (stroke, peripheral arterial disease, pulmonary disease, and renal insufficiency), and rural location. Odds of medication initiation increased during the study period (adjusted OR: 1.08; 95% CI: 1.06-1.10)., Conclusions: Nearly 1 in 6 patients received all indicated HF-related medications on admission, increasing to 1 in 3 on discharge with an average of 1 new medication initiation. Opportunities to initiate evidence-based medications persist, particularly among women, those with comorbidities, and those receiving care at rural hospitals., Competing Interests: Funding Support and Author Disclosures Dr Swat has received funding from the National Institutes of Health (NIH) T32 Training Grant 5T32-HL-007822-22. The GWTG-HF (Get With The Guidelines–Heart Failure) program is provided by the American Heart Association. GWTG-HF is sponsored, in part, by Novartis, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Bayer, Tylenol, and Alnylam Pharmaceuticals. Dr Allen has received grant funding from American Heart Association (AHA), NIH, and Patient-Centered Outcomes Research Institute (PCORI); and has received consulting fees from Abbott, ACI Clinical, Amgen, Boston Scientific, Cytokinetics, and Novartis. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; has received speaker fees from Boehringer Ingelheim; and has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, PharmaIN, Roche Diagnostics, Sanofi, Urovant Pharmaceuticals, and Vifor. Dr DeVore has received research funding through his institution from the American Heart Association, Amgen, Biofourmis, Bodyport, Cytokinetics, American Regent Inc, the National Heart, Lung, and Blood Institute (NHLBI), and Novartis; he has also provided consulting services for and/or received honoraria from Abiomed, Amgen, AstraZeneca, Cardionomic, InnaMed, LivaNova, Natera, Novartis, Procyrion, Story Health, Vifor, and Zoll; he has also received nonfinancial support from Abbott for educational and research activities. Dr Peterson is supported by the NHLBI of the NIH under Award Number R33HL143324. Dr Fonarow has consulted for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis. Dr Hess is supported by VA Career Development Award HX002621 and American Heart Association Career Development Award 19CDA34760126. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Background: Vericiguat reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HF) in patients with worsening HF and reduced left ventricular ejection fraction (LVEF)., Objectives: The authors assessed the association of LVEF with biomarker levels, risk of outcome, and whether the effect of vericiguat was homogeneous across LVEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction) trial., Methods: Patients were grouped by LVEF tertiles (≤24%, 25%-33%, and >33%). Patient characteristics, clinical outcomes, and efficacy and safety of vericiguat were examined by tertile. Prespecified biomarkers including N-terminal pro-B-type natriuretic peptide, cardiac troponin T, growth differentiation factor 15, interleukin 6, high-sensitivity C-reactive protein, and cystatin C were examined., Results: The mean LVEF was 29% ± 8% (range: 5%-45%). A pattern of higher N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and interleukin 6 was evident in patients in the lowest LVEF tertile vs the other tertiles. Patients with lower LVEF experienced higher rates of the composite outcome (41.7%, 36.3%, and 33.4% for LVEF ≤24, 25-33, and >33; P < 0.001). There was no significant treatment effect heterogeneity of vericiguat across LVEF groups (adjusted HR from lowest to highest tertiles: 0.79 [95% CI: 0.68-0.94]; 0.95 [95% CI: 0.82-1.11]; 0.94 [95% CI: 0.79-1.11]; P for interaction = 0.222), although the HR was numerically lower in the lowest tertile. There was also no heterogeneity of effect for CVD and HF hospitalization individually (P interaction for CVD = 0.964; HF hospitalization = 0.438). Discontinuation of treatment because of adverse events, symptomatic hypotension, or syncope was consistent across the range of LVEF., Conclusions: Patients with lower LVEF had a distinctive biomarker profile and a higher risk for adverse clinical outcomes vs those with a higher LVEF. There was no significant interaction for the benefit of vericiguat across LVEF tertiles, although the largest signal for benefit in both the primary outcome and HF hospitalizations was noted in tertile 1 (LVEF ≤24%). (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures The VICTORIA trial was funded by Merck Sharp and Dohme Corp, a subsidiary of Merck and Co Inc, and Bayer AG. 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 Lund is a consultant for Bayer/Merck; has received grants unrelated to the present work from AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, and Novartis; has received consulting fees from Merck, Vifor, AstraZeneca, Bayer, Pharmacosmos, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, and Servier; has received speaker honoraria from Abbott, MedScape, Radcliffe, AstraZeneca, Novartis, and patent AnaCardio; and has stock ownership in AnaCardio. Dr deFilippi has received institutional research grants from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics; and has received consulting fees from FujiRebio, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics. Dr Blaustein is an employee of Merck and Co, Inc. Mr Ezekowitz has received research grants and consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Freitas is an employee of Bayer AG. Dr Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and has received honoraria from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr O’Connor has received research grants from Merck; and has received consulting fees from Bayer, Dey LP, and Bristol Myers Squibb Foundation. Dr Voors has received research grants from Boehringer Ingelheim and Roche Diagnostics; and has received consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Dr Westerhout has received consulting fees from Bayer. Dr Lam has received research grants from Bayer and Roche Diagnostics; has received consulting fees from Abbott, Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and 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 is a cofounder and nonexecutive director of Us2.ai. Dr Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche and Développement, Boehringer Ingelheim, and CSL Limited; and has received consulting fees from Merck, Bayer, AstraZeneca, and Novartis., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Black people have a higher incidence and prevalence of heart failure (HF) than White people, and once HF has developed, they may have worse outcomes. There is also evidence that the response to several pharmacologic therapies may differ between Black and White patients., Objectives: The authors sought to examine the outcomes and response to treatment with dapagliflozin according to Black or White race in a pooled analysis of 2 trials comparing dapagliflozin to placebo in patients with heart failure with reduced ejection fraction (DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure]) and heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure])., Methods: Because most self-identified Black patients were enrolled in the Americas, the comparator group was White patients randomized in the same regions. The primary outcome was the composite of worsening HF or cardiovascular death., Results: Of the 3,526 patients randomized in the Americas, 2,626 (74.5%) identified as White and 381 (10.8%) as Black. The primary outcome occurred at a rate of 16.8 (95% CI: 13.8-20.4) in Black patients compared with 11.6 (95% CI: 10.6-12.7) per 100 person-years in White patients (adjusted HR: 1.27; 95% CI: 1.01-1.59). Compared with placebo, dapagliflozin decreased the risk of the primary endpoint to the same extent in Black (HR: 0.69; 95% CI: 0.47-1.02) and White patients (HR: 0.73 [95% CI: 0.61-0.88]; P interaction  = 0.73). The number of patients needed to treat with dapagliflozin to prevent one event over the median follow-up was 17 in White and 12 in Black patients. The beneficial effects and favorable safety profile of dapagliflozin were consistent across the range of left ventricular ejection fractions in both Black and White patients., Conclusions: The relative benefits of dapagliflozin were consistent in Black and White patients across the range of left ventricular ejection fraction, with greater absolute benefits in Black patients. (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DAPA-HF and DELIVER trials were funded by AstraZeneca. Prof McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217. Dr Butt has received advisory board honoraria from Bayer. Dr Docherty has received honoraria from AstraZeneca and a research grant to his institution from Boehringer Ingelheim. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr Desai has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside of the submitted work. Dr Fang has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Petersson is an employee and shareholder of AstraZeneca. Dr Langkilde is an employee and shareholder of AstraZeneca. Dr de Boer’s institution, the UMCG, has received research grants and fees (outside of 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 Hernandez has received research support from American Regent, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, 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, Myokardia, Merck, Novartis, and Vifor. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. 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 Køber has received compensation from Novartis, Novo Nordisk, and AstraZeneca for other services. 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 and 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 Martinez has received personal fees from AstraZeneca. Dr Ponikowski has received compensation from AstraZeneca, Boehringer Ingelheim, Servier, Amgen, and Vifor Pharma for consultant services; and compensation from AstraZeneca, Pfizer, Novartis, and 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, Quark Pharmaceuticals; and has done consulting 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 Vardeny has received either personal or institutional research support for DELIVER from AstraZeneca. Dr O’Meara or her institution has received financial support for clinical trials from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Novartis; and has served as a consultant or speaker for Amgen, Boehringer Ingelheim, Novartis, and AstraZeneca. Dr Saraiva has received research grant support from Pfizer, Daichii Sankyo, Sanofi, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Janssen, Amgen, and Novartis; and has received honorarium from Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Amgen. Dr Shah has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, and Relypsa; has had speaker engagements with Novartis and Roche Diagnostics; and has participated on clinical endpoint committees for studies sponsored by Galmed and Novartis. Dr Jhund's employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials. Dr Jhund has received personal fees from Novartis and Cytokinetics; and has received grants from Boehringer Ingelheim. 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 fees and fees for other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP)., (Copyright © 2023. Published by Elsevier Inc.)

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used for diagnostic and prognostic evaluation in heart failure (HF). Previous clinical trials in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) have shown potential heterogeneity in the treatment response by baseline NT-proBNP levels., Objectives: The purpose of this study was to assess the treatment effect of dapagliflozin across baseline levels of NT-proBNP among patients with HFmrEF or HFpEF., Methods: This was a post hoc analysis from DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure), a randomized, placebo-controlled trial of dapagliflozin in patients with HFmrEF or HFpEF. Elevated NT-proBNP was part of the inclusion criteria (≥300 ng/L for non-atrial fibrillation or flutter [AFF]; ≥600 ng/L for AFF). Baseline NT-proBNP was categorized in quartiles and additionally analyzed continuously. The primary composite outcome was cardiovascular death or worsening HF events., Results: Among the 6,262 included patients (mean: 71.7 years and 3,516 [56%] men), the median baseline concentration of NT-proBNP was 716 (Q1-Q3: 469-1,280) ng/L and 1,399 (Q1-Q3: 962-2,212) ng/L for non-AFF and AFF, respectively. Higher NT-proBNP levels were linearly associated with a greater risk of the primary outcome (adjusted HR for log 2 NTpro-BNP was 1.53 [95% CI: 1.46-1.62] and Q4 vs Q1: 3.46 [95% CI: 2.48-4.22]; P < 0.001), with consistent results regardless of AFF status. The clinical benefit of dapagliflozin was present irrespective of baseline NT-proBNP concentration (P value for interaction = 0.40 by quartiles and = 0.19 continuously for the primary outcome) and the absolute risk reduction was, therefore, greater with higher NT-proBNP concentrations. The effect on health status and safety of dapagliflozin was similarly consistent across NT-proBNP quartiles., Conclusions: Dapagliflozin is safe and improves outcomes irrespective of baseline NT-proBNP concentrations in HFmrEF or HFpEF, with the greatest absolute benefit likely seen in patients with higher NT-proBNP concentrations. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DELIVER trial was funded by AstraZeneca. Dr Myhre has consulted for Amgen, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; speaker engagements with AstraZeneca, Novartis, and Roche Diagnostics; and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Amgen, Cardurion, Corvia, and Novartis. Dr Jhund’s employer has been remunerated for his work on the DELIVER and DAPA-HF trials by AstraZeneca; consulting and speaker fees from Novartis, AstraZeneca, and Boehringer Ingelheim; research funding from Boehringer Ingelheim; and remuneration for clinical trial work from NovoNordisk and Bayer. Dr De Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic 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, Eidos, Intercept, Merck, and Novartis. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an advisory board for Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. 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 non-executive director of Us2.ai. Dr Martinez has received consultation fees and research grants from AstraZeneca, Baliarda, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gador, Milestone, Novartis, Pfizer, and St Lukes University. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer, and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Desai has received institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and has received consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Merck, Novartis, Parxel, Regeneron, Roche, and Verily. Drs Lindholm, Petersson, and Langkilde are employees and shareholders of AstraZeneca. Dr McMurray has received payments through Glasgow University for work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). 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/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, 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, and Akros. Dr Miao has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background: The effect of vericiguat on sequential N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and influence of this relationship on clinical outcomes is unknown., Objectives: This study assessed the relationship between changes in NT-proBNP and the primary outcome (cardiovascular death or heart failure hospitalization); evaluated the effect of vericiguat on changes in NT-proBNP; and explored the association between the efficacy of vericiguat and changes in NT-proBNP., Methods: NT-proBNP was measured at randomization and at 16, 32, 48, and 96 weeks in 4,805 of 5,050 patients. The association between NT-proBNP change at week 16 and the primary outcome was assessed. The relationship between changes in NT-proBNP and the primary outcome according to treatment group was assessed by using joint modeling and mediation analysis., Results: A significant and sustained decline in NT-proBNP levels was seen in both treatment groups. After week 16, NT-proBNP levels decreased more with vericiguat vs placebo (any reduction: odds ratio [OR]: 1.45 [95% CI: 1.28-1.65]; P < 0.001; ≥50% reduction: OR: 1.27 [95% CI: 1.10-1.47]; P = 0.001) and were less likely to increase (≥20% increase: OR: 0.68 [95% CI: 0.59-0.78]; P < 0.001; ≥50% increase: OR: 0.70 [95% CI: 0.59-0.82]; P < 0.001). The treatment effect related to serial NT-proBNP on the primary composite outcome was HR: 0.96 (95% CI: 0.95-0.99) at week 16, which increased to HR: 0.90 (95% CI: 0.85-0.96) at week 48; the average extent of mediation of the composite outcome related to NT-proBNP was 45%., Conclusions: In patients with worsening HFrEF, vericiguat significantly decreased NT-proBNP levels compared with placebo. This change appeared associated with a modest relative improvement in the primary outcome of cardiovascular death or heart failure hospitalization. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures The VICTORIA trial was funded by Merck Sharp & Dohme Corporation, a subsidiary of Merck & Co, Inc, and Bayer AG. Dr Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche & Développement, Boehringer Ingelheim, and CSL Limited; and consulting fees from Merck, Bayer, AstraZeneca, and Novartis. Dr Troughton has received research grants and personal fees from Merck and Roche Diagnostics. Dr Lund has received consulting honoraria from Bayer/Merck; and unrelated to this present work, he has received grants from AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, and Novartis; he has received consulting fees from Merck, Vifor, AstraZeneca, Bayer, Pharmacosmos, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, and Servier; he has received speaker's honoraria from Abbott, MedScape, Radcliffe, AstraZeneca, and Novartis; and he has a patent and stock ownership with AnaCardio. Dr Lam has received research grants from Bayer, National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; and 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. Dr Lam also has patent PCT/SG2016/050217 pending and patent 16/216929 pending and is co-founder and non-executive director of eKo.ai. Dr Westerhout has received consulting fees from Bayer Canada. Dr Blaustein is an employee of Merck & Co. 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 Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and honoraria from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr Roessig is an employee of Bayer AG. Dr O’Connor has received research funding from Merck; and consulting fees from Bayer, Dey LP, and Bristol Myers Squibb Foundation. 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 Ezekowitz has received research grants from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics; and consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction., Objectives: The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction., Methods: In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan., Results: Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance., Conclusions: Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors. (EntrestoTM [LCZ696] in Advanced Heart Failure [LIFE Study] [HFN-LIFE] NCT02816736)., Competing Interests: Funding Support and Author Disclosures Research reported in this publication was supported by the NHLBI of the NIH under award number U10 HL084904 (for the Coordinating Center) and award numbers U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336, and U10 HL110337 (for the Regional Clinical Centers). The NHLBI contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Novartis Pharmaceutical Corporation provided study drug and partial funding through its investigator-initiated trial program CLCZ696BUS04T, but did not contribute to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Neither the NHLBI nor Novartis Pharmaceutical Corporation were involved in manuscript submission. Dr Mann serves on the steering committee for the PARADISE-MI trial for Novartis; and is a member of the Scientific Advisory Board for MyoKardia. Dr Anstrom has received research support from the National Institutes of Health (NIH), Merck, Bayer, and PCORI. Dr Starling serves on the steering committee for the PARAGLIDE trial sponsored by Novartis. Dr Desvigne-Nickens is an employee of the NHLBI; and is a consultant for Novartis. Dr Hernandez has received research grants and consulting fees from AstraZeneca, Amgen, Bayer, Merck, and Novartis. Dr Braunwald has received research support through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and is a consultant for Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, Novo-Nordisk, and Verve. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. All rights reserved.)

Acute coronary syndrome (ACS) is frequently complicated by evidence of heart failure (HF). Those at highest risk for acute decompensated HF in the setting of ACS (ACS-HF) are older, female, and have preexisting heart disease, type 2 diabetes mellitus, hypertension, and/or kidney disease. The presence of ACS-HF is strongly associated with higher mortality and more frequent readmissions, especially for HF. Low implementation of guideline-directed medical therapy has further complicated the clinical care of this high-risk population. Improved utilization of current therapies, coupled with further investigation of strategies to manage ACS-HF, is desperately needed to improve outcomes in this vulnerable population, and the results of currently ongoing or recently concluded ACS-HF studies in this population are of great interest. In this review, we explore the pathophysiology, epidemiology, risk factors, and outcomes for patients with ACS-HF, and describe both existing evidence for management of this challenging condition and areas requiring further research., Competing Interests: Funding Support and Author Disclosures Dr Jones has received research grants from the Agency for Healthcare Research and Quality, Boehringer Ingelheim, Doris Duke Charitable Foundation, National Institutes of Health, and Patient-Centered Outcomes Research Institute; and honorarium/other from Bayer, Bristol-Myers Squibb, and Janssen Pharmaceuticals. Dr Udell has received speaker/consulting honoraria from Amgen, Boehringer Ingelheim/Eli Lilly, GlaxoSmithKline, Novartis, and Sanofi; and grant support from AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Janssen, Novartis, and Sanofi. Dr Bhatt has served on the advisory board of Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; served on the board of directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; served as Inaugural Chair, American Heart Association Quality Oversight Committee; served on the data monitoring committees of Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Novartis, Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, 89Bio; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Philips, and Svelte; as trustee for the American College of Cardiology; and has received unfunded research for FlowCo, Merck, Takeda. Dr Petrie has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and has served as a consultant and on endpoint committees for Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, Abbvie, Bayer, Takeda, Cardiorentis, and Pharmacosmos. Dr Anker has received fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma; and grant support from Abbott and Vifor Pharma. Dr Vedin is an employee of Boehringer Ingelheim; Dr Butler has served as a consultant to Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin Cures, Boehringer Ingelheim, Bristol-Myers Squib, CVRx, G3 Pharmaceutical, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Occlutech, Relypsa, Roche, Sanofi, SC Pharma, V-Wave Limited, and Vifor. Dr Hernandez has received research grants from American Regent, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squib, Merck, Novartis, and Verily; and consulted from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Myokardia, Relypsa. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The authors sought to characterize associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes (overall and by ejection fraction [EF] phenotype)., Background: Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these therapies on clinical outcomes among patients with comorbid HF and diabetes is unclear., Methods: The authors evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-Heart Failure Registry between 2006 and 2014 with diabetes and not prescribed metformin or sulfonylurea before admission. In parallel separate analyses for metformin and sulfonylurea, patients with newly prescribed therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between prescription of therapy, and mortality and hospitalization for HF (HHF) at 12 months. Negative control (falsification) endpoints included hospitalization for urinary tract infection, hospitalization for gastrointestinal bleed, and influenza vaccination. Prespecified subgroup analyses were stratified by EF ≤40% versus >40%., Results: Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was independently associated with reduced risk of composite mortality/HHF (HR: 0.81; 95% CI: 0.67-0.98; P = 0.03), but individual components were not statistically significant. Findings among patients with EF >40% accounted for associations with mortality/HHF (HR: 0.68; 95% CI: 0.52-0.90) and HHF (HR: 0.58; 95% CI: 0.40-0.85) endpoints (all P for interaction ≤0.04). After adjustment, sulfonylurea initiation was associated with increased risk of mortality (HR: 1.24; 95% CI: 1.00-1.52; P = 0.045) and HHF (HR: 1.22; 95% CI: 1.00-1.48; P = 0.050) with nominal statistical significance. Associations between sulfonylurea initiation and endpoints were consistent regardless of EF (all P for interaction >0.11). Neither metformin initiation nor sulfonylurea initiation were associated with negative control endpoints., Conclusions: In this population of older U.S. adults hospitalized for HF with comorbid diabetes, metformin initiation was independently associated with substantial improvements in 12-month clinical outcomes, driven by findings among patients with EF >40%. By contrast, sulfonylurea initiation was associated with excess risk of death and HF hospitalization, regardless of EF., Competing Interests: Funding Support and Author Disclosures This work was supported in part by an American Heart Association (AHA) grant award #16SFRN30180010 (to Dr DeVore). The GWTG-HF program is provided by the AHA and sponsored, in part, by Novartis, Boehringer Ingelheim and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer. Dr Sharma has received support from the Fonds de Recherche Santé Quebec (FRSQ) Junior 1 Clinical Research Scholar, Canada Institute for Health Research grant #175095, European Society of Cardiology young investigator grant, Roche Diagnostics, Boehringer Ingelheim, Novartis, AstraZeneca, and Takeda. Dr DeVore has received research funding through the Duke Clinical Research Institute from the AHA, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, Inc, the National Heart, Lung, and Blood Institute (NHLBI), Novartis, and the Patient-Centered Outcomes Research Institute; and consulting for AstraZeneca. Dr Felker has received research grants from National Heart, Lung, and Blood Institute (NHLBI), AHA, Amgen, Bayer Merck, Cytokinetics, and Myokardia; has been a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Innolife, Boehringer Ingelheim, American Reagent, Abbott, Eidos Therapeutics, Reprieve, and Sequana; 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 Hernandez has received consulting fees from AstraZeneca, Bayer, Boston Scientific, Merck, Novartis, and Sanofi; and research support from AstraZeneca, GlaxoSmithKline, Luitpold, Merck, and Novartis. Dr Butler has been a consultant to Abbott, Adrenomed, Arena Pharma, Array, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Sequana Medical, V-Wave Limited, and Vifor. Dr Peterson has received research funding from the NHLBI; and personal fees from American Heart Association outside the submitted work. Dr Fonarow has received research funding from the National Institutes of Health; and has been a consultant for Amgen, Bayer, Medtronic, and Novartis. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, the AHA, NHLBI, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, and Cytokinetics; and has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, and Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials., Background: The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF)., Methods: Adults with symptomatic HF and LVEF >40%, with or without type 2 diabetes mellitus, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo., Results: A total of 6,263 patients were randomized (mean age: 72 ± 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index ≥30 kg/m 2 ; and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 ± 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF., Conclusions: DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213])., Competing Interests: Funding Support and Author Disclosures The DELIVER study was funded by AstraZeneca. 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, 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, CellProThera, Moderna, American Regent, and Sarepta. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical endpoint committees for studies sponsored by Galmed and Novartis. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr De Boer’s institution, the UMCG, 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 the submitted work). Dr DeMets has received consulting fees from Frontier Science, Actelion, Bristol Myers Squibb, Medtronic, Boston Scientific, GlaxoSmithKline, and Merck; and has received consulting fees and is the owner of DL DeMets Consulting. Dr Hernandez has received research support from American Regent, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, 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, Myokardia, Merck, Novartis, and Vifor. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. 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 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 non-executive director of Us2.ai. Dr Martinez has received personal fees from AstraZeneca. Drs Shah and Belohjavek have received either personal or institutional research support for DELIVER from AstraZeneca. Dr Chiang has received honoraria and consultation fees from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi. Dr Borleffs has received speaker fees and institutional research support from AstraZeneca; has received speaker fees from Novartis; and has received institutional research support from Boehringer Ingelheim. Dr Comin-Comet has received personal and institutional financial support for the DELIVER study from AstraZeneca; outside this work, he has received fees for speaking and fees for consultancy from Boehringer Ingelheim, Novartis, Orion Pharma, and Vifor Pharma; and he has received research grants from Novartis, Orion Pharma, and Vifor Pharma. Dr Dobreanu has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Drozdz has received personal and institutional research support for DELIVER from AstraZeneca. Dr Fang has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Gamba has received personal fees from Sanfer, Roche, Amgen, Asofarma, Sanofi, AstraZeneca, Eli Lilly, Boehringer, Bristol Myers Squibb, Bayer, Pfizer, Merck, Abbott, Silanes, Servier, Jansen Cilag, Medtronic, and Boston Scientific. Drs Al Habeeb, Han, Cabrera, Janssens, Vardeny, and Nguyen have received either personal or institutional research support for DELIVER from AstraZeneca. Dr Katova has received fees for serving as national coordinator from Novartis and AstraZeneca. Dr Kitakaze has received support for the present manuscript (funding, provision of study materials, medical writing, article processing charges, etc) from AstraZeneca, has received grants or contracts from the Japanese government through the Japan Agency for Medical Research and Development Japan Heart Foundation, and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Ono, Novartis, Tanabe-Mitsubishi, Japan Medical Data Center, Takeda, Pfizer, Daiichi-Sankyo, Otsuka, Sanofi, Boehringer Ingelheim, Amgen, Kowa, Toyama-Kagaku, Kureha, Viatris, and Mochida. Dr Merkely has received personal fees from AstraZeneca and Servier. Dr O’Meara has served as a consultant and speaker for AstraZeneca, Bayer, Boehringer Ingelheim, and Novartis; has served as a steering committee member or a national lead investigator with contracts between her institution (Montreal Heart Institute Research Center) and American Regent, AstraZeneca, Cytokinetics, Merck, and Novartis; and has ongoing clinical trial participation with Amgen, Abbott, American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eidos, Novartis, Merck, Pfizer, and Sanofi. Dr Kerr Saraiva has received research grant support from Pfizer, Daichii Sankyo, Sanofi, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Janssen, Amgen, and Novartis; and has received honorarium from Boehringer Ingelheim, Novo Nordisk, Astra Zeneca, and Amgen. Dr Tereshchenko has received personal fees from Servier, AstraZeneca, Pfizer, Novartis, and Boehringer Ingelheim. Dr Thierer has received support for lectures and advisory boards from AstraZeneca, Boehringer Ingelheim, and Pfizer. Dr Verma has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Drs Wilderäng, Zaozerska, Lindholm, and Petersson are employees and shareholders of AstraZeneca. Dr McMurray has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to evaluate differences in clinical and patient-reported outcomes between women and men hospitalized for acute HF., Background: Among patients hospitalized for heart failure (HF), it is unclear if symptom burden, response to therapy, and patient-reported quality of life (QOL) are different in women as compared with men., Methods: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized 7,141 patients hospitalized for HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. Clinical endpoints included 30-day mortality and rehospitalization and 180-day mortality. Patient-reported QOL was assessed at baseline, discharge, and 30 days using the EuroQOL 5 dimensions (EQ-5D) survey., Results: Among 7,141 total patients, 4,697 (65.8%) were men and 2,444 (34.2%) were women. Among patients with EF ≤40%, women were less likely to receive angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker and beta-blocker therapy, and less likely to have an implantable cardioverter-defibrillator (all p < 0.03). Signs and symptoms of HF were similar between men and women (all p > 0.05), but women experienced less in-hospital weight loss and urine output (all p < 0.01). In unadjusted and adjusted analyses, men and women had similar risk of all mortality and rehospitalization endpoints (all p ≥ 0.41). Women reported lower EQ-5D utility and visual analogue scores at admission, discharge, and 30 days. Women continued to have significantly lower EQ-5D scores at all in-hospital and post-discharge time points after adjustment for clinical characteristics (all p < 0.01)., Conclusions: In this acute HF population, women had similar risk of mortality and rehospitalization as compared with men, but experienced worse patient-reported QOL during and after hospitalization that persisted after adjustment for demographic and clinical factors. Current acute HF management may work similarly in either sex for purposes of preventing clinical events, but may be less equipped to improve patient-reported outcomes in women as compared with men., Competing Interests: Funding Support and Author Disclosures Scios Inc. (Mountain View, California) provided financial and material support for the ASCEND-HF trial. Database management and statistical analysis was performed by the Duke Clinical Research Institute. Dr. Greene has received research support from the American Heart Association, Amgen, AztraZeneca, Bristol-Myers Squibb, Merck, and Novartis; has served on advisory boards for Amgen and Cytokinetics; and has served as a consultant for Amgen and Merck. Dr. Butler is a consultant to Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squib, CVRx, G3 Pharmaceutical, Impulse Dynamics, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, V-Wave Limited, and Vifor. Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Medtronic, Merck, Novartis, Roche, Sanofi, and Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The authors estimated changes of stressed blood volume (SBV) induced by splanchnic nerve block (SNB) in patients with either decompensated or ambulatory heart failure with reduced ejection fraction (HFrEF)., Background: The splanchnic vascular capacity is a major determinant of the SBV, which in turn determines cardiac filling pressures and may be modifiable through SNB., Methods: We analyzed data from 2 prospective, single-arm clinical studies in decompensated HFrEF (splanchnic HF-1; resting hemodynamics) and ambulatory heart failure (splanchnic HF-2; exercise hemodynamics). Patients underwent invasive hemodynamics and short-term SNB with local anesthetics. SBV was simulated using heart rate, cardiac output, central venous pressure, pulmonary capillary wedge pressure, systolic and diastolic systemic arterial and pulmonary artery pressures, and left ventricular ejection fraction. SBV is presented as ml/70 kg body weight., Results: Mean left ventricular ejection fraction was 21 ± 11%. In patients with decompensated HFrEF (n = 11), the mean estimated SBV was 3,073 ± 251 ml/70 kg. At 30 min post-SNB, the estimated SBV decreased by 10% to 2,754 ± 386 ml/70 kg (p = 0.003). In ambulatory HFrEF (n = 14) patients, the mean estimated SBV was 2,664 ± 488 ml/70 kg and increased to 3,243 ± 444 ml/70 kg (p < 0.001) at peak exercise. The resting estimated SBV was lower in ambulatory patients with HFrEF than in decompensated HFrEF (p = 0.019). In ambulatory patients with HFrEF, post-SNB, the resting estimated SBV decreased by 532 ± 264 ml/70 kg (p < 0.001). Post-SNB, with exercise, there was no decrease of estimated SBV out of proportion to baseline effects (p = 0.661)., Conclusions: The estimated SBV is higher in decompensated than in ambulatory heart failure. SNB reduced the estimated SBV in decompensated and ambulatory heart failure. The reduction in estimated SBV was maintained throughout exercise. (Splanchnic Nerve Anesthesia in Heart Failure, NCT02669407; Abdominal Nerve Blockade in Chronic Heart Failure, NCT03453151)., Competing Interests: Funding Support and Author Disclosures This study was supported by American Heart Association (AHA) Grant, 17MCPRP33460225 and Translating Duke Health Award. Dr. Fudim has received grants from the American Heart Association (Grant 17MCPRP33460225), National Institutes of Health (NIH) T32 grant 5T32HL007101, Mario Family Award, Translating Duke Health Award; and has received consulting fees from AxonTherapies, Daxor, and Galvani. Dr. M.R. Patel has received research grants from HeartFlow, Bayer, Janssen, and the National Heart, Lung, and Blood Institute (NHLBI); and is on advisory boards for HeartFlow, Bayer, and Janssen. Dr. Borlaug has received research funding from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) (R01 HL128526, U01 HL125205), AstraZeneca, Corvia, Medtronic, Mesoblast, GlaxoSmithKline, and TENAX; and is on advisory boards/consults for Merck, Novartis, Lilly, and Novo Nordisk. Dr. DeVore has received research funding through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, Inc., the NHLBI, Novartis, and PCORI; has received consulting fees from Amgen, AstraZeneca, Bayer, CareDx, InnaMed, LivaNova, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, Story Health, and Zoll; and has received nonfinancial support from Abbott for educational activities. Dr. Lopes has received research grants from Bristol-Myers Squibb and Pfizer; has received personal fees from Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Bayer AG; and has received grants from Amgen Inc., GlaxoSmithKline, Medtronic PLC, and Sanofi Aventis outside the submitted work. Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Medtronic, Merck, Novartis, Roche, Sanofi, and Vifor. Dr. Felker has received research funding from NHLBI, AHA, Amgen, Cytokinetics, Merck; and has received consulting fees from Novartis, Amgen, Cytokinetics, Bristol-Myers Squibb, Innolife, Medtronic, EBR Systems, Cardionomic, SC Pharma, and Myokardia. Dr. Hernandez has received research funding from AstraZeneca, GlaxoSmithKline, Merck, and Novartis; and has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, and Pfizer. Dr. Burkhoff has received institutional grants from Abiomed, Ancora Heart, Tenax Therapeutics, and Fire 1; and has received consulting fees from PVLoops LLC and Axon Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The authors sought to evaluate the association of heart failure hospitalization (HFH) with guideline-directed medical therapy (GDMT) prescribing patterns among patients with heart failure with reduced ejection fraction (HFrEF)., Background: HFH represents an important opportunity to titrate GDMT among patients with HFrEF., Methods: The CHAMP-HF (Change the Management of Patients With Heart Failure) registry is a prospective registry of adults with HFrEF (ejection fraction ≤40%). Using data from the CHAMP-HF registry (N = 4,365), adjusted time-to-event models were created to study the association of HFH with GDMT prescribing patterns., Results: HFH (compared with no HFH) was positively associated with initiation of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA). HFH positively associated with dose escalation of ACE inhibitor/ARB (probability ratio: 1.71, 95% confidence interval [CI]: 1.36 to 2.16) and MRA (probability ratio: 8.71, 95% CI: 4.19 to 18.10). In those on prior therapy, HFH was associated with discontinuation and de-escalation of all classes of GDMT. ACE inhibitor/ARB, angiotensin receptor-neprilysin inhibitor, beta-blocker, and MRA de-escalation/discontinuation after HFH was associated with increased risk of all-cause mortality with hazard ratios of 3.82 (95% CI: 2.42 to 6.03), 4.76 (95% CI: 2.06 to 11.03), 2.94 (95% CI: 2.04 to 4.25), and 4.81 (95% CI: 2.61 to 8.87), respectively., Conclusions: HFH positively associated with changes in GDMT, including initiation, dose escalation, discontinuation, and dose de-escalation. De-escalation/discontinuation of GDMT after HFH associated with increased risk of all-cause mortality. Educational endeavors are needed to ensure GDMT is not inappropriately held in the setting of HFH. For those in whom GDMT must be held/decreased, improvement tools at discharge and post-discharge titration clinics may help ensure lifesaving GDMT regimens remain optimized., Competing Interests: Author Disclosures The CHAMP HF registry and this study were funded by Novartis. Dr. DeVore has received research funding from the American Heart Association, Amgen, Bayer, Intra-Cellular Therapies, Luitpold Pharmaceuticals, the National Heart, Lung, and Blood Institute, Novartis, and PCORI; and has provided consulting services for Amgen, AstraZeneca, Bayer, InnaMed, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, and Zoll. Dr. Albert has been a consultant for Amgen, AstraZeneca, Boston Scientific, and Novartis. Dr. Spertus has been a consultant for Novartis, Amgen, Bayer, Janssen, United Healthcare, and AstraZeneca; has served on the board of directors for Blue Cross Blue Shield of Kansas City; and has equity in Health Outcomes Sciences and copyright ownership of KCCQ, SAQ and PAQ. Dr. Duffy is an employee of Novartis. Dr. Hernandez has received research funding from AstraZeneca, American Regent, Novartis, and Verily; and has provided consulting services for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, and Novartis. Dr. Fonarow has been a consultant for Abbott, Amgen, CHF Solutions, Janssen, Medtronic, Merck, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization., Background: Vericiguat compared with placebo reduced the primary outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH) in patients with HF with reduced ejection fraction (HFrEF) in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. Because an interaction existed between treatment and the primary outcome according to pre-specified quartiles of NT-proBNP at randomization, we examined this further., Methods: This study evaluated the NT-proBNP relationship with the primary outcome in 4,805 of 5,050 patients as a risk-adjusted, log-transformed continuous variable. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented., Results: Median NT-proBNP was 2,816 pg/ml (25th to 75th percentile: 1,556 to 5,314 pg/ml). The study treatment effect varied across the spectrum of NT-proBNP at randomization (with log 2 transformation, p for interaction = 0.002). A significant association between treatment effects existed in patients with levels <4,000 pg/ml and remained evident up to 8,000 pg/ml. A 23% relative risk reduction occurred in the primary endpoint with NT-proBNP ≤4,000 pg/ml (HR: 0.77; 95% CI: 0.68 to 0.88). For NT-proBNP values ≤4,000 pg/ml (n = 3,100), the HR was 0.78 (95% CI: 0.67 to 0.90) for HFH and 0.75 (95% CI: 0.60 to 0.94) for CVD. For NT-proBNP ≤8,000 pg/ml (n = 4,133), the HR was 0.85 (95% CI: 0.76 to 0.95) for the primary outcome, 0.84 (95% CI: 0.75 to 0.95) for HFH, and 0.84 (95% CI: 0.71 to 0.99) for CVD. For NT-proBNP >8,000 pg/ml (n = 672), the HR was 1.16 (95% CI: 0.94 to 1.41) for the primary outcome., Conclusions: A reduction in the primary composite endpoint and its CVD and HFH components was observed in patients on vericiguat compared with subjects on placebo with NT-proBNP levels up to 8,000 pg/ml. This provided new insight into the benefit observed in high-risk patients with worsening HFrEF. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534)., Competing Interests: Author Relationship With Industry This study was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and Bayer AG. Mr. Ezekowitz has received research grants from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics; has received consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr. O’Connor has received research funding from Merck; and has received consulting fees from Bayer, Dey LP, and Bristol-Myers Squibb Foundation. Dr. Troughton has received research grants from and personal fees from Merck and Roche Diagnostics. Dr. Voors has received research grants from Boehringer Ingelheim and Roche Diagnostics; and has received consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Dr. Butler has received consulting fees from Bayer, Merck, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, G3 Pharmaceutical, Janssen, Luitpold, Medtronic, Novartis, Vifor, and Novo Nordisk. 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 a patents pending for PCT/SG2016/050217 and 16/216,929; and is the Cofounder and non-executive director of eKo.ai. Dr. Ponikowski has received research grants from Vifor Pharma Ltd, and Servier; has received consulting fees from MSD, Novartis, Vifor Pharma Ltd, Servier, Bristol-Myers Squibb, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuardSolution, and Berlin Chemie. Dr. Pieske has received research grants from MSD, Bayer, and Servier; has received consulting fees from MSD, Bayer, Servier, Bristol-Myers Squibb, MedScape, Daiichi-Sankyo, and Novartis; and has received non-financial support from MSD, Bayer, and Novartis. Dr. Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and has received consulting fees from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr. Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche & Développement, Boehringer Ingelheim, and CSL Limited; and has received consulting fees from Merck, Bayer, AstraZeneca, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We hypothesized that splanchnic nerve blockade (SNB) would attenuate increased exercise-induced cardiac filling pressures in patients with chronic HF., Background: Chronic heart failure (HF) is characterized by limited exercise capacity driven in part by an excessive elevation of cardiac filling pressures., Methods: This is a prospective, open-label, single-arm interventional study in chronic HF patients. Eligible patients had a wedge pressure ≥15 mm Hg at rest or ≥25 mm Hg with exercise on baseline right heart catheterization. Patients underwent cardiopulmonary exercise testing with invasive hemodynamic assessment, followed by percutaneous SNB with ropivacaine., Results: Nineteen patients were enrolled, 15 of whom underwent SNB. The average age was 58 ± 13 years, 7 (47%) patients were women and 6 (40%) were black. Left ventricular ejection fraction was ≤35% in 14 (93%) patients. No procedural complications were encountered. SNB reduced mean pulmonary arterial pressure at peak exercise from 54.1 ± 14.4 (pre-SNB) to 45.8 ± 17.7 mm Hg (p < 0.001) (post-SNB). Similarly, SNB reduced exercise-induced wedge pressure from 34.8 ± 10.0 (pre-SNB) to 25.1 ± 10.7 mm Hg (p < 0.001) (post-SNB). The cardiac index changed with peak exercise from 3.4 ± 1.2 (pre-SNB) to 3.8 ± 1.1 l/min/m 2 (p = 0.011) (post-SNB). After SNB, patients exercised for approximately the same duration at a greater workload (33 ± 24 W vs. 50 ± 30 W; p = 0.019) and peak oxygen consumption VO 2 (9.1 ± 2.5 vs. 9.8 ± 2.7 ml/kg/min; p = 0.053)., Conclusions: SNB reduced resting and exercise-induced pulmonary arterial and wedge pressure with favorable effects on cardiac output and exercise capacity. Continued efforts to investigate short- and long-term effects of SNB in chronic HF are warranted. Clinical Trials Registration (Abdominal Nerve Blockade in Chronic Heart Failure; NCT03453151)., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: The purpose of this study was to characterize the clinical profile, treatment patterns, and clinical outcomes of patients with comorbid diabetes mellitus (DM) and heart failure with reduced ejection fraction (HFrEF) in a contemporary, real-world U.S. outpatient registry in the context of evolving treatment strategies., Background: Specific antihyperglycemic classes have differential risks and benefits with respect to HF. Limited data are available evaluating contemporary treatment patterns and outcomes of patients with comorbid DM and HFrEF., Methods: Among 4,970 patients with chronic HFrEF (≤40%) across 152 U.S. sites in the CHAMP-HF prospective, observational registry (2015 to 2017), we examined therapies and clinical outcomes by DM status., Results: Median age was 68 (58 to 75) years of age; 29% were women; 73.5% were white; and 64% had coronary artery disease. Overall, 42% (n = 2,085) had comorbid DM with a median hemoglobin A1c (HbA1c) level of 7.2% (interquartile range [IQR]: 6.4% to 8.3%). One-fourth of DM patients (24%) were not treated with an antihyperglycemic therapy. Most patients with DM were taking 1 (46%) or 2 (23%) antihyperglycemic therapies: metformin (40%); insulin (33%); sulfonylureas (24%); dipeptidyl peptidase-4 inhibitors (10%); glucagon-like peptide (GLP)-1 receptor agonists (4%); sodium-glucose cotransporter (SGLT)-2 inhibitors (2%); and thiazolidinediones (2%). Among patients with DM, 62%, 16%, 80%, and 33.5% were receiving any angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitor (ARNI), β-blockers, or mineralocorticoid receptor antagonists (MRAs) at baseline, respectively. Among patients without DM, corresponding baseline rates were 65%, 15%, 80%, and 37%, respectively. Patients with or without DM were infrequently treated with guideline-directed HFrEF therapies at target doses (≤27% across classes). During median 15-month follow-up, patients with DM experienced higher rates of all-cause mortality or HF hospitalization (30% vs. 23%, respectively), independent of 11 pre-specified covariates (adjusted hazard ratio: 1.35 (95% confidence interval: 1.21 to 1.52); p < 0.001)., Conclusions: Despite higher risk-adjusted clinical event rates in patients with comorbid HFrEF and DM, guideline-directed medical therapies for both disease states are incomplete and represent an important target for quality improvement through multidisciplinary care pathways., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to evaluate the association of physical activity (PA) level and longitudinal PA trajectory with a composite heart failure hospitalization and mortality endpoint over a 5-year follow-up period following implantation., Background: Low device measured PA early after implantation of an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) is associated with poor outcomes., Methods: We linked daily PA data from the Boston Scientific ALTITUDE dataset of patients with ICD or CRT-D implantation to Medicare claims data. We used a joint model to investigate the association of the composite endpoint with 1) the time-varying point estimate of PA and 2) the time-varying trajectory/slope of PA during follow-up., Results: Among 20,927 patients with median activity level 85 min/day, 14.1% and 49.6% experienced the composite endpoint at 1 and 5 years. Adjusted joint model results showed that there was a 1.13 (95% confidence interval: 1.12 to 1.13)-fold increase in the hazard of the composite endpoint for 75 min of daily PA relative to 85 min of PA; and a within-patient 10-min decrease in average daily PA over an 8-week period from 85 to 75 min was associated with a hazard ratio of 4.02 (95% confidence interval: 3.82 to 4.22) for the composite endpoint., Conclusions: Patients with large decreases in PA have significantly higher risk of experiencing heart failure hospitalization or death. PA data from implantable devices may identify patients before clinical decompensation., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In heart failure with reduced ejection fraction (HFrEF), elevated soluble neprilysin (sNEP) levels are associated with an increased risk of cardiovascular death, and its inhibition with sacubitril/valsartan has improved survival., Objectives: This study sought to determine the relevance of sNEP as a biomarker in heart failure with preserved ejection fraction (HFpEF) and to compare circulating sNEP levels in patients with HFpEF with normal controls., Methods: A case-control study was performed in 242 symptomatic patients with HFpEF previously enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) and Nitrates's Effect on Activity Tolerance in Heart Failure With Preserved Ejection (NEAT-HFpEF) clinical trials and 891 asymptomatic subjects without HF or diastolic dysfunction (confirmed by NT-proBNP levels <200 pg/ml and echocardiography) who were enrolled in the Prevalence of Asymptomatic Left Ventricular Dysfunction study. sNEP was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) in all subjects., Results: Overall, sNEP levels were lower in HFpEF compared with controls (3.5 ng/ml; confidence interval [CI]: 2.5 to 4.8 vs. 8.5 ng/ml; CI: 7.2 to 10.0; p < 0.001). After adjusting for age, gender, body mass index (BMI), and smoking history, mean sNEP levels were also lower in HFpEF compared with controls (4.0 ng/ml [CI: 2.7 to 5.4] vs. 8.2 ng/ml [CI: 6.8 to 9.7]; p = 0.002). The cohorts were propensity matched based on age, BMI, diabetes, hypertension, smoking history, and renal function, and sNEP levels remained lower in HFpEF compared with controls (median 2.4 ng/ml [interquartile range: 0.6 to 27.7] vs. 4.9 ng/ml [interquartile range: 1.2 to 42.2]; p = 0.02)., Conclusions: Patients with HFpEF on average have significantly lower circulating sNEP levels compared with controls. These findings challenge our current understanding of the complex biology of circulating sNEP in HFpEF., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The mandatory federal pay-for-performance Hospital Readmissions Reduction Program (HRRP) was created to decrease 30-day hospital readmissions by instituting accountability and stimulating quality care and coordination, particularly during care transitions. The HRRP has changed the landscape of hospital readmissions and reimbursement within the United States by imposing substantial Medicare payment penalties on hospitals with higher-than-expected readmission rates. However, the HRRP has been controversial since its inception, particularly in the field of heart failure. Proponents argue that it has reduced national readmission rates, in part by raising awareness and investment in mechanisms to better assist patients during discharge and transitions; opponents contend that it unfairly penalizes hospitals for issues beyond their control, has unintended negative consequences due to incentivizing readmission over survival, that it encourages "gaming" the system, was not tested before implementation, and that it does not specify how hospitals can improve their performance. This paper incorporates the diverse, nuanced, and sometimes divergent interpretations presented during a multifaceted expert clinician discussion regarding the HRRP and heart failure; in cases in which consensus opinions were achieved, they are presented, including regarding potential new iterations of the HRRP for the future. Potential improvements include more comprehensive incorporation of outcomes into the HRRP measure and better risk adjustment to improve equality and fairness., (Copyright © 2020 American College of Cardiology Foundation. All rights reserved.)

The adoption of mobile health (mHealth) devices is creating a unique opportunity to improve heart failure (HF) care. The rise of mHealth is driven by multiple factors including consumerism, policy changes in health care, and innovations in technology. Wearable health devices are one aspect of mHealth that may improve the delivery of HF care by allowing for medical data collection outside of a clinician's office or hospital. Wearable devices are externally applied and capture functional or physiological data in order to monitor and improve patients' health. Most wearable sensors capture data continuously and may be incorporated into accessories (e.g., a watch or clothing) or may be applied as a cutaneous patch. Wearable devices are often paired with another device, such as a smartphone, to collect, interpret, or transmit data. This study assessed the potential applications of wearable devices in HF care, summarizes available data for wearables, and discusses the future of wearables for improving the health of patients with HF., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the degree to which U.S. patients enrolled in a heart failure (HF) trial represent patients in routine U.S. clinical practice according to race and sex., Background: Black patients and women are frequently under-represented in HF clinical trials. However, the degree to which black patients and women enrolled in trials represent such patients in routine practice is unclear., Methods: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized patients hospitalized for HF to receive nesiritide or placebo from May 2007 to August 2010 and was neutral for clinical endpoints. This analysis compared non-Hispanic white (n = 1,494) and black (n = 1,012) patients enrolled in ASCEND-HF from the U.S. versus non-Hispanic white and black patients included in a U.S. hospitalized HF registry (i.e., Get With The Guidelines-Heart Failure [GWTG-HF]) during the ASCEND-HF enrollment period and meeting trial eligibility criteria., Results: Among 79,291 white and black registry patients, 49,063 (62%) met trial eligibility criteria (white, n = 37,883 [77.2%]; black, n = 11,180 [22.8%]). Women represented 35% and 49% of the ASCEND-HF and trial-eligible GWTG-HF cohorts, respectively. Compared with trial-enrolled patients, trial-eligible GWTG-HF patients tended to be older with higher blood pressure and higher ejection fraction. Trial-eligible patients had higher in-hospital mortality (2.3% vs. 1.3%), 30-day readmission (20.2% vs. 16.8%), and 180-day mortality (21.2% vs. 18.6%) than those enrolled in the trial (all p < 0.02), with consistent mortality findings by race and sex. After propensity score matching, mortality rates were similar; however, trial-eligible patients continued to have higher rates of 30-day readmission (23.1% vs. 17.3%; p < 0.01), driven by differences among black patients and women (all p for interaction ≤0.02)., Conclusions: Patients with HF seen in U.S. practice and eligible for the ASCEND-HF trial had worse clinical outcomes than those enrolled in the trial. After accounting for clinical characteristics, trial-eligible real-world patients continued to have higher rates of 30-day readmission, driven by differences among black patients and women. Social, behavioral, and other unmeasured factors may impair representativeness of patients enrolled in HF trials, particularly among racial/ethnic minorities and women. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the rate of use of target doses of foundational guideline-directed medical therapy (GDMT) in a contemporary cohort of patients with heart failure with reduced ejection fraction (HFrEF) across systolic blood pressure (SBP) categories., Background: Patients with HFrEF are infrequently titrated to recommended doses of GDMT. The relationship between SBP and achieving GDMT target doses is not well studied., Methods: Patients enrolled in the CHAMP-HF (Change the Management of Patients With Heart Failure) registry without documented intolerance to angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and beta blockers (BBs) were assessed at enrollment. We estimated the proportion receiving target doses (% of target dose [95% confidence interval (CI)]) based on the most recent American College of Cardiology/American Heart Association/Heart Failure Society of America heart failure guidelines at baseline in all patients, and by SBP category (≥110 vs. <110 mm Hg)., Results: Of the 3,095 patients eligible for analysis, 2,421 (78.2%) had SBP ≥110 mm Hg. The proportion of patients receiving target doses were 18.7% (95% CI: 17.3% to 20.0%; BB), 10.8% (95% CI: 9.7% to 11.9%; ACEI/ARB), and 2.0% (95% CI: 1.5% to 2.5%; ARNI). Among those with SBP <110 mm Hg (n = 674), 17.5% (95% CI: 14.6% to 20.4%; BB), 6.2% (95% CI: 4.4% to 8.1%; ACEI/ARB), and 1.8% (95% CI: 0.8% to 2.8%; ARNI) were receiving target doses. Among those with SBP ≥110 mm Hg (n = 2,421), 19.0% (95% CI: 17.4% to 20.6%; BB), 12.1% (95% CI: 10.8% to 13.4%; ACEI/ARB), and 2.0% (95% CI: 1.5% to 2.6%; ARNI) were receiving target doses., Conclusions: In a large, contemporary registry of outpatients with chronic HFrEF eligible for treatment with BBs and ACEI/ARB/ARNI, <20% of patients were receiving target doses, even among those with SBP ≥110 mm Hg., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to characterize the course of decongestion among patients hospitalized for acute heart failure (AHF) by history of atrial fibrillation (AF) and/or atrial flutter (AFL)., Background: AF/AFL and chronic heart failure (HF) commonly coexist. Little is known regarding the impact of AF/AFL on relief of congestion among patients who develop AHF., Methods: We pooled patients from 3 randomized trials of AHF conducted within the Heart Failure Network, the DOSE (Diuretic Optimization Strategies) trial, the ROSE (Renal Optimization Strategies) trial, and the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial. The association between history of AF/AFL and in-hospital changes in various metrics of congestion was assessed using covariate-adjusted linear and ordinal logistic regression models., Results: Of 750 unique patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27%, respectively; p < 0.001), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were nonsignificantly lower at baseline (4,210 pg/ml vs. 5,037 pg/ml, respectively; p = 0.27) in patients with AF/AFL. After adjustment of covariates, history of AF/AFL was associated with less substantial loss of weight (-5.7% vs. -6.5%, respectively; p = 0.02) and decrease in NT-proBNP levels (-18.7% vs. -31.3%, respectively; p = 0.003) by 72 or 96 h. History of AF/AFL was also associated with a blunted increase in global sense of well being at 72 or 96 h (p = 0.04). There was no association between history of AF/AFL and change in orthodema congestion score (p = 0.67) or 60-day composite clinical endpoint (all-cause mortality or any rehospitalization; hazard ratio: 1.21; 95% confidence interval: 0.92 to 1.59; p = 0.17)., Conclusions: More than half of the patients admitted with AHF had a history of AF/AFL. History of AF/AFL was independently associated with a blunted course of in-hospital decongestion. Further research is required to understand the utility of specific therapies targeting AF/AFL during hospitalization for AHF., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate and contribute to the limited data on U.S. hospital practice patterns with respect to respiratory vaccination in patients hospitalized with heart failure (HF)., Background: Respiratory infection is a major driver of morbidity in patients with HF, and many influenza and pneumococcal infections may be prevented by vaccination., Methods: This study evaluated patients hospitalized at centers participating in the Get With The Guidelines-HF (GWTG-HF) registry from October 2012 to March 2017. The proportion of patients receiving vaccination was described for influenza and pneumococcal vaccination, respectively. The association of hospital-level vaccination rates with individual GWTG-HF performance measures and defect-free care was evaluated using multivariable modeling., Results: This study evaluated 313,761 patients discharged from 392 hospitals during the study period. The proportion of patients receiving influenza vaccination was 68% overall and declined from 70% in 2012 to 2013 to 66% in 2016 to 2017 (p < 0.001), although this was not statistically significant after adjustment (odds ratio: 1.05 per flu season; 95% confidence interval [CI]: 0.94 to 1.18). The proportion of patients receiving pneumococcal vaccination was 66% overall and decreased over the study period from 71% in 2013 to 60% in 2016 (p < 0.001), remaining significant after adjustment (odds ratio: 0.75 per calendar year; 95% CI: 0.67 to 0.84). Hospitals with higher vaccination rates were more likely to discharge patients with higher performance on defect-free care and individual GWTG-HF performance measures (p < 0.001). In a subset of patients with linked Medicare claims, vaccinated patients had similar rates of 1-year all-cause mortality (adjusted hazard ratio: 0.96 [95% CI: 0.89 to 1.03] for influenza vaccination; adjusted hazard ratio: 0.95 [95% CI: 0.89 to 1.01] for pneumococcal vaccination) compared with those not vaccinated., Conclusions: Nearly 1 in 3 patients hospitalized with HF at participating hospitals were not vaccinated for influenza or pneumococcal pneumonia, and vaccination rates did not improve from 2012 to 2017. Hospitals that exhibited higher vaccination rates performed well with respect to other HF quality of care measures. Vaccination status was not associated with differences in clinical outcomes. Further randomized controlled data are needed to assess the relationship between vaccination and outcomes., (Copyright © 2018. Published by Elsevier Inc.)

Objectives: This study sought to describe the health status of outpatients with heart failure and reduced ejection fraction (HFrEF) by sex, race/ethnicity, and socioeconomic status (SES)., Background: Although a primary goal in treating patients with HFrEF is to optimize health status, whether disparities by sex, race/ethnicity, and SES exist is unknown., Methods: In the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, the associations among sex, race, and SES and health status, as measured by the Kansas City Cardiomyopathy Questionnaire-overall summary (KCCQ-os) score (range 0 to 100; higher scores indicate better health status) was compared among 3,494 patients from 140 U.S. clinics. SES was categorized by total household income. Hierarchical multivariate linear regression estimated differences in KCCQ-os score after adjusting for 31 patient characteristics and 10 medications., Results: Overall mean KCCQ-os scores were 64.2 ± 24.0 but lower for women (29% of sample; 60.3 ± 24.0 vs. 65.9 ± 24.0, respectively; p < 0.001), for blacks (60.5 ± 25.0 vs. 64.9 ± 23.0, respectively; p < 0.001), for Hispanics (59.1 ± 21.0 vs. 64.9 ± 23.0, respectively; p < 0.001), and for those with the lowest income (<$25,000; mean: 57.1 vs. 63.1 to 74.7 for other income categories; p < 0.001). Fully adjusted KCCQ-os scores were 2.2 points lower for women (95% confidence interval [CI]: -3.8 to -0.6; p = 0.007), no different for blacks (p = 0.74), 4.0 points lower for Hispanics (95% CI: -6.6 to -1.3; p = 0.003), and lowest in the poorest patients (4.7 points lower than those with the highest income (95% CI: 0.1 to 9.2; p = 0.045; p for trend = 0.003)., Conclusions: Among outpatients with HFrEF, women, blacks, Hispanics, and poorer patients had worse health status, which remained significant for women, Hispanics, and poorer patients in fully adjusted analyses. This suggests an opportunity to further optimize treatment to reduce these observed disparities., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to analyze cumulative Medicare expenditures at index admission and after discharge by race or ethnicity., Background: Heart failure with preserved ejection fraction (HFpEF) is a growing proportion of heart failure (HF) admissions. Research on health care expenditures for patients with HFpEF is limited., Methods: Records of patients discharged from the Get With The Guidelines-Heart Failure registry between 2006 and 2014 were linked to Medicare data. The primary outcome was unadjusted payments for acute care services. Comparisons between race/ethnic groups were made using generalized linear mixed models. Cost ratios were reported by race/ethnicity, and adjustments were made sequentially for patient characteristics, hospital factors, and regional socioeconomic status., Results: Median Medicare costs for index hospitalizations were $7,241 for the entire cohort, $7,049 for whites, $8,269 for blacks, $8,808 for Hispanics, $8,477 for Asians, and $8,963 for other races. Median costs at 30 days for readmitted patients were $9,803 and $17,456 for the entire cohort at 1-year. No significant differences were seen in index admission cost ratios by race/ethnicity. At 30 days among readmitted patients, costs were 9% higher (95% confidence interval [CI]: 1% to 17%; p = 0.020) for blacks in the fully adjusted model than whites. At 1 year, costs were 14% higher (95% CI: 9% to 18%; p < 0.001) for blacks, 7% higher (95% CI: 0% to 14%; p = 0.041) for Hispanics, and 24% higher (95% CI: 8% to 42%; p = 0.003) for patients of other races. No significant differences between white and Asian expenditures were noted., Conclusions: Minority patients with HFpEF have greater acute care service costs. Further research of improving care delivery is needed to reduce acute care use for vulnerable populations., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: As the largest acute heart failure (AHF) trial conducted to date, the global ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial database presented an opportunity to systematically describe the relationship among time of hospital presentation, clinical profile, inpatient management, and outcomes among patients admitted with AHF., Background: Time of hospital presentation has been shown to impact outcomes among patients hospitalized with many conditions. However, the association among time of presentation and patient characteristics, management, and clinical outcomes among patients hospitalized with AHF has not been well characterized., Methods: A post hoc analysis of the ASCEND-HF trial was performed, which enrolled 7,141 patients hospitalized for AHF. Patients were divided based on when they presented to the hospital; regular hours were defined as 9 am to 5 pm, Monday through Friday, and off hours were defined as 5 pm to 9 am, Monday through Friday and weekends. Clinical characteristics and outcomes were compared by time of presentation., Results: Overall, 3,298 patients (46%) presented during off hours. Off-hour patients were more likely to have orthopnea (80% vs. 74%, respectively) and rales (56% vs. 49%, respectively) than regular-hour patients. Off-hour patients were more likely to receive intravenous (IV) nitroglycerin (18% vs. 11%, respectively) and IV loop diuretics (92% vs. 86%, respectively) as initial therapy and reported greater relief from dyspnea at 24 h (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.04 to 1.24; p = 0.01) than regular-hour patients. After adjustment, off-hour presentation was associated with significantly lower 30-day mortality (OR: 0.74; 95% CI: 0.57 to 0.96; p = 0.03) and 180-day mortality (hazard ratio [HR]: 0.82; 95% CI: 0.72 to 0.94; p = 0.01) but similar 30-day rehospitalization rates (p = 0.40)., Conclusions: In this AHF trial, patients admitted during off hours exhibited a distinct clinical profile, experienced greater dyspnea relief, and had lower post-discharge mortality than regular-hour patients. These findings have implications for future AHF trials., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This trial sought to evaluate whether vericiguat, a novel oral soluble guanylate cyclase (sGC) stimulator, was superior to placebo, on a background of standard of care, in increasing the time to the first occurrence of the composite endpoints of cardiovascular (CV) death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Deficiency in sGC-derived cyclic guanosine monophosphate (cGMP) causes both myocardial dysfunction and impaired endothelium-dependent vasomotor regulation that includes the myocardial microcirculation. Experimental studies have suggested multiple potential benefits of sGC stimulators including prevention, or even reversal, of left ventricular hypertrophy and fibrosis, as well as reduction of ventricular afterload through both systemic and pulmonary vasodilation. Hence, restoration of sufficient nitric oxide (NO)-sGC-cGMP signaling has been proposed as an important treatment target in HF. Vericiguat has been shown to directly stimulate sGC and enhance sGC sensitivity to endogenous NO. Available phase IIb data in HFrEF patients indicate vericiguat is safe and well-tolerated, and exploratory analyses indicate that it results in a dose-dependent, clinically significant reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at the highest tested dose. VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) is a randomized, placebo-controlled, parallel group, multicenter, double-blind, event-driven phase 3 trial of vericiguat in subjects with HFrEF. Approximately 4,872 subjects will be randomized to evaluate the efficacy and safety of vericiguat compared with placebo on a background of standard of care. After a screening phase of up to 30 days, eligible subjects will be treated until the required number of cardiovascular deaths is observed. The estimated median follow-up duration is approximately 18 months. All subjects will be followed until study completion to assess for the occurrence of endpoint events. VICTORIA will establish the efficacy and safety of vericiguat on cardiovascular death and HF hospitalization in patients with HFrEF. (A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction [HFrEF]-VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study analyzed HFpEF patient characteristics and clinical outcomes according to race/ethnicity and adjusted for patient and hospital characteristics along with socioeconomic status (SES)., Background: The proportion of hospitalizations for heart failure with preserved ejection fraction (HFpEF) has increased over the last decade. Whether the short- and long-term outcomes differ between racial/ethnic groups is not well described., Methods: The Get With The Guidelines-Heart Failure registry was linked to Medicare administrative data to identify hospitalized patients with HFpEF ≥65 years of age with left ventricular ejection fraction ≥50% between 2006 and 2014. Cox proportional hazards models were used to report hazard ratios (HRs) for 30-day and 1-year readmission and mortality rates with sequential adjustments for patient characteristics, hospital characteristics, and SES., Results: The final cohort included 53,065 patients with HFpEF. Overall 30-day mortality was 5.87%; at 1 year, it was 33.1%. The 30-day all-cause readmission rate was 22.2%, and it was 67.0% at 1 year. After adjusting for patient characteristics, hospital characteristics, and SES, 30-day mortality was lower for black patients (HR: 0.84; 95% confidence interval [CI]: 0.71 to 0.98; p = 0.031) and Hispanic patients (HR: 0.78; 95% CI: 0.64 to 0.96; p = 0.017) compared with white patients. One-year mortality was lower for black patients (HR: 0.93; 95% CI: 0.87 to 0.99; p = 0.031), Hispanic patients (HR: 0.83; 95% CI: 0.75 to 0.91; p < 0.001), and Asian patients (HR: 0.76; 95% CI: 0.66 to 0.88; p < 0.001) compared with white patients. Black patients had a higher risk of readmission at 30 days (HR: 1.09; 95% CI: 1.02 to 1.16; p = 0.012) and 1 year (HR: 1.14; 95% CI: 1.09 to 1.20; p < 0.001) compared with white patients., Conclusions: Black, Hispanic, and Asian patients had a lower mortality risk after a hospitalization for HFpEF compared with white patients; black patients had higher readmission rates. These differences in mortality and readmission risk according to race/ethnicity persisted after adjusting for patient characteristics, SES, and hospital factors., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to ascertain the impact of heart failure (HF) guideline change on the number of patients eligible to undergo cardiac resynchronization therapy (CRT)., Background: The 2013 HF guideline of the American College of Cardiology Foundation and American Heart Association (ACCF/AHA) narrowed the recommendations for CRT. The impact of this guideline change on the number of eligible patients for CRT has not been described., Methods: Using data from Get With The Guidelines-Heart Failure between 2012 and 2015, this study evaluated the proportion of hospitalized patients with HF who were eligible for CRT on the basis of historical and current guideline recommendations. The authors identified 25,102 hospitalizations for HF that included patients with a left ventricular ejection fraction (LVEF) ≤35% from 283 hospitals. Patients with a medical, system-related, or patient-related reason for not undergoing CRT were excluded., Results: Overall, 49.1% (n = 12,336) of patients with HF, an LVEF ≤35%, and no documented contraindication were eligible for CRT on the basis of historical guidelines, and 33.1% (n = 8,299) of patients were eligible for CRT on the basis of current guidelines, a 16.1% absolute reduction in eligibility (p < 0.0001). Patients eligible for CRT on the basis of current guidelines were more likely to have CRT with an implantable cardioverter-defibrillator or CRT with pacing only placed or prescribed at discharge (57.8% vs. 54.9%; p < 0.0001) compared with patients eligible for CRT on the basis of historical guidelines., Conclusions: In this population of patients with HF, an LVEF ≤35%, and no documented contraindication for CRT, the current ACCF/AHA HF guidelines reduce the proportion of patients eligible for CRT by approximately 15%., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Acute heart failure (HF) is a major public health problem with substantial associated economic costs. Because most patients who present to hospitals are admitted irrespective of their level of risk, novel approaches to manage acute HF are needed, such as the use of same-day access clinics for outpatient diuresis and observation units from the emergency department. Current published data lacks a comprehensive overview of the present state of acute HF management in various clinical settings. This review summarizes the strengths and limitations of acute HF care in the outpatient and emergency department settings. Finally, a variety of innovative technologies that have the potential to improve acute HF management are discussed., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the prevalence and variation in angiotensin receptor/neprilysin inhibitor (ARNI) prescription among a real-world population with heart failure with reduced ejection fraction (HFrEF)., Background: The U.S. Food and Drug Administration approved sacubitril/valsartan for patients with HFrEF in July 2015. Little is known about the early patterns of use of this novel therapy., Methods: The study included patients discharged alive from hospitals in Get With the Guidelines-Heart Failure (GWTG-HF), a registry of hospitalized patients with heart failure, between July 2015 and June 2016 who had documentation of whether ARNIs were prescribed at discharge. Patient and hospital characteristics were compared among patients with HFrEF (ejection fraction ≤40%) with and without ARNI prescription at discharge, excluding those with documented contraindications to ARNIs. To evaluate hospital variation, hospitals with at least 10 eligible hospitalizations during the study period were assessed., Results: Of 21,078 patients hospitalized with HFrEF during the study period, 495 (2.3%) were prescribed ARNIs at discharge. Patients prescribed ARNIs were younger (median age 65 years vs. 70 years; p < 0.001), had lower ejection fractions (median 23% vs. 25%; p < 0.001), and had higher use of aldosterone antagonists (45% vs. 31%; p < 0.001) at discharge. At the 241 participating hospitals with 10 or more eligible admissions, 125 (52%) reported no discharge prescriptions of ARNIs., Conclusions: Approximately 2.3% of patients hospitalized for HFrEF in a national registry were prescribed ARNI therapy in the first 12 months following Food and Drug Administration approval. Further study is needed to identify and overcome barriers to implementing new evidence into practice, such as ARNI use among eligible patients with HFrEF., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) is a chronic syndrome characterized by acute exacerbations. There is significant overlap between respiratory infections and exacerbation of underlying HF. Vaccination against respiratory infections in patients with HF could serve as a potential cost-effective intervention to improve patients' quality of life and clinical outcomes. The benefits of influenza vaccination in secondary prevention of ischemic heart disease have been previously studied. However, the evidence for influenza and pneumococcal vaccination specifically in the HF population is less well established. Furthermore, questions around the optimal timing, dose, frequency, and implementation strategies are largely unanswered. This review highlights the current evidence for vaccination against influenza and pneumococcal pneumonia in HF and cardiovascular disease. It summarizes current understanding of the pathophysiologic mechanisms in which vaccination may provide cardioprotection. Finally, it offers opportunities for further investigation on the effects of vaccination in the HF population, spanning basic science, translational research, and large clinical trials., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to examine the relationships between in-hospital and post-discharge body weight changes and outcomes among patients hospitalized for acute heart failure (AHF)., Background: Body weight changes during and after hospitalization for AHF and the relationships with outcomes have not been well characterized., Methods: A post hoc analysis was performed of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial, which enrolled patients admitted for AHF regardless of ejection fraction. In-hospital body weight change was defined as the difference between baseline and discharge/day 10, whereas post-discharge body weight change was defined as the difference between discharge/day 10 and day 30. Spearman rank correlations of weight change, urine output (UOP), and dyspnea relief as assessed by a 7-point Likert scale are described. Logistic and Cox proportional hazards regression was used to evaluate the relationship between weight change and outcomes., Results: Study participants with complete body weight data (n = 4,172) had a mean age of 65 ± 14 years, and 66% were male. Ischemic heart disease was reported in 60% of patients and the average ejection fraction was 30 ± 13%. The median change in body weight was -1.0 kg (interquartile range: -2.1 to 0.0 kg) at 24 h and -2.3 kg (interquartile range: -5.0 to -0.7 kg) by discharge/day 10. At hour 24, there was a weak correlation between change in body weight and UOP (r = -0.381), and minimal correlation between body weight change and dyspnea relief (r = -0.096). After risk adjustment, increasing body weight during hospitalization was associated with a 16% increase per kg in the likelihood of 30-day mortality or HF readmission for patients showing weight loss ≤1 kg or weight gain during hospitalization (odds ratio per kg increase 1.16, 95% confidence interval [CI]: 1.09 to 1.27; p < 0.001). Among the subset of patients experiencing >1-kg increase in body weight post-discharge, increasing body weight was associated with higher risk of 180-day mortality (hazard ratio per kg increase 1.16; 95% CI: 1.09 to 1.23; p < 0.001)., Conclusions: A substantial number of patients experienced minimal weight loss or frank weight gain in the context of an AHF trial, and increasing body weight in this subset of patients was independently associated with a worse post-discharge prognosis., Competing Interests: All other authors declare no relevant financial disclosures., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine whether processes of care and long-term clinical outcomes for heart failure (HF) admissions across Get With The Guidelines-Heart Failure (GWTG-HF) program participating centers differ according to HF-specific risk-adjusted 30-day readmission rates (excess readmission ratio [ERR]) as determined by the Hospital Readmission Reduction Program (HRRP)., Background: HRRP penalizes hospitals with higher than expected risk-adjusted 30-day readmission rates (ERR >1) for common conditions including HF. However, it is unclear whether the differences in this metric of hospital performance used by HRRP and related penalties are associated with measured quality of care and long-term outcomes., Methods: We analyzed data from the GWTG-HF registry linked to Medicare claims from July 2008 to June 2011. Using publically available data on HF-ERR in 2013, we stratified the participating centers into groups with low (HF-ERR ≤1) versus high (HF-ERR >1) risk-adjusted readmission rates. We compared the care quality, in-hospital, and 1-year clinical outcomes across the 2 groups in unadjusted and multivariable adjusted analysis., Results: The analysis included 171 centers with 43,143 participants; 49% of centers had high risk-adjusted 30-day readmission rates (HF-ERR >1). There were no differences between the low and high risk-adjusted 30-day readmission groups in median adherence rate to all performance measures (95.7% vs. 96.5%; p = 0.37) or median percentage of defect-free care (90.0% vs. 91.1%; p = 0.47). The composite 1-year outcome of death or all-cause readmission rates was also not different between the 2 groups (median 62.9% vs. 65.3%; p = 0.10). The high HF-ERR group had higher 1-year all-cause readmission rates (median 59.1% vs. 54.7%; p = 0.01). However, the 1-year mortality rates were lower among high versus low HF-ERR group with a trend toward statistical significance (median 28.2% vs. 31.7%; p = 0.07)., Conclusions: Quality of care and clinical outcomes were comparable among hospitals with high versus low risk-adjusted 30-day HF readmission rates. These findings raise questions about the validity of the HRRP performance metric in identifying and penalizing low-performance centers., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Although therapy with mineralocorticoid receptor antagonists (MRAs) is recommended for patients with chronic heart failure (HF) with reduced ejection fraction and in post-infarction HF, it has not been studied well in acute HF (AHF) despite being commonly used in this setting. At high doses, MRA therapy in AHF may relieve congestion through its natriuretic properties and mitigate the effects of adverse neurohormonal activation associated with intravenous loop diuretics. The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) trial is a randomized, double-blind, placebo-controlled study of the safety and efficacy of 100 mg/day spironolactone versus placebo (or continued low-dose spironolactone use in participants who are already receiving spironolactone at baseline) in 360 patients hospitalized for AHF. Patients are randomized within 24 h of receiving the first dose of intravenous diuretics. The primary objective is to determine if high-dose spironolactone, compared with standard care, will lead to greater reductions in N-terminal pro-B-type natriuretic peptide levels from randomization to 96 h. The secondary endpoints include changes in the clinical congestion score, dyspnea relief, urine output, weight change, loop diuretic dose, and in-hospital worsening HF. Index hospital length of stay and 30-day clinical outcomes will be assessed. Safety endpoints include risk of hyperkalemia and renal function. Differences among patients with reduced versus preserved ejection fraction will be determined. (Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure [ATHENA-HF]; NCT02235077)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to determine the temporal trends in the adherence to heart failure (HF)-related process of care measures and clinical outcomes among patients with acute decompensated HF with reduced ejection fraction (HFrEF) and end-stage renal disease (ESRD)., Background: Previous studies have demonstrated significant underuse of evidence-based HF therapies among patients with coexisting ESRD and HFrEF. However, it is unclear if the proportional use of evidence-based medical therapies and associated clinical outcomes among these patients has changed over time., Methods: Get With The Guidelines-HF study participants who were admitted for acute HFrEF between January 2005 and June 2014 were stratified into 3 groups on the basis of their admission renal function: normal renal function, renal insufficiency without dialysis, and dialysis. Temporal change in proportional adherence to the HF-related process of care measures and incidence of clinical outcomes (1-year mortality, HF hospitalization, and all-cause hospitalization) during the study period was evaluated across the 3 renal function groups., Results: The study included 111,846 patients with HFrEF from 390 participating centers, of whom 19% had renal insufficiency but who did not require dialysis, and 3% were on dialysis. There was a significant temporal increase in adherence to evidence-based medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker: p trend <0.0001, β-blockers: p trend = 0.0089; post-discharge follow-up referral: p trend <0.0001) and defect-free composite care (p trend <0.0001) among dialysis patients. An improvement in adherence to these measures was also observed among patients with normal renal function and patients with renal insufficiency without a need for dialysis. There was no significant change in cumulative incidence of clinical outcomes over time among the HF patients on dialysis., Conclusions: In a large contemporary cohort of HFrEF patients with ESRD, adherence to the HF process of care measures has improved significantly over the past 10 years. Unlike patients with normal renal function, there was no significant change in 1-year clinical outcomes over time among HF patients on dialysis., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study assessed the comparative frequency of precipitating clinical factors leading to hospitalization among heart failure (HF) patients with reduced, borderline, and preserved ejection fraction (EF) BACKGROUND: There are few data assessing the comparative frequency of clinical factors leading to HF among hospitalized among patients with reduced, borderline, and preserved EF., Methods: We analyzed the factors potentially contributing to HF hospitalization among 99,825 HF admissions from 305 hospitals in the Get With The Guidelines-HF (GWTG-HF) database between January 2005 and September 2013 and assessed their association with length of stay and in-hospital mortality., Results: Mean patient age was 72.6 ± 14.2 years, 49% were female, and mean EF was 39.3 ± 17.2%. Common factors included pneumonia/respiratory process (28.2%), arrhythmia (21.7%), medication noncompliance (15.8%), worsening renal failure (14.7%), and uncontrolled hypertension (14.5%). In patients with borderline EF (EF 40% to 49%), pneumonia was associated with longer hospital stay, whereas dietary and medication noncompliance were associated with reduced length of stay. In patients with preserved EF (EF ≥50% or qualitative assessment of normal or mild dysfunction), pneumonia, weight gain, and worsening renal function were independently associated with longer lengths of stay. Worsening renal function and pneumonia were independently associated with higher in-hospital mortality in all HF groups, and acute pulmonary edema was associated with higher mortality in reduced EF. Dietary noncompliance (14.7%) was associated with reduced mortality for all groups but reached statistical significance in the subgroups of reduced (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46 to 0.91) and preserved systolic function (OR: 0.52; 95% CI: 0.33 to 0.83). Patients presenting with ischemia had a higher mortality rate (OR: 1.31; 95% CI: 1.02 to 1.69; and 1.72; 95% CI: 1.27 to 2.33, respectively, in the 2 groups)., Conclusions: Potential precipitating factors among patients hospitalized with HF vary by EF group and are independently associated with clinical outcomes., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess temporal trends and factors associated with digoxin use at discharge among patients admitted with heart failure (HF)., Background: Digoxin has class IIa recommendations for treating HF with reduced ejection fraction (HFrEF) in the United States. Digoxin use, temporal trends, and clinical characteristics of HF patients in current clinical practice in the United States have not been well studied., Methods: An observational analysis of 255,901 patients hospitalized with HF (117,761 with HFrEF and 138,140 with preserved EF [HFpEF]) from 398 hospitals participating in the Get With The Guidelines-HF registry between January 2005 and June 2014 was conducted to assess the temporal trends and factors associated with digoxin use., Results: Among 117,761 HFrEF patients, only 19.7% received digoxin at discharge. Digoxin prescriptions decreased from 33.1% in 2005 to 10.7% in 2014 (ptrend < 0.0001). Factors associated with digoxin use in HFrEF included atrial fibrillation (AF) (odds ratio [OR]: 2.14; 95% confidence intervals [CI]: 2.02 to 2.28), history of implantable cardioverter defibrillator use (OR: 1.39; 95% CI: 1.32 to 1.46), chronic obstructive pulmonary disease (OR: 1.13, 95% CI: 1.08 to 1.18), diabetes mellitus (OR: 1.10, 95% CI: 1.06 to 1.14), younger age (OR: 0.96, 95% CI: 0.95 to 0.97), lower blood pressure (OR: 0.96, 95% CI: 0.96 to 0.97), and having no history of renal insufficiency (OR: 0.91, 95% CI: 0.85 to 0.97). Use of digoxin in patients with HFpEF (n = 138,140) without AF was 9.8% in 2005, which decreased to 2.2% in 2014 (ptrend < 0.0001)., Conclusions: One in 5 HFrEF patients received digoxin at discharge, with a significant downward temporal trend in use over the study period. Use of digoxin in HFpEF patients without AF was very low and decreased over the study period., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study assessed the association between pulse pressure (PP) and adverse outcomes at 1 year in patients hospitalized for heart failure (HF)., Background: PP has been shown to be predictive of the development of HF. The value and utility of PP assessment in patients with prevalent HF is less clear., Methods: We conducted a retrospective cohort study from clinical registry data linked to Medicare claims for 40,421 HF patients entered in the Get With the Guidelines-HF program. Cox proportional hazards models were used to estimate the association between discharge PP and all-cause mortality and the composite outcome of all-cause mortality/readmission by 1 year., Results: A nonlinear association between PP and mortality (expressed as hazard ratio [HR] per 10-mm Hg increase in PP) was observed in patients with HF and reduced (<0.40) ejection fraction (EF). Risk decreased as PP increased up to 50 mm Hg (adjusted HR: 0.946; 95% confidence interval [CI]: 0.900 to 0.995; p = 0.03). When PP was ≥50 mm Hg, risk increased as PP increased (adjusted HR: 1.091; 95% CI: 1.050 to 1.135; p < 0.001). In patients with HF and preserved EF (≥0.40), there was a significant association between PP and mortality with risk increasing as PP increased, although the magnitude of the risk was significantly impacted by systolic blood pressure (SBP). Qualitatively similar observations were obtained for the composite outcome and use of EF ≥0.50 to define HF with preserved EF., Conclusions: The association between PP at hospital discharge and 1-year outcomes is a function of HF phenotype, SBP, and absolute PP., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The study sought to investigate the association between soluble growth stimulation expressed gene 2 (sST2) level and adverse outcomes in acute heart failure (HF)., Background: Several studies have demonstrated the prognostic utility of sST2 levels in HF., Methods: sST2 levels were measured in sequential baseline and follow-up (48 to 72 h and 30 days) plasma samples from 858 acute HF subjects enrolled in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial biomarker substudy and were related to in-hospital and post-discharge clinical outcomes., Results: Higher sST2 levels were associated with increased death risk at 180 days (baseline hazard ratio [HR]: 2.21; follow-up HR: 2.64; both p < 0.001). These results were not independent of covariates and aminoterminal pro-B-type natriuretic peptide for baseline sST2 (HR: 1.29, p = 0.243), but were borderline significant for follow-up sST2 (HR: 1.61, p = 0.051). Subjects with persistently high (>60 ng/ml) sST2 levels at follow-up had higher 180-day death rates than those with lower follow-up sST2 levels (adjusted HR: 2.91, p = 0.004). Neither baseline nor follow-up sST2 levels were associated with dyspnea improvement. Changes in sST2 from baseline were less in the nesiritide versus placebo group at follow-up, but were similar at 30 days., Conclusions: Elevated levels of sST2 were associated with an increased risk of adverse clinical events in acute HF, but prognostic value of baseline sST2 diminished after adjusting for clinical covariates and aminoterminal pro-B-type natriuretic peptide. In those with elevated baseline sST2 levels, persistently elevated sST2 levels at follow-up were associated with increased mortality risk. In addition, nesiritide did not demonstrate an incremental impact on sST2 levels over standard therapy., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)