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Background: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients., Methods and Results: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51)., Conclusions: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients., Competing Interests: Declaration of Competing Interest K.F.D. has received financial support to attend educational meetings from Cytokinetics during the conduct of the study, personal fees from AstraZeneca, consulting fees from Us2.ai and research grants to his institution from AstraZeneca and Boehringer Ingelheim outside the submitted work. J.J.V.M. has received funding to his institution from Amgen and Cytokinetics for his participation in the Steering Committee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, 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). R.D. has received research grants and other payment or honoraria from Amgen. G.M.F. has received grant funding to his institution from American Heart Association, Amgen, Bayer, Bristol Myers Squibb, CSL-Behring, Cytokinetics, Merck, Myokardia, and National Institutes of Health; has received consulting fees from Abbott, American Regent, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cardionomic, Cytokinetics, Medtronic, Myovant, Novartis, Reprieve, Sequana, Windtree Therapeutics, and WhiteSwell; and has participated on Data Safety Monitoring boards or advisory boards for EBR Systems, LivaNova, Medtronic, Siemens, Rocket Pharma, and V-Wave. M.M. has received funding to his institution from Amgen and Cytokinetics as participant to the Executive Committee during the trial and for patients’ enrolment; has received consulting fees for participation to advisory boards from AstraZeneca, Bayer, and Boehringer Ingelheim; has received personal fees as member of Executive or Data Monitoring Committees of sponsored clinical trials from LivaNova and Vifor Pharma; has received speaker fees from Abbott Vascular and Edwards Therapeutics for speeches at sponsored meetings; and has participated on Data Safety Monitoring boards for Actelion. S.D.S. has received grant funding to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis Pharmaceuticals, 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 received consulting fees from Abbott, Action, Akros, Alnylam, American Regent, Amgen, Anacardio, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior, Cardurion, CellProthera, Corvia, Cytokinetics, Daiichi Sankyo, Dinaqor, GlaxoSmithKline, Janssen, Lexicon, Lilly, Merck, Moderna, Myokardia, Novartis, Puretech Health, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta, Tenaya, Theracos, and Tremeau. K.F.A. has received research grants from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals Inc., Eli Lilly USA, LivaNova USA, Merck, Novartis, and Otsuka; acted as a consultant to Amgen, Cytokinetics, Inc., Novartis, Roche Diagnostics, Relypsa, and Windtree Therapeutics. M.B. has received funds from the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and personal fees from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, ReCor, Servier, Vifor Pharma, and Boehringer Ingelheim. A.R.G. reports consulting fees for clinical trials from Amgen, Novartis, KOWA, and Bayer outside the submitted work; personal payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk outside the submitted work; support for attending meetings and/or travel from Pfizer, AstraZeneca, and Boehringer Ingelheim; and leadership or fiduciary role as President, Bulgarian Society of Cardiology 2020-22. J.G.H. has received grants and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, and Pfizer; has received personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, and Pfizer; and is Co-Chair of the Heart Failure Pathway Group of the Province of Alberta, Heart Failure lead at University of Calgary, and in the Canadian Cardiovascular Society Guidelines and Development Committees. M.L. has received grant funding and personal fees from Amgen; has received honoraria from Novartis; and has served as the New Zealand Chairperson for Cardiac Society Australia and New Zealand. P.P. has received research grants to his institution from Amgen and Vifor Pharma; and has received consulting fees or honoraria from Abbott Vascular, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Cibiem, Coridea, Impulse Dynamics, Novartis, Pfizer, Renal Guard Solutions, Servier, and Vifor Pharma. M.B.Y. reports funding to his institution from Amgen, Bayer, Novartis, and Dalcor Pharmaceuticals outside the submitted work. F.Z. reports consulting fees from Cardior, Cereno pharmaceutical, Cellprothera, Owkin, Novo Nordisk, Vifor, and Fresenius; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer and Bayer; payment for expert testimony from Cardiorentis; stock or stock options in Cereno pharmaceutical; and steering committee personal fees from Applied Therapeutics, Amgen, Bayer, Boehringer, CVRx, Novartis, and Merck. B.L.C. has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. Z.M.M. has no conflicts of interest to disclose. S.A.A. is an employee and shareholder of Amgen. P.H.D., S.B.H., S.K., and F.I.M. are employees and shareholders of Cytokinetics. J.R.T. has received personal fees as Chairperson of the GALACTIC-HF Executive Committee from Amgen and Cytokinetics; has received personal fees for research contracts and/or consulting fees from 3ive Labs, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Medtronic, Merck, Novartis, Verily, ViCardia, and Windtree Therapeutics; has served as Secretary and Treasurer of Heart Failure Society of America; and is currently President-Elect of the Heart Failure Society of America. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)