BACKGROUND: In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) (n = 8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF) (≤35%). OBJECTIVES: The purpose of this study was to evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil. METHODS: Outcomes in patients treated with omecamtiv mecarbil were compared with placebo according to EF. RESULTS: The risk of the PCE in the placebo group was nearly 1.8-fold greater in the lowest EF (≤22%) compared with the highest EF (≥33%) quartile. Amongst the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the PCE (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased, with a 17% relative risk reduction for the PCE in patients with baseline EF ≤22% (n = 2,246; hazard ratio: 0.83; 95% confidence interval: 0.73 to 0.95) compared with patients with EF ≥33% (n = 1,750; hazard ratio: 0.99; 95% confidence interval: 0.84 to 1.16; interaction as EF by quartiles, p = 0.013). The absolute reduction in the PCE increased with decreasing EF (EF ≤22%; absolute risk reduction, 7.4 events per 100 patient-years; number needed to treat for 3 years = 11.8), compared with no reduction in the highest EF quartile. CONCLUSIONS: In heart failure patients with reduced EF, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug's mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).

Amgen Inc Thousand Oaks California USA

British Heart Foundation Cardiovascular Research Centre University of Glasgow Glasgow United Kingdom

Cardiology ASST Spedali Civili Department of Medical and Surgical Specialties Radiological Sciences and Public Health University of Brescia Brescia Italy

Cardiology Department Middlemore Hospital Otahuhu Auckland New Zealand

Cytokinetics Inc South San Francisco California USA

Department of Cardiology Herlev and Gentofte Hospital and Department of Biomedical Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Division of Cardiology Duke University School of Medicine and Duke Clinical Research Institute Durham North Carolina USA

Division of Cardiovascular Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

Estudios Clinicos Latino America Rosario Argentina

Henry Ford Heart and Vascular Institute Detroit Michigan USA

Medical University of Vienna Vienna Austria

Montreal Heart Institute and Université de Montréal Montreal Quebec Canada

Saarland University Klink für Innere Medizin 3 (Kardiologie Angiologie und Internistische Intensivmedizin Universitätsklinikum des Saarlandes Homburg Germany

Saitama Citizens Medical Center Saitama Japan

Section of Cardiology San Francisco Veterans Affairs Medical Center and School of Medicine University of California San Francisco San Francisco California USA

University Hospital St Ann and Medical Faculty Brno Czech Republic

University of Utah Salt Lake City Utah USA

Wroclaw Medical University Wroclaw Poland

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$a Effect of Ejection Fraction on Clinical Outcomes in Patients Treated With Omecamtiv Mecarbil in GALACTIC-HF / $c JR. Teerlink, R. Diaz, GM. Felker, JJV. McMurray, M. Metra, SD. Solomon, T. Biering-Sørensen, M. Böhm, D. Bonderman, JC. Fang, DE. Lanfear, M. Lund, SI. Momomura, E. O'Meara, P. Ponikowski, J. Spinar, JH. Flores-Arredondo, BL. Claggett, SB. Heitner, S. Kupfer, SA. Abbasi, FI. Malik, GALACTIC-HF Investigators

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$a BACKGROUND: In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) (n = 8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF) (≤35%). OBJECTIVES: The purpose of this study was to evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil. METHODS: Outcomes in patients treated with omecamtiv mecarbil were compared with placebo according to EF. RESULTS: The risk of the PCE in the placebo group was nearly 1.8-fold greater in the lowest EF (≤22%) compared with the highest EF (≥33%) quartile. Amongst the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the PCE (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased, with a 17% relative risk reduction for the PCE in patients with baseline EF ≤22% (n = 2,246; hazard ratio: 0.83; 95% confidence interval: 0.73 to 0.95) compared with patients with EF ≥33% (n = 1,750; hazard ratio: 0.99; 95% confidence interval: 0.84 to 1.16; interaction as EF by quartiles, p = 0.013). The absolute reduction in the PCE increased with decreasing EF (EF ≤22%; absolute risk reduction, 7.4 events per 100 patient-years; number needed to treat for 3 years = 11.8), compared with no reduction in the highest EF quartile. CONCLUSIONS: In heart failure patients with reduced EF, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug's mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).

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