John R Teerlink1, Rafael Diaz2, G Michael Felker3, John J V McMurray4, Marco Metra5, Scott D Solomon6, Tor Biering-Sørensen7, Michael Böhm8, Diana Bonderman9, James C Fang10, David E Lanfear11, Mayanna Lund12, Shin-Ichi Momomura13, Eileen O'Meara14, Piotr Ponikowski15, Jindrich Spinar16, Jose H Flores-Arredondo17, Brian L Claggett6, Stephen B Heitner18, Stuart Kupfer18, Siddique A Abbasi17, Fady I Malik18. 1. Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California San Francisco, San Francisco, California, USA. Electronic address: john.teerlink@ucsf.edu. 2. Estudios Clinicos Latino America (ECLA), Rosario, Argentina. 3. Division of Cardiology, Duke University School of Medicine and Duke Clinical Research Institute, Durham, North Carolina, USA. 4. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. 5. Cardiology, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy. 6. Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 7. Department of Cardiology, Herlev & Gentofte Hospital & Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 8. Saarland University, Klink für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg, Germany. 9. Medical University of Vienna, Vienna, Austria. 10. University of Utah, Salt Lake City, Utah, USA. 11. Henry Ford Heart and Vascular Institute, Detroit, Michigan, USA. 12. Cardiology Department, Middlemore Hospital, Otahuhu, Auckland, New Zealand. 13. Saitama Citizens Medical Center, Saitama, Japan. 14. Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada. 15. Wroclaw Medical University, Wroclaw, Poland. 16. University Hospital St. Ann and Medical Faculty, Brno, Czech Republic. 17. Amgen, Inc., Thousand Oaks, California, USA. 18. Cytokinetics, Inc., South San Francisco, California, USA.
Abstract
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). Published by Elsevier Inc.
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). Published by Elsevier Inc.
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