Effect of Ejection Fraction on Clinical Outcomes in Patients Treated With Omecamtiv Mecarbil in GALACTIC-HF

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).

Keywords: cardiovascular outcomes trial; heart failure with reduced ejection fraction; myotrope.

Conflict of interest statement

Funding Support and Author Disclosures The GALACTIC-HF trial was funded by Amgen, Cytokinetics, and Servier. The executive committee designed and oversaw the conduct and analysis of the trial in collaboration with the sponsors, Amgen, Cytokinetics, and Servier. Dr. Teerlink has received research grants and/or consulting fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics; has received support for attending meetings and/or travel from Abbott Laboratories, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, EBR Systems, LivaNova, Medtronic, Servier, and WindTree Therapeutics; and has served as Treasurer to Heart Failure Society of America. Dr. Diaz has received research grants and/or consulting fees from Amgen, Cytokinetics, and Servier. Dr. Felker has received grant funding to his institution from Amgen, Bayer, Cytokinetics, Merck, and Myokardia; has received consulting fees personally from Abbott, American Regent, Amgen, AstraZeneca, Becton Dickinson, Boehringer Ingelheim, Bristol Myers Squibb, Cardionomic, Cytokinetics, Medtronic, Novartis, and Sequana; and has served on the Board of Directors for the Heart Failure Society of America. Dr. McMurray has received consulting fees paid to his institution from Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardialysis, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Merck, Novartis, Pfizer, and Theracos. Dr. Metra has received consulting fees from Abbott Vascular, Actelion, Amgen, AstraZeneca, Bayer, Edwards Therapeutics, Livanova, Servier, Vifor Pharma, and WindTree Therapeutics. Dr. Solomon has received grants from Celladon, Eidos, Ionis, Lone Star Heart, Mesoblast, National Institutes of Health/National Heart, Lung, and Blood Institute, and Sanofi Pasteur; has received grants and personal fees from Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol Myers Squibb, Cytokinetics, Gilead, GlaxoSmithKline, MyoKardia, Novartis, and Theracos; and has received personal fees from Akros, AoBiome, Arena, Cardiac Dimensions, Cardior, Cardurion, Corvia, Daiichi-Sankyo, Dinaqor, Ironwood, Janssen, Merck, Moderna, Quantum Genomics, Roche, Takeda, and Tenaya. Dr. Biering-Sørensen has received personal fees or research grants from Amgen, GE Healthcare, Novartis, and Sanofi Pasteur as member of trial committees or for lectures at sponsored meetings. Dr. Böhm has received funds from the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor, Servier, and Vifor. Dr. Bonderman has received speaker’s fees and honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Novartis. Dr. Fang has received consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, and Capricor; and has served on the Board of Directors for the Heart Failure Society of America. Dr. Lanfear has received grants or research contracts from Abbott, Amgen, AstraZeneca, Bayer, Critical Diagnostics, Janssen, Novartis, Ortho Diagnostics, and Somalogic; and has received consulting fees from Amgen, DCRI, and Janssen. Dr. Lund 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. Dr. Momomura has received personal fees from Amgen, Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Japanese Circulation Society, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, and Terumo. Dr. O’Meara has received consultation and speaker fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Novartis; has served on the steering committee and as national lead investigator for clinical studies, with fees paid to her institution (Montreal Heart Institute Research Center), from American Regent, AstraZeneca, Cytokinetics, Merck, and Novartis; and has participated in clinical trials for Amgen, Abbott, American Regent, and AstraZeneca. Dr. Ponikowski 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. Dr. Spinar has received grants and personal fees from Amgen. Drs. Flores-Arredondo and Abbasi are employees and stockholders of Amgen. Dr. Claggett has received consulting fees from Amgen and Myokardia. Drs. Heitner, Kupfer, and Malik are employees and stockholders of Cytokinetics.

Published by Elsevier Inc.