Assessment of Omecamtiv Mecarbil for the Treatment of Patients With Severe Heart Failure: A Post Hoc Analysis of Data From the GALACTIC-HF Randomized Clinical Trial

Abstract

Importance: Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies.

Objective: To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial.

Design, setting, and participants: The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months.

Interventions: Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo.

Main outcomes and measures: The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability.

Results: Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo.

Conclusions and relevance: In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited.

Trial registration: ClinicalTrials.gov Identifier: NCT02929329.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Felker reported receiving grants and personal fees from Amgen and Cytokinetics during the conduct of the study; grants from Bayer and Merck & Co; and personal fees from American Regent, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Medtronic, and Novartis outside the submitted work. Dr Solomon reported receiving grants (via Brigham and Women’s Hospital) from Amgen and Cytokinetics during the conduct of the study; grants (via Brigham and Women’s Hospital) from Actelion, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bellerophon Therapeutics, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos Therapeutics, Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Ionis Pharmaceuticals, Mesoblast, Myocardium, the National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos; and consulting fees from Abbott Laboratories, Action Pharma, Akros Pharma, Alnylam Pharmaceuticals, American Regent, Amgen, Arena Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior Pharmaceuticals, Cardurion Pharmaceuticals, CellProthera, Corvia Medical, Cytokinetics, Daiichi Sankyo, Dinaqor, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Merck & Co, Moderna, Myokardia, Novartis, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta Therapeutics, Tenaya Therapeutics, Theracos, and Tremeau Pharmaceuticals outside the submitted work. Dr Claggett reported receiving grants (via Brigham and Women’s Hospital) from Amgen and Cytokinetics during the conduct of the study and consulting fees from Amgen, Boehringer Ingelheim, Corvia Medical, Myokardia, and Novartis outside the submitted work. Dr Diaz reported receiving grants from Amgen during the conduct of the study. Dr McMurray reported receiving travel fees and nonfinancial support (via the University of Glasgow) from Amgen during the conduct of the study; travel fees and nonfinancial support (via the University of Glasgow) from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Cyclerion Therapeutics, Cytokinetics, DalCor Pharmaceuticals, GlaxoSmithKline, Novartis, Pfizer, Servier Laboratories, and Theracos; and personal fees from Abbott Laboratories, Hikma Pharmaceuticals, Servier Laboratories, and Sun Pharmaceutical Industries outside the submitted work. Dr Metra reported receiving personal fees from Amgen and Servier Laboratories during the conduct of the study and personal fees from Abbott Laboratories, Actelion, AstraZeneca, Edwards Lifesciences, LivaNova, Vifor Pharma, and Windtree Therapeutics outside the submitted work. Dr Anand reported receiving personal fees from Amgen during the conduct of the study and personal fees from ARCA Biopharma, Boehringer Ingelheim, Boston Scientific, Novartis, and Zensun outside the submitted work. Dr Crespo-Leiro reported receiving grants from Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) and personal fees from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Novartis, and Vifor Pharma outside the submitted work. Dr Dahlström reported receiving grants from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Pfizer, Roche Diagnostics, and Vifor Pharma and personal fees from Amgen and Pfizer outside the submitted work. Dr Goncalvesová reported receiving personal fees from Amgen and Servier Laboratories during the conduct of the study; personal fees from Bayer, Boehringer Ingelheim, Janssen Pharmaceuticals, Merck & Co, Novartis, and Pfizer; and nonfinancial support from AOP Orphan Pharmaceuticals outside the submitted work. Dr Howlett reported receiving grants from Amgen, AstraZeneca, Boehringer Ingelheim, Medtronic, and Pfizer and personal fees from Alnylam Pharmaceuticals, AstraZeneca, Boerhinger Ingelheim, Janssen Pharmaceuticals, Novartis, Pfizer, and Servier Laboratories outside the submitted work. Dr MacDonald reported receiving grants from Amgen during the conduct of the study and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis outside the submitted work. Dr Parkhomenko reported receiving grants from Vifor Pharma and personal fees from AstraZeneca, Boehringer Ingelheim, and Servier Laboratories outside the submitted work. Dr Tomcsányi reported receiving grants from Amgen during the conduct of the study. Dr Abbasi reporting owning stock in Amgen during the conduct of the study. Dr Heitner reported owning stock in Cytokinetics outside the submitted work. Dr Hucko reported owning stock in Amgen during the conduct of the study. Dr Kupfer reported owning stock in Cytokinetics outside the submitted work. Dr Teerlink reported receiving grants from Amgen and Cytokinetics; personal fees from Amgen, Cytokinetics, and Servier Laboratories; and nonfinancial support from Amgen and Cytokinetics during the conduct of the study and grants from Abbott Laboratories, Bayer, Boerhinger Ingelheim, Bristol Myers Squibb, EBR Systems, LivaNova, Medtronic, Novartis, and Windtree Therapeutics and personal fees from Amgen, AstraZeneca, Cytokinetics, Merck & Co, and Servier Laboratories outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Kaplan-Meier Curves

CV indicates cardiovascular; HF, heart failure; HR, hazard ratio; and OM, omecamtiv mecarbil.

Figure 2.. Event Rates for Primary End Point by Treatment Assignment and Heart Failure Severity Criteria Met

A, A total of 3864 patients were in NYHA class III to IV, 4368 patients were in NYHA class II, 5842 patients had LVEF of 30% or less, 2390 patients had LVEF greater than 30%, 6308 patients were hospitalized within the previous 6 months, and 1924 patients were not hospitalized within the previous 6 months. B, A total of 424 patients met 0 criteria, 1860 patients met 1 criterion, 3690 patients met 2 criteria, and 2258 patients met 3 criteria. HF indicates heart failure; LVEF, left ventricular ejection fraction; and NYHA, New York Heart Association.