BACKGROUND: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. METHODS: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512. FINDINGS: From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p<0·0001), stroke volume 3·6 mL (0·5-6·7, p=0·0217), left ventricular end-systolic diameter -1·8 mm (-2·9 to -0·6, p=0·0027), left ventricular end-diastolic diameter -1·3 mm, (-2·3 to 0·3, p=0·0128), heart rate -3·0 beats per min (-5·1 to -0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p=0·0069). The frequency of adverse clinical events did not differ between groups. INTERPRETATION: Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. FUNDING: Amgen.

Amgen Thousand Oaks CA USA

British Heart Foundation Cardiovascular Research Centre University of Glasgow Glasgow UK

Cardiology Department St John of God Hospital Budapest Hungary

Cytokinetics South San Francisco CA USA

Department of Cardiology AZ St Lucas Ghent Belgium

Department of Cardiology Queen Giovanna University Hospital and Medical University Sofia Sofia Bulgaria

Department of Heart Diseases Medical University and Centre for Heart Diseases Military Hospital Wrocław Poland

Department of Medicine University of Alberta Edmonton AB Canada

Division of Cardiology Duke University School of Medicine Durham NC USA

Division of Cardiology University of Brescia Brescia Italy

Division of Cardiology University of North Carolina at Chapel Hill Chapel Hill NC USA

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

Emergency Centre Vilnius University Hospital Santariskiu Klinikos and Vilnius University Vilnius Lithuania

Heart Transplant Unit St Vincent's Hospital and Transplantation Research Laboratory Victor Chang Cardiac Research Institute and University of New South Wales Sydney NSW Australia

Kerckhoff Klinik Forschungsgesellschaft Frankfurt Germany; Johann Wolfgang Goethe University Main Germany

National Heart and Lung Institute Royal Brompton and Harefield Hospitals Imperial College London UK; Robertson Centre for Biostatistics and Clinical Trials University of Glasgow Glasgow UK

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

University Hospital Brno and Medical Faculty of Masaryk University Brno Czech Republic

University of Groningen University Medical Centre Groningen Groningen Netherlands

Lancet. 2016 Dec 10;388(10062):2845-2847. doi: 10.1016/S0140-6736(16)31725-1. PubMed

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Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials

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ClinicalTrials.gov
NCT01786512