Summary:
Background: Impaired contractility is a fundamental abnormality in heart failure with reduced ejection fraction (HFrEF). We evaluated the pharmacokinetics of chronic therapy with the cardiac myosin activator omecamtiv mecarbil as well as its effect on cardiac function and structure in such patients.
Methods: In this randomised, parallel-group, double-blind study, 448 patients from 87 sites in 13 countries with stable, symptomatic chronic heart failure and left ventricular ejection fraction ≤40% were randomly assigned (1:1:1) using an interactive web response system to oral omecamtiv mecarbil (25 mg twice daily; or 25 mg twice daily with pharmacokinetic-guided uptitration to 50 mg twice daily, PK-titration group) or placebo for 20 weeks. The primary endpoint was the maximal omecamtiv mecarbil plasma concentration (Cmax); secondary endpoints were changes from baseline in cardiac function and dimensions, heart rate and NT-proBNP at week 20. (ClinicalTrials.gov, NCT01786512)
Findings: In patients enrolled from March 17, 2014 through March 5, 2015, Cmax (mean ± SD) at 12 weeks was 200±71 and 318±129 ng/mL in the 25 mg (n = 147) and PK-titration (n = 141) groups, respectively. Differences were seen in all secondary endpoints by 20 weeks in the PK titration group (n = 149) compared to placebo (n = 149): systolic ejection time [least square mean difference (95% CI); +25 (18, 32) msec, p<0·0001], stroke volume [+3·6 (0·5, 6·7) mL, p=0·0217], left ventricular end-systolic and end-diastolic dimensions [ 1·8 (-2·9, -0·6) mm, p=0·0027; 1·3 (-2·3, 0·3) mm, p=0·0128, respectively], heart rate [ 3·0 (-5·1, -0·8) bpm, p=0·0070] and NT-proBNP [ 970 (-1672, -268) pg/mL, p=0·0069). The maximum changes from baseline in plasma troponin-I concentrations were greater in patients assigned to omecamtiv mecarbil [PK titration: 0·020 ng/mL, (0·005, 0·038); median (Q1, Q3), p<0·0001] than placebo [0·010 ng/mL (0·000, 0·020)]. No important differences in adverse clinical events were observed.
Interpretation: In patients with chronic HFrEF, pharmacokinetic-guided dosing of omecamtiv mecarbil achieved plasma concentrations associated with improvements in cardiac performance and ventricular dimensions.