The effect of the cardiac myosin activator, omecamtiv mecarbil, on diastolic filling and function in chronic systolic heart failure (cosmic-hf)

Introduction: Omecamtiv mecarbil (OM) is a selective cardiac myosin activator which increases cardiac contractility and systolic ejection time (SET). Objective: The objective of this post-hoc analysis was to determine the effect of chronic therapy with OM on diastolic function in patients with heart failure (HF). Methods: In the COSMIC-HF trial, 448 patients with stable, symptomatic HF and left ventricular ejection fraction (LVEF) <40% were randomly assigned to double-blind oral OM [25 mg twice daily; or 25 mg twice daily with pharmacokinetic-guided uptitration to 50 mg twice daily (PK group)] or placebo for 20 weeks. We assessed by echocardiography measures of diastolic filling and function [early (E-wave) and late (A) peak mitral inflow velocities, early peak myocardial relaxation velocity (e') and isovolumic relaxation time (IVRT)], tricuspid regurgitation velocity (TRV) and diastolic filling time between the placebo (n=149), the 25 mg group (n=150) and the PK group (n=149) at week 20. Results: Patients were 63±11 years old, predominantly (82%) male, with LVEF of 29.1±7.3%, E/A ratio of 1.4±0.9, E/e' ratio of 14±8, IVRT of 102±15 ms and a TRV of 2.7±0.5 m/s. Based on the current diastolic grading guidelines, 82% of patients had signs of an increased filling pressure. Patients receiving OM showed non-significant decrease in the E-wave and in E/A-ratio that appeared dose dependent (Figure). OM had no effect on either E/e' or e' (Figure). There was a small increase (< 5 ms) in the duration of the IVRT. Tricuspid regurgitant velocity, an indicator of pulmonary pressure, decreased significantly with OM therapy (Figure). OM had no effect on the duration of the diastolic filling time (p=0.99). Conclusion: In patients with chronic HF and reduced systolic function, although systolic ejection time increased, OM did not worsen diastolic filling, and was associated with improvement in pulmonary pressures and increased IVRT indicating an improvement in diastolic function.