Efficacy of cardiac myosin activators compared to placebo in patients with heart failure and reduced ejection fraction: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Cardiac myosin activators (CMAs) have been explored as a potential therapy to enhance cardiac contractility in patients with heart failure with reduced ejection fraction (HFrEF). However, their effect on clinical outcomes, including mortality, cardiovascular (CV) events, and heart failure (HF) symptoms, remains unclear. OBJECTIVES: This study aimed to evaluate the efficacy and safety of CMAs compared to placebo in patients with HFrEF through a systematic review and meta-analysis of randomized controlled trials. METHODS AND RESULTS: A systematic search of PubMed, Cochrane, Embase, and Scopus identified randomized controlled trials comparing CMAs to placebo in HFrEF patients. Meta-analyses were performed using a random-effects model, including 10,019 patients from nine trials, with 5204 receiving CMAs. CMAs had no significant effect on CV death (risk ratio [RR]: 1.01; 95 % confidence interval [CI]: 0.92-1.10; p = 0.85), HF events (RR: 0.95; 95 % CI: 0.89-1.02; p = 0.15), or all-cause mortality (RR: 1.00; 95 % CI: 0.93-1.07; p = 0.95). However, CMAs significantly reduced the composite outcome of CV death, HF hospitalization, and urgent outpatient visits for HF (hazard ratio [HR]: 0.92; 95 % CI: 0.90-0.93; p < 0.00001) and lowered stroke risk compared to placebo (p = 0.006). CONCLUSION: CMAs, particularly omecamtiv mecarbil, did not significantly impact all-cause mortality, cardiovascular death, or HF recurrence in patients with HFrEF. However, modest reductions were observed in composite outcomes and stroke. These findings should be interpreted cautiously, and further trials are needed to validate their clinical role.