Abstract Body (Do not enter title and authors here): Background: Older age is associated with a high prevalence of comorbidities and worse cardiovascular (CV) outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Omecamtiv mecarbil (OM), a selective cardiac myosin activator, is relatively hemodynamically neutral with no known extra-cardiac effects, and thus may be well-tolerated in older individuals with comorbidities (e.g., low blood pressure or renal dysfunction). The safety profile and clinical benefits of OM across the age spectrum remain uncertain.

Purpose: To assess the CV outcomes, treatment response and tolerability to OM according to age, in patients enrolled in the GALACTIC-HF trial.

Methods: GALACTIC-HF was a randomized, double-blind clinical trial testing OM vs placebo in patients with symptomatic HF. Key eligibility criteria included an age between 18 and 85 years, elevated natriuretic peptides and a left ventricular ejection fraction (LVEF) ≤35%. We examined the treatment effect of OM vs placebo for the primary endpoint of CV death or first HF event (hospitalization or urgent visit for HF), in the overall population and severe HF subgroup (LVEF≤30%, New York Heart Association [NYHA] Class III/IV, HF hospitalization within 6 months), as well as safety outcomes according to predefined age groups (<65 or ≥65).

Results: A total of 8,232 patients (age 64.5±11.4 years, 54.5% ≥65 years, 21% women) were included. The rate of the primary outcome was 21.4 per 100py in age <65 years and 28.8 per 100py in age ≥65 years. The treatment effect of OM for the primary outcome (hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.86-0.99; p=0.025) was consistent in age groups (P_interaction=0.73, Figure 1 Panel A) and irrespective of age as a continuous variable (P_interaction=0.19), after adjustment for treatment interactions with known modifiers of the effects of OM (LVEF and baseline atrial fibrillation status). In patients with severe HF, OM significantly reduced the risk of the primary outcome in both age <65 years (HR 0.77; 95% CI 0.64-0.92) and age ≥65 years (HR 0.83; 95% CI 0.71-0.97; P_interaction=0.72, Figure 1 Panel B). The safety profile of OM was consistent irrespective of age (P_interaction>0.05 for all, Table 1).

Conclusions: In GALACTIC-HF, older individuals were well-represented and faced higher risks of CV events. Treatment with OM was safe irrespective of age, and reduced the risk of CV death or first HF event across the age spectrum, especially in those with severe HF.