Effect of Ejection Fraction on Clinical Outcomes in Patients treated with Omecamtiv Mecarbil in GALACTIC-HF

ABSTRACT: Background In GALACTIC-HF (n=8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF≤35%). Objective Evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil. Methods Outcomes in patients treated with omecamtiv mecarbil were compared to placebo according to EF. Results The risk of the PCE in the placebo group was nearly 1.8-fold greater in the lowest (EF≤22%) compared to the highest (EF≥33%) EF quartile. Amongst the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the PCE (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased with a 17% relative risk reduction for the PCE in patients with baseline EF≤22% (n= 2246; Hazard Ratio 0.83; 95% Confidence Interval 0.73-0.95) compared to patients with EF≥33% (n= 1750; HR 0.99; 95%CI 0.84-1.16; interaction as EF by quartiles, p=0.013). The absolute reduction in the PCE increased with decreasing EF (EF≤22%: absolute risk reduction, 7.4 events per 100 patient-years; number-needed-to-treat for 3 years = 11.8), compared to no reduction in the highest EF quartile. Conclusion In HFrEF patients, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug’s mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk.