GALACTIC-HF: The Therapeutic Benefits of Omecamtiv Mecarbil Increase with decreasing Ejection Fraction in HFrEF Patients

28 Jul, 21

Introduction

Several of the currently available therapies improve the cardiovascular (CV) outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Nevertheless, none of them directly improve the central defect of HFrEF. The GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) study has now demonstrated that the cardiac myosin activator, omecamtiv mecarbil, significantly reduces the primary composite endpoint (PCE) of time-to-first HF event or CV death in patients with HFrEF. The drug increases systolic function by selectively facilitating the actin-myosin interaction and by increasing the contractile force without altering the cardiomyocyte calcium transient.

Aim

To evaluate the impact of baseline EF on the therapeutic efficacy and safety of omecamtiv mecarbil

Patient Profile

Participants from the GALACTIC HF study with symptomatic [New York Heart Association (NYHA) functional class II to IV) HFrEF and EF ≤35% (n=8256)
Patients had elevated natriuretic peptides [N-terminal pro–B-type natriuretic peptide (NT-proBNP) ≥400 pg/ml; 1,200 pg/ml for patients in atrial fibrillation (AF) or B-type natriuretic peptide (BNP) ≥125 pg/ml; 375 pg/ml for patients in AF]
All patients were already receiving optimized background HF therapy
Patients were either currently hospitalized for HF or had either been admitted to emergency department (ED) or were hospitalized for HF within one year.

Methods

Study Design

A sub-group analysis of the GLACTIC HF study
GALACTIC HF was a phase III, global, double-blind, placebo-controlled randomized controlled trial

Treatment Strategy

Patients were randomized to receive either omecamtiv mecarbil or placebo

Outcomes

Primary Outcome

Composite of the time-to-first HF event or death due to CV causes

Secondary Outcomes

Time to CV death
Time to first HF hospitalization
Time to all-cause death
Change in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS; scale: 0-100, with a higher score indicating fewer symptoms) from baseline to week 24

Results

More than half of the study population (n=4,456) had a median EF ≤28% during the study.
Patients in the lowest EF quartile (EF ≤22%) had a 1.8-fold higher incidence of the primary outcome of first HF event or CV death as compared with patients in the highest EF quartile (EF ≥33%) (35.6 per 100 patient-years vs. 20 per 100 patient-years).
Patients in the lowest EF quartile compared with those in the highest EF quartile had a 90% higher incidence of first HF event (28.3 events vs. 14.9 events per 100 patient-years) and a 68% higher incidence of CV death (14.1 deaths vs. 8.4 deaths per 100 patient-years)
Amongst the pre-specified subgroups, EF had the strongest influence on 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 with a decreasing baseline EF decreased. Thus, patients in the lowest quartile [n=2246; hazard ratio (HR): 0.83; 95% confidence interval (CI): 0.73-0.95] had a 17% relative risk reduction for the PCE as compared with the patients in the highest EF quartile (n=1750; HR: 0.99; 95% CI: 0.84-1.16) (interaction as EF by quartiles, p=0.013).
The absolute risk reduction (aRR) in the PCE increased with decrease in EF (EF ≤22%; aRR, 7.4 events per 100 patient-years; number needed to treat for 3 years =11.8). There was no significant aRR evident in the highest EF quartile.
Patients in the lowest EF quartile vs. those in the highest quartile had significantly greater reduction in the NT-proBNP levels with omecamtiv mecarbil treatment (22%; p<0.001 vs. 3%; p=0.54; p_interaction<0.001)
Patients treated with omecamtiv mecarbil had improvement in the KCCQ-TSS vs. placebo, but the difference was not statistically significant.
The adverse effect profile did not differ significantly for the patients treated with omecamtiv mecarbil or placebo.

Conclusions

Amongst patients with HFrEF, the therapeutic benefits (absolute reduction in the risk of HF events and CV death) of omecamtiv mecarbil increased progressively with the decreasing baseline EF.
Patients with EFs approximately ≤30% are likely to benefit the most with the omecamtiv mecarbil treatment.
Patients with more severe HF may derive greater clinical benefits from cardiac myosin activator therapy.

J Am Coll Cardiol 2021;78:97–108.