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Study Summary

Omecamtiv mecarbil is a selective cardiac myosin activator that augments sarcomere function and force of contraction without increased energy consumption. The GALACTIC-HF trial investigators randomly assigned 8,256 patients with chronic heart failure and reduced ejection fraction (≤35%) to receive omecamtiv mecarbil (25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart failure therapy. Over a median of 21.8 months, a primary-outcome event — a first heart failure event or cardiovascular-related death —occurred in 37.0% of the omecamtiv mecarbil group compared with 39.1% of the placebo group (HR 0.92; 95% CI 0.86-0.99; P = 0.03; see accompanying Hurst’s Central Illustration). Deaths from cardiovascular-related causes were noted for 19.6% of the omecamtiv mecarbil group and 19.4% of the placebo group (P = NS). No significant differences in secondary outcomes were found between the two groups, including change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptoms score or frequency of cardiac ischemic and ventricular arrhythmia events.

Commentary

Study Strengths: This was a large, international, multicenter, placebo-controlled trial with few exclusion criteria, which enhances the external validity of the study. The trial excluded patients with systolic blood pressure <85 mmHg or an estimated glomerular filtration rate <20 ml/min/1.73 m2, which allowed the inclusion of sicker patients with hypotension or chronic kidney disease when compared to previous heart failure trials.

Study Limitations: The trial excluded patients over the age of 85 years and those with a clinically unstable condition. Only 7% of the patients self-reported as black, though this is higher than in many previous heart failure trials. Only 21% of the patients were women. Although the background therapy was generally excellent, only 19% of patients were receiving sacubitril–valsartan at baseline and only 2.6% were receiving a sodium–glucose cotransporter 2 inhibitor. Whether omecamtiv mecarbil would add incremental value in addition to these medications is unclear.

Next Steps/Clinical Perspective: This trial supports the hypothesis that selectively targeting the cardiac sarcomere with omecamtiv mecarbil to improve cardiac function can improve clinical outcomes. However, given the modest effect size on the primary outcome (absolute difference, 2.1 percentage points) and the low use of contemporary effective heart failure medications in the trial, omecamtiv mecarbil is unlikely to become a first-line treatment for heart failure. A heterogeneity of treatment effect was suggested by a potentially greater effect in patients with an ejection fraction ≤28%, compared with an ejection fraction >28%. Additional subgroup analyses may provide further insights into groups who may benefit more from omecamtiv mecarbil, such as patients who are sicker, with lower blood pressure or chronic kidney disease, for whom heart failure treatment options are lacking.

Trial Reference

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Teerlink  JR, Diaz  R, Felker  GM,  et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N. Engl. J. Med. doi:10.1056/NEJMoa2025797.

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