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Study Summary

In the recent GALACTIC-HF trial, the novel, selective cardiac myosin activator omecamtiv mecarbil was shown to significantly reduce the primary composite end point of time to first heart failure event or cardiovascular death among patients with heart failure and reduced ejection fraction (EF ≤35%; https://accesscardiology.mhmedical.com/updatesContent.aspx?gbosid=555013). A prespecified subgroup analysis evaluating the effect of baseline EF on the therapeutic effect of omecamtiv mecarbil has now been presented. Amongst the pre-specified subgroups for the GALACTIC-HF trial, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the primary end point, while also being the strongest predictor of the primary end point amongst the placebo group. Amongst the subgroups, ARNi use was highest within the quartile EF <22% (24%) and beta blocker usage was not significantly different amongst the subgroups (~95%). The largest absolute treatment effect of omecantiv mecarbil was seen in patient quartile with the lowest baseline EF (≤22%, n= 2246; HR 0.83, 95% CI 0.73-0.95). Of note, the significant difference in the primary end point was driven by a reduction in the hospitalizations while no significant differences in all-cause and cardiovascular deaths were noted in any subgroup. Overall, omecamtiv mecarbil resulted in greater therapeutic benefit as baseline EF decreased (see accompanying Hurst’s Central Illustration).

Commentary

Study Strengths: This pre-determined subgroup analysis of the GALACTIC-HF trial successfully investigates the influence of EF on the efficacy of omecamtiv mecarbil in reducing the time to first heart failure event or cardiovascular death among patients with heart failure and reduced EF. The size of the subgroups in this analysis was larger than in most trials (approximately 2000 patients per quartile/subgroup). Therefore, with multivariate analysis employed, the significant difference shown was unlikely to be from chance alone.

Study Limitations: Despite pre-determination in GALACTIC-HF, the chances of confounders affecting the results are increased because the study is a subgroup analysis. The proportions of nonischemic cardiomyopathy and male patients were higher within the lowest quartile subgroup. Both covariates could have confounded the results, showing a larger absolute effect of omecantiv mecarbil within that subgroup. Similarly, ARNi use being highest in the lowest quartile subgroup could also have confounded the results. In addition, SGLT2 inhibition was sparse amongst all study groups (approximately 3%), which questions the additive effect of this medication to current guideline-directed care. Lastly, despite the reduction of the primary composite end point driven by hospitalizations, there was no observed benefit of the study drug on the KCCQ scores for patients in any subgroup.

Next Steps/Clinical Perspective: Overall, the present prespecified subgroup analysis offers additional evidence to support the clinical efficacy of omecantiv mecarbil in patients with heart failure and reduced EF, particularly among those with more-severe left ventricular systolic dysfunction. Such patients may be intolerant of optimal doses of guideline-directed medical therapy and therefore may derive the largest benefit. The intolerance of guideline-directed medical therapy generally signifies an advanced patient population wherein omecamtiv mecarbil may be considered as an alternative and/or additive therapy (for the purposes of reducing hospitalizations) in addition to the consideration of advanced therapies. The disappointing aspects of this trial remain the lack of survival benefit as well as a lack of improvement in KCCQ scores. While future studies will likely elucidate specific populations who may derive benefit, current focus of clinical practice should be on the implementation of guideline directed medical therapy for patients with heart failure with reduced EF, which includes beta blockers, angiotensin receptor neprilysin inhibitors, sodium glucose transporter 1 inhibitors and mineralocorticoid receptor antagonists.

References

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Teerlink  JR, Diaz  R, Felker  GM,  et al Effect of ejection fraction on clinical outcomes in patients treated with omecamtiv mecarbil in GALACTIC-HF. J. Am. Coll. Cardiol. doi: 10.1016/j.jacc.2021.04.065.

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