Omecamtiv Mecarbil in Chronic Heart Failure with Reduced Ejection Fraction: The Global Approach To Lowering Adverse Cardiac Outcomes Through Improving Contractility In Heart Failure (GALACTIC-HF) trial

Presented at the AHA Scientific Sessions 2020 by John R. Teerlink (San Francisco, CA, USA)

Introduction and methods

The central defect and initiating factor in heart failure with reduced ejection fraction (HFrEF) is a decrease in systolic heart function. So far, no therapies for chronic HFrEF that specifically targeted systolic dysfunction have improved cardiac outcome.

Omecamtiv mecarbil is a novel cardiac myosin activator, a cardiac myotrope, that has demonstrated to improve cardiac remodeling and systolic function of the heart and decrease heart rate and NT-proBNP levels in patients with HFrEF.

The Global Approach To Lowering Adverse Cardiac Outcomes Through Improving Contractility In Heart Failure (GALACTIC-HF) trial tested whether omecamtiv mecarbil improved clinical outcomes in HFrEF patients compared to placebo.

The GALACTIC-HF trial was a multicentered, international, randomized, double-blind, placebo-controlled, event-driven phase 3 study in symptomatic, chronic HFrEF patients. Inclusion criteria were defined as: NYHA class II-IV, LVEF ≤35%, elevated BNP/NT-proBNP, and receiving standard HF therapies. Both patients hospitalized for HF (inpatients) or patients in need of an urgent visit to the hospital or hospitalization due to HF within 1 year of screening (outpatients) were enrolled. Patients (n=8256) were randomized to omecamtiv mecarbil using a pharmacokinetic-guided dose selection (25, 37.5, or 50 mg orally, twice a day with a starting dose of 25 mg) performed at week 2 and 6 or they were randomized to placebo. The primary outcome was a composite of time to first HF event or CV death. Median follow-up was approximately 22 months.

Main results

• The primary outcome, time to first HF event or CV death, was significantly reduced in patients treated with omecamtiv mecarbil compared to placebo (HR 0.92, 95% CI: 0.86-0.99, P=0.025).
• The individual components of the primary outcome time to first HF event and CV death were not significantly reduced in patients receiving omecamtiv mecarbil compared to patients receiving placebo.
• The change in the symptom score of the KCCQ-TSS from baseline to week 24 was 2.5 points higher in the omecamtiv mecarbil group compared to placebo (95% CI: 0.54-4.46) in inpatients and 0.5 points lower in the omecamtiv mecarbil group compared to placebo (95% CI: 1.40-0.48) in outpatients (Pjoint test=0.028). These results did not meet the prespecified statistical significance threshold of P=0.002 for improvement in health status.
• Subgroup analysis revealed a reduced risk for HF hospitalization and CV death in HFrEF patient with a baseline LVEF of ≤28% compared to patients with a higher LVEF >28% (HR 0.84, 95% CI:0.77-0.92 vs. HR 1.04, 95% CI: 0.94-1.16, Pinteraction=0.003).
• Adverse events were balanced between the omecamtiv mecarbil and placebo groups.

Conclusion

Omecamtiv mecarbil significantly reduced the risk for a first HF event or CV death in HFrEF patients. Moreover, the cardiac myosin activator tended to be more beneficial in HFrEF patients with a low LVEF.

Discussion

Paul Heidenreich (Stanford University School of Medicine, Stanford, CA, USA) reminded the audience that the GALACTIC-HF trial analyzed the effect of a cardiac myotrope with a novel mechanism. While previous drugs did improve heart function, patients’ outcomes were ultimately worsened with these drugs.

Heidenreich continued and elaborated on the treatment benefits by omecamtiv mecarbil in regard to survival, health status and health cost. GALACTIC-HF met its primary endpoint, time to first HF event or CV death. The results suggested that this was primarily caused by reduced hospitalization, and emergency and urgent care visits due to HF, which will lower the cost in healthcare. Furthermore, there was a suggestive, but non-significant improvement in health status. Both outcomes are encouraging, according to Heidenreich.

There appear to be two promising signs when comparing omecamtiv mecarbil to the established and new HF therapies, said Heidenreich. Firstly, unlike in many other established therapies, there is no reduction in blood pressure, which is often a limiting factor in many HF patients. And secondly, certain subgroups, especially patients with the lowest LVEF, may have the greatest benefit with this treatment.

- Our reporting is based on the information provided during AHA Scientific Sessions 2020 –

The findings of this study were simultaneously published in the N Eng J Med. Watch a video on the GALACTIC-HF trial