Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial
Gregory D Lewis1, Adriaan A Voors2, Alain Cohen-Solal3
1Division of Cardiology, Massachusetts General Hospital, Boston.
Insights
Omecamtiv mecarbil did not improve exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF). This study suggests it is not a viable treatment for enhancing physical function in HFrEF patients.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Exercise limitation is a key symptom of heart failure with reduced ejection fraction (HFrEF).
- Current guideline-directed medical therapies do not consistently improve exercise capacity in HFrEF patients.
- Omecamtiv mecarbil is a novel direct myosin activator investigated for improving cardiac performance.
Purpose of the Study:
- To evaluate the efficacy of omecamtiv mecarbil in improving peak exercise capacity in patients with chronic HFrEF.
- To assess the impact of omecamtiv mecarbil on exercise capacity and other functional measures in HFrEF.
Main Methods:
- Phase 3, double-blind, placebo-controlled randomized trial involving 276 HFrEF patients.
- Patients received either omecamtiv mecarbil or placebo orally twice daily for 20 weeks.
- Primary endpoint was the change in peak oxygen uptake (V̇o2) from baseline to week 20.
Main Results:
- No significant difference in the mean change in peak V̇o2 was observed between the omecamtiv mecarbil and placebo groups.
- The least square mean difference in peak V̇o2 was -0.45 mL/kg/min (95% CI, -1.02 to 0.13; P=.13).
- Adverse events were generally similar between groups, with no significant increase in major adverse cardiac events.
Conclusions:
- Omecamtiv mecarbil did not significantly improve exercise capacity in patients with chronic HFrEF over a 20-week treatment period.
- These findings do not support the use of omecamtiv mecarbil for improving exercise capacity in HFrEF.
- Further research may be needed to explore alternative therapeutic strategies for exercise limitation in HFrEF.
Importance:
Exercise limitation is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but is not consistently improved by any of the current guideline-directed medical therapies.
Objective:
To determine whether omecamtiv mecarbil, a novel direct myosin activator that improves cardiac performance and reduces the risk for cardiovascular death or first HF event in HFrEF, can improve peak exercise capacity in patients with chronic HFrEF.
Design, Setting, And Participants:
Phase 3, double-blind, placebo-controlled randomized trial of patients with HFrEF (left ventricular ejection fraction ≤35%), New York Heart Association class II-III symptoms, N-terminal pro-B-type natriuretic peptide level of 200 pg/mL or greater, and baseline peak oxygen uptake (V̇o2) of 75% or less of predicted. Patients were randomized in a 2:1 ratio (omecamtiv mecarbil to placebo) between March 2019 and May 2021 at 63 sites in North America and Europe, with the last patient visit occurring on November 29, 2021.
Interventions:
Omecamtiv mecarbil (n = 185) or matching placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels, for 20 weeks.
Main Outcomes And Measures:
The primary end point was a change in exercise capacity (peak V̇o2) from baseline to week 20. Secondary end points included total workload, ventilatory efficiency, and daily physical activity as determined by accelerometry.
Results:
Among 276 patients who were randomized (median age, 64 years; IQR, 55-70 years; 42 women [15%]), 249 (90%) completed the trial. The median left ventricular ejection fraction was 28% (IQR, 21-33) and the median baseline peak V̇o2 was 14.2 mL/kg/min (IQR, 11.6-17.4) in the omecamtiv mecarbil group and 15.0 mL/kg/min (IQR, 12.0-17.2) in the placebo group. Mean change in peak V̇o2 did not differ significantly between the omecamtiv mecarbil and placebo groups (mean, -0.24 mL/kg/min vs 0.21 mL/kg/min; least square mean difference, -0.45 mL/kg/min [95% CI, -1.02 to 0.13]; P = .13). Adverse events included dizziness (omecamtiv mecarbil: 4.9%, placebo: 5.5%), fatigue (omecamtiv mecarbil: 4.9%, placebo: 4.4%), heart failure events (omecamtiv mecarbil: 4.9%, placebo: 4.4%), death (omecamtiv mecarbil: 1.6%, placebo: 1.1%), stroke (omecamtiv mecarbil: 0.5%, placebo: 1.1%), and myocardial infarction (omecamtiv mecarbil: 0%, placebo: 1.1%).
Conclusions And Relevance:
In patients with chronic HFrEF, omecamtiv mecarbil did not significantly improve exercise capacity over 20 weeks compared with placebo. These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03759392.
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