METEORIC-HF: Omecamtiv mecarbil fails to improve exercise performance in HFrEF
WASHINGTON — In well-treated patients with chronic HF with reduced ejection fraction, omecamtiv mecarbil did not improve measures of exercise capacity over 20 weeks compared with placebo, researchers reported.
Exercise is a “cardinal manifestation” of HF but is not improved by current medical therapies, G. Michael Felker, MD, MHS, professor of medicine at Duke Clinical Research Institute, said during a late-breaking clinical trial presentation at the American College of Cardiology Scientific Session. In the previous GALACTIC-HF trial, researchers observed that omecamtiv mecarbil (Cytokinetics), a novel selective cardiac myosin activator, had been shown to improve HFrEF outcomes and had a mechanism that directly affected cardiac performance, Felker said.
Assessing exercise tolerance
For METEORIC-HF, researchers assessed exercise capacity in 276 participants with symptomatic HFrEF who were treated with maximally tolerated guideline-directed medical therapy. The median age of patients was 64 years, 89% were white, 15% were women and most had NYHA class II HF. Researchers randomly assigned participants 2:1 to omecamtiv mecarbil or placebo for 20 weeks followed by cardiopulmonary exercise testing. The primary endpoint was change in peak oxygen uptake from baseline to week 20, measured by cardiopulmonary exercise testing. Secondary endpoints included changes in peak workload, ventilatory efficiency, ventilatory anaerobic threshold, circulatory power, oxygen uptake kinetics, daily activity by actigraphy and perceived functional capacity by Kansas City Cardiomyopathy Questionnaire.
“One of the challenges of conducting this trial during a pandemic was this is something that cannot be done remotely,” Felker said. “Cardiopulmonary exercise testing, which is the gold standard of exercise performance, requires specialized equipment.”
Researchers found that peak oxygen uptake was not significantly different between the omecamtiv mecarbil and placebo groups at 20 weeks, with a least-squares mean difference of –0.45 (95% CI, –1 to 0.13; P = .13).
Researchers also observed a nominal decrease in overall change in workload during exercise in the omecamtiv mecarbil group; Felker said this was driven “by a single outlier who exercised submaximally at week 20.” There were no between-group differences in change in ventilatory efficiency or in actigraphy at 20 weeks.
Researchers did not observe safety signals with omecamtiv mecarbil, including during peak exercise, Felker said.
“Omecamtiv mecarbil did not improve measures of exercise capacity over a 20-week period,” Felker said. “Identifying therapies that can safely improve exercise capacity, one of the cardinal symptoms of HF, remains an unmet challenge.”
Tailoring treatment
After the presentation, Felker noted that the cohort was particularly well treated with guideline-directed medical therapy and most had class II HF, both factors that may have affected the exercise findings.
“When we look at GALACTIC-HF, we saw that patients who were sicker tended to have a greater treatment effect with omecamtiv,” Felker told Healio. “It is certainly possible if we had enrolled a sicker population we would have found a difference. It’s challenging in an exercise trial like METEORIC-HF; one of the things you want is for everything else to be stable. If you have a sick population getting hospitalized, it makes the trial more challenging.”
In an interview, Gregory Lewis, MD, section head of heart failure, director of the cardiopulmonary exercise testing laboratory and medical director of cardiology ICU and mechanical circulatory support at Massachusetts General Hospital, who also participated in METEROIC-HF, said the magnitude of treatment effect of omecamtiv mecarbil may not have been sufficient to overcome the chronic impact of HF on exercise intolerance in this cohort.
“Chronic HF impacts all organ systems in the body that are responsible for permitting us to exercise,” Lewis told Healio. “For example, skeletal muscle and lung function are adversely impacted by long-term exposure to HF. On average, our patients had been living with symptomatic HF for at least 5 years. Improving exercise capacity with heart failure interventions remains an unmet need in the care of patients with HF.”
Perspective
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It is somewhat disappointing the investigators did not see any incremental benefits in exercise capacity with the study drug, omecamtiv mecarbil, compared with placebo. The question remains if the drug itself, although improving the cardiac contractile function, can improve exercise functional capacity.
These findings are not surprising, as most patients with HF may have a wide range of reasons for which they are deconditioned, or perhaps they have exercise intolerance. These data show the challenges of using this rather novel endpoint, in part because of the heterogeneity of exercise intolerance across different people.
Much more work must be done to better understand how the heart interacts with and influences exercise intolerance and what measurement is best to assess symptomatic improvement.
Perspective
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I would not call the outcome of METEORIC-HF disappointing. It is an important trial because we are exploring a completely new class of medications for HF. In this particular case, we are looking at myosin activation; the findings must be interpreted in a broader context.
In GALACTIC-HF, findings were mildly positive, showing just 2% fewer primary outcome events in the treatment group compared with placebo. We know there is some effect in a broader HF population. Now, it is up to us to tease out which subsets of patients derive the most benefit.
In GALACTIC-HF, we saw the sickest patients benefitted the most. Those were not the patients enrolled in METEORIC-HF. We must next test this medication in people with more severe HF and lower EF. This trial provides the knowledge that, in well-treated, primarily class II HF patients, this myosin activator does not provide improvement in exercise performance. It also provided information that exercise does not cause adverse effects; we know this drug is safe.
Overall, this is an important trial that adds to the body of knowledge we have about myosin activators.
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Felker GM, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2022; Washington, D.C. (hybrid meeting).