Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lewis reported receiving research funding from the National Institutes of Health (R01-HL 151841, R01-HL131029, and R01-HL159514), American Heart Association (15GPSGC-24800006), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie. He also reported receiving honoraria for advisory boards outside of the current study from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen and royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Voors reported receiving personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, MyoKardia, Novo Nordisk, Novartis, Moderna, and Roche Diagnostics and grants from Novo Nordisk and Roche Diagnostics outside the submitted work. Dr Cohen-Solal reported receiving fees or honoraria from Amgen, Vifor Pharma, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Impulse Dynamics, Novartis, CVRx, Leo, Sanofi, We-Health, and Merck. Dr Metra reported receiving personal fees from Amgen during the conduct of the study and honoraria from AstraZeneca, Abbott Vascular, Amgen, and Edwards Therapeutics and personal fees from Abbott Vascular, Actelion, Amgen, AstraZeneca, Edwards Therapeutics, LivaNova, Servier, Vifor Pharma, and Windtree Therapeutics outside the submitted work. Dr Whellan reported receiving research grants to his institution from Novo Nordisk and consulting fees or honoraria from CVRx, Cytokinetics, and Novo Nordisk. Dr Ezekowitz reported receiving personal fees from Cytokinetics and grants from Amgen during the conduct of the study and personal fees from Bayer, Bristol Myers Squibb, Merck, AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Sanofi, Servier, Otsuka, and American Regent, and owning equity in Us2.ai outside the submitted work. Dr Böhm reported receiving funds from the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and personal fees from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, ReCor, Servier, Vifor Pharma, and Boehringer Ingelheim outside the submitted work. Dr Teerlink reported receiving research contract and consulting fees from Amgen and Cytokinetics during the conduct of the study and personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Verily, and Windtree Therapeutics outside the submitted work; having a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for the Heart Failure Society of America as a secretary, treasurer, and president-elect; and his son being employed by Cytokinetics. Dr Docherty reported receiving financial support to attend educational meetings from Cytokinetics during the conduct of the study and personal fees from AstraZeneca and a research grant to his institution from Boehringer Ingelheim outside the submitted work. Dr Lopes reported receiving consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi and grants to his institution from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr Divanji reported employment and stock options from Cytokinetics. Dr Heitner reported employment and stock options from Cytokinetics. Dr Kupfer reported employment and stock options from Cytokinetics. Dr Malik reported employment and stock options from Cytokinetics. Dr Meng reported employment and stock options from Cytokinetics. Ms Wohltman reported employment and stock options from Cytokinetics. Dr Felker reported receiving grants from Cytokinetics and Amgen during the conduct of the study and grants or contracts from the National Institutes of Health, American Heart Association, Bayer, Bristol Myers Squibb, and Merck and personal fees from Novartis, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree, Whiteswell, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Recruitment, Randomization, and Follow-up in the METEORIC-HF Trial

METEORIC-HF indicates Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure. aReasons for participants not meeting inclusion/exclusion criteria (participants may have multiple reasons from the following list for not meeting criteria): 56 due to N-terminal pro-B-type natriuretic peptide less than 200 pg/mL; 40 due to peak oxygen uptake greater than 75% predicted normal value or respiratory exchange ratio less than 1.05; 29 due to left ventricular ejection fraction greater than 35%; 12 due to chronotropic incompetence during exercise; 10 due to estimated glomerular filtration rate less than 30 mL/min/1.73 m2; 8 due to resting heart rate greater than 90 beats per minute or fewer than 50 beats per minute at screening; 7 due to resting systolic blood pressure greater than 140 mm Hg or less than 85 mm Hg, or diastolic blood pressure greater than 90 mm Hg at screening; 6 due to paroxysmal atrial fibrillation or flutter documented within the previous 6 months or direct-current cardioversion or ablation procedure for atrial fibrillation within 6 months; 4 due to not satisfying all screening assessments, including at least 7 days of the screening actigraphy wear period; 3 due to New York Heart Association class I or IV at screening; 3 due to a major medical event or procedure within 3 months prior to randomization, including hospitalization, surgery, kidney replacement therapy, or cardiac procedure; 3 due to hemoglobin level of less than 10.0 g/dL at screening; 2 due to malignancy within 5 years prior to randomization with exceptions: localized basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, stage 1 prostate carcinoma; and 1 due to each of the following reasons, including lack of informed consent, less than 3-month history of heart failure, β-blocker dose not stable for 1 month, untreated severe ventricular arrhythmias, use of mobility assistive device, and a significant adverse finding (see Trial Protocol in Supplement 1) during exercise testing at screening that precludes safe participation in the study, per investigators. bOther reasons include out-of-window exercise test, out-of-window randomization, and technical problems with the ergometer.

Figure 2.. Baseline Values and Changes in Peak Oxygen Uptake (V̇o2)

Baseline peak oxygen uptake (V̇o2) values and week 20 peak V̇o2 values are shown for individual patients receiving omecamtiv mecarbil and placebo in panel A. Changes in peak V̇o2 (medians and IQRs) in mL/kg/min from baseline to week 20 are shown in panel B. Box edges indicate the IQRs, the horizontal lines in between the edges indicate the medians. Whiskers extend to the upper and lower adjacent values and dots represent outside values. See Table 1 footnotes for explanation of scales and measures.

Figure 3.. Change in Secondary End Points From Baseline to 20 Weeks

Box edges indicate the IQRs, the horizontal lines in between the edges indicate the medians. Whiskers extend to the upper and lower adjacent values, and dots represent outside values. See Table 1 footnotes for explanation of scales and measures.