美国杜克大学医学中心G. Michael Felker团队联合马萨诸塞州总医院Gregory D. Lewis团队研究了Omecamtiv Mecarbil对射血分数降低的慢性心力衰竭患者运动能力的影响。相关论文于2022年7月19日发表在《美国医学会杂志》上。

运动受限是射血分数降低（HFrEF）型心衰的主要表现，但目前的任何指南指导的药物治疗都未能持续改善。

为了确定omecamtiv-mecarbil（一种新型直接肌球蛋白激活剂，可改善心脏功能，降低HFrEF患者心血管死亡或首次心衰事件的风险）是否可以提高慢性HFrEF患者的峰值运动能力，研究组进行了一项临床3期、双盲、安慰剂对照随机试验，2019年3月至2021年5月，在北美和欧洲的63个地点招募HFrEF（左室射血分数≤35%）患者，其纽约心脏协会II-III级症状，N端B型钠尿肽前体水平为200 pg/mL或更高，基线峰值摄氧量（V?o₂）为预测值的75%或更低。

将这些患者以2：1的比例随机分组（omecamtiv-mecarbil组与安慰剂组），最后一次患者随访时间为2021年11月29日。其中omecamtiv mecarbil组185例，匹配的安慰剂组91例，每天口服两次，剂量为25 mg、37.5 mg或50 mg（基于目标血浆水平），持续20周。主要终点是从基线检查到第20周运动能力（峰值V?o₂）的变化。次要终点包括总负荷、通气效率和由加速度计确定的每日体力活动。

276名随机化患者的中位年龄为64岁，42名为女性（15%），共249人（90%）完成了试验。Omecamtiv-mecarbil组的平均左室射血分数为28%，平均基线峰值Vo₂为14.2 mL/kg/min，安慰剂组为15.0 mL/kg/min。Omecamtiv-mecarbil组和安慰剂组之间峰值Vo₂的平均变化没有显著差异（平均值分别降低0.24 mL/kg/min与增加0.21 mL/kg/min）。不良事件包括头晕（omecamitv-mecarbil组有4.9%，安慰剂组有5.5%）、疲劳（两组分别为4.9%和4.4%）、心力衰竭事件（4.9%与4.4%）、死亡（1.6%与1.1%）、中风（0.5%与1.1%）和心肌梗死（0%与1.1%）。

研究结果表明，对于慢性HFrEF患者，与安慰剂相比，omecamtiv-mecarbil在20周内没有显著改善运动能力。这些发现不支持使用omecamtiv mecarbil治疗HFrEF以提高运动能力。

附：英文原文

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

Author: Gregory D. Lewis, Adriaan A. Voors, Alain Cohen-Solal, Marco Metra, David J. Whellan, Justin A. Ezekowitz, Michael Bhm, John R. Teerlink, Kieran F. Docherty, Renato D. Lopes, Punag H. Divanji, Stephen B. Heitner, Stuart Kupfer, Fady I. Malik, Lisa Meng, Amy Wohltman, G. Michael Felker

Issue&Volume: 2022/07/19

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 (Vo2) 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 Vo2) 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 Vo2 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 Vo2 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.

DOI: 10.1001/jama.2022.11016

Source: https://jamanetwork.com/journals/jama/article-abstract/2794362