ImportancePatients with heart failure with preserved ejection fraction (HFpEF) who have left ventricular ejection fraction (LVEF) of 60% or greater have limited treatment options.ObjectiveTo examine the effects of cardiac myosin inhibition with mavacamten in patients with HFpEF with LVEF of 60% or greater.Design, Setting, and ParticipantsThe EMBARK-HFpEF trial was a phase 2a, open-label, single-arm, multicenter trial conducted from November 6, 2020, to February 26, 2024, at 20 sites in the US and Canada. Patients with symptomatic HFpEF (defined as a New York Heart Association [NYHA] functional class II or III), LVEF of 60% or greater, elevated N-terminal pro-B-type natriuretic peptide (NTproBNP), and left ventricular hypertrophy were eligible for inclusion.InterventionMavacamten treatment for 26 weeks, starting at 2.5 mg and potentially titrated up to 5 mg at week 14 based on prespecified LVEF and NTproBNP criteria.Main Outcomes and MeasuresPrimary efficacy end points (measured as the change from baseline to week 26) included NTproBNP and high-sensitivity troponin T (hsTnT); additional efficacy end points included changes in high-sensitivity troponin I (hsTnI), NYHA functional class, and echocardiographic parameters (resting and peak exercise). Safety end points included treatment-emergent adverse events and reductions in LVEF to less than 30%.ResultsA total of 30 patients were enrolled and treated with mavacamten. Median (IQR) patient age was 76 (70-80) years, and 16 patients (53.3%) were female. From baseline to week 26, mavacamten was associated with reductions in NTproBNP (mean reduction, −26%; 95% CI, −44% to −4%; P = .04), hsTnT (mean reduction, −13%; 95% CI, −23% to −3%; P = .02), and hsTnI (mean reduction, −20%; 95% CI, −32% to −6%; P = .01). Cardiac biomarker values returned toward baseline levels 8 weeks after drug discontinuation. NYHA class improved in 10 of 24 patients (41.7%) who had evaluable NYHA class data at the end of treatment, and improvements in echocardiographic markers of LV diastolic function were observed. Mean LVEF decreased by 3.2 absolute percentage points (95% CI, 1.1-5.4; P = .005) during treatment. Mavacamten was interrupted in 3 patients (10% of the study population; 95% CI, 2.1%-26.5%) due to protocol prespecified criteria of LVEF less than 50% (n = 2) or a more than 20% relative decrease from baseline (n = 1; nadir LVEF, 58%), with LVEF recovery observed in all 3 patients. There were no deaths or instances of LVEF less than 30%; 1 patient had worsening heart failure deemed unrelated to the study drug.Conclusions and RelevanceIn an open-label trial in patients with HFpEF with LVEF of 60% or greater, mavacamten was associated with improvements in biomarkers of cardiac wall stress and injury, with no sustained reductions in LVEF observed.Trial RegistrationClinicalTrials.gov Identifier: NCT04766892

中文翻译：

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射血分数正常和超正常心力衰竭中的心脏肌球蛋白抑制


重要性左心室射血分数保留 （HFpEF） 患者左心室射血分数 （LVEF） ≥60% 的治疗选择有限。目的探讨 mavacamten 抑制心肌肌球蛋白对 LVEF ≥ 60% 的 HFpEF 患者的影响。设计、设置和参与者EMBARK-HFpEF 试验是一项 2a 期、开放标签、单臂、多中心试验，于 2020 年 11 月 6 日至 2024 年 2 月 26 日在美国和加拿大的 20 个地点进行。有症状的 HFpEF （定义为纽约心脏协会 [NYHA] 功能分级 II 或 III）、LVEF 为 60% 或更高、N 末端 B 型利钠肽前体 （NTproBNP） 升高和左心室肥厚的患者符合纳入条件。干预 Mavacamten 治疗 26 周，从 2.5 mg 开始，根据预先设定的 LVEF 和 NTproBNP 标准，可能在第 14 周滴定至 5 mg。主要结局和测量主要疗效终点（以从基线到第 26 周的变化来衡量）包括 NTproBNP 和高敏肌钙蛋白 T （hsTnT）;其他疗效终点包括高敏肌钙蛋白 I （hsTnI） 、 NYHA 功能分级和超声心动图参数 （静息和峰值运动） 的变化。安全终点包括治疗中出现的不良事件和 LVEF 降低至 30% 以下。结果共纳入 30 例患者并接受 mavacamten 治疗。中位 （IQR） 患者年龄为 76 （70-80） 岁，其中 16 例患者 （53.3%） 为女性。从基线到第 26 周，mavacamten 与 NTproBNP 的降低相关（平均减少，-26%;95% CI，-44% 至 -4%;P = .04）、hsTnT（平均减少，-13%;95% CI，-23% 至 -3%;P = .02） 和 hsTnI （平均减少，-20%;95% CI，-32% 至 -6%;P = .01）。 停药后 8 周心脏生物标志物值恢复到基线水平。24 例患者中有 10 例 （41.7%） 在治疗结束时具有可评估的 NYHA 分级数据，NYHA 分级有所改善，并观察到 LV 舒张功能的超声心动图标志物有所改善。平均 LVEF 下降了 3.2 个绝对百分点 （95% CI，1.1-5.4;P = .005）。3 例患者 （占研究人群的 10%;95% CI，2.1%-26.5%） 因方案预先设定的 LVEF 小于 50% （n = 2） 或相对降低超过 20% （n = 1;最低 LVEF，58%）中断 Mavacamten，所有 3 例患者均观察到 LVEF 恢复。没有死亡或 LVEF 低于 30% 的情况;1 名患者被认为与研究药物无关的心力衰竭恶化。结论和相关性在一项针对 LVEF 为 60% 或更高的 HFpEF 患者的开放标签试验中，mavacamten 与心脏壁应力和损伤生物标志物的改善相关，未观察到 LVEF 持续降低。试验注册临床试验。gov 标识符： NCT04766892