N Engl J Med:Aficamten治疗症状性梗阻性肥厚型心肌病

7天前 来源:N Engl J Med

本文由小咖机器人翻译整理

期刊来源:N Engl J Med

原文链接:https://doi.org/10.1056/NEJMoa2401424

摘要内容如下:

背景

在梗阻性肥厚型心肌病(HCM)患者中,运动不耐受和限制性症状的主要决定因素之一是左心室流出道梗阻导致的心内压升高。Aficamten是一种口服选择性肌球蛋白抑制剂,可通过减轻心脏过度收缩来降低左心室流出道压差。

方法

在这项3期、双盲试验中,我们将有症状性梗阻性肥厚型心肌病的成人随机分为两组,一组接受阿菲卡坦(起始剂量,5 mg;最大剂量,20 mg),另一组接受安慰剂,为期24周,根据超声心动图结果进行剂量调整。主要终点是通过心肺运动试验评估的从基线到第24周的峰值摄氧量的变化。10个预先指定的次要终点(按等级进行测试)是堪萨斯城心肌病问卷临床总结评分(KCCQ-CSS)的变化、纽约心脏协会(NYHA)功能分级的改善、Valsalva动作后压力梯度的变化、Valsalva动作后压力梯度小于30 mm Hg的发生率以及间隔减容治疗的合格持续时间(均在第24周进行评估);KCCQ-CSS的变化、NYHA功能级别的改善、Valsalva动作后压力梯度的变化以及Valsalva动作后压力梯度低于30 mm Hg的发生率(均在第12周进行评估);以及在第24周通过心肺运动试验评估的总工作负荷的变化。

结果

共有282名患者接受了随机分组:142名患者接受了阿菲卡坦组,140名患者接受了安慰剂组。平均年龄为59.1岁,59.2%为男性,基线平均静息左心室流出道压差为55.1 mm Hg,基线平均左心室射血分数为74.8%。在24周时,最大摄氧量的平均变化在阿菲卡坦组为1.8 ml/kg/min(95%可信区间[CI],1.2-2.3),在安慰剂组为0.0 ml/kg/min(95%CI,-0.5-0.5)(最小二乘平均组间差异,1.7 ml/kg/min;95%可信区间为1.0~2.4;P<0.001)。与安慰剂组相比,阿菲卡坦组所有10个次要终点的结果均得到显著改善。两组的不良事件发生率相似。

结论

在症状性梗阻性肥厚型心肌病患者中,与安慰剂相比,阿菲卡坦治疗导致峰值摄氧量显著改善。(由Cytokinetics资助;Sequoia-HCM ClinicalTrials.gov编号,NCT05186818。)

英文原文如下:

Abstracts

BACKGROUND  One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility.

METHODS  In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24.

RESULTS  A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups.

CONCLUSIONS  Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

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