Background

Improving symptoms is a primary treatment goal in patients with obstructive hypertrophic cardiomyopathy. Currently available pharmacological options for hypertrophic cardiomyopathy are not disease-specific and are often inadequate or poorly tolerated. We aimed to assess the effect of mavacamten, a first-in-class cardiac myosin inhibitor, on patients' health status—ie, symptoms, physical and social function, and quality of life.

Methods

We did a health status analysis of EXPLORER-HCM, a phase 3, double-blind, randomised, placebo-controlled trial. The study took place at 68 clinical cardiovascular centres in 13 countries. Adult patients (≥18 years) with symptomatic obstructive hypertrophic cardiomyopathy (gradient ≥50 mm Hg and New York Heart Association class II–III) were randomly assigned (1:1) to mavacamten or placebo for 30 weeks, followed by an 8-week washout period. Both patients and staff were masked to study treatment. The primary outcome for this secondary analysis was the Kansas City Cardiomyopathy Questionnaire (KCCQ), a well validated disease-specific measure of patients' health status. It was administered at baseline and weeks 6, 12, 18, 30 (end of treatment), and 38 (end of study). Changes from baseline to week 30 in KCCQ overall summary (OS) score and all subscales were analysed using mixed model repeated measures. This study is registered with ClinicalTrials.gov, NCT03470545.

Findings

Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned. Of 123 patients randomly assigned to mavacamten, 92 (75%) completed the KCCQ at baseline and week 30 and of the 128 patients randomly assigned to placebo 88 (69%) completed the KCCQ at baseline and week 30. At 30 weeks, the change in KCCQ-OS score was greater with mavacamten than placebo (mean score 14·9 [SD 15·8] vs 5·4 [13·7]; difference +9·1 [95% CI 5·5–12·8]; p<0·0001), with similar benefits across all KCCQ subscales. The proportion of patients with a very large change (KCCQ-OS ≥20 points) was 36% (33 of 92) in the mavacamten group versus 15% (13 of 88) in the placebo group, with an estimated absolute difference of 21% (95% CI 8·8–33·4) and number needed to treat of five (95% CI 3–11). These gains returned to baseline after treatment was stopped.

Interpretation

Mavacamten markedly improved the health status of patients with symptomatic obstructive hypertrophic cardiomyopathy compared with placebo, with a low number needed to treat for marked improvement. Given that the primary goals of treatment are to improve symptoms, physical and social function, and quality of life, mavacamten represents a new potential strategy for achieving these goals.

Funding

MyoKardia, a Bristol Myers Squibb company.

中文翻译：

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Mavacamten 治疗症状性阻塞性肥厚型心肌病 (EXPLORER-HCM)：一项随机、双盲、安慰剂对照、3 期试验的健康状况分析

背景

改善症状是阻塞性肥厚型心肌病患者的主要治疗目标。目前可用的肥厚性心肌病药理学选择不是疾病特异性的，并且通常不足或耐受性差。我们旨在评估一流的心肌肌球蛋白抑制剂 mavacamten 对患者健康状况（即症状、身体和社会功能以及生活质量）的影响。

方法

我们对 EXPLORER-HCM 进行了健康状况分析，这是一项 3 期、双盲、随机、安慰剂对照试验。该研究在 13 个国家的 68 个临床心血管中心进行。患有症状性阻塞性肥厚性心肌病（梯度≥50 mm Hg 和纽约心脏协会 II-III 级）的成年患者（≥18 岁）被随机分配（1:1）接受 mavacamten 或安慰剂治疗 30 周，然后是 8 周冲洗期。患者和工作人员都被蒙面以研究治疗方法。该次要分析的主要结果是堪萨斯城心肌病问卷 (KCCQ)，这是一项经过充分验证的疾病特异性衡量患者健康状况的方法。它在基线和第 6 周、第 12 周、第 18 周、第 30 周（治疗结束）和第 38 周（研究结束）给药。使用混合模型重复测量分析 KCCQ 总体总结 (OS) 评分和所有分量表从基线到第 30 周的变化。该研究已在 ClinicalTrials.gov 注册，NCT03470545。

发现

在 2018 年 5 月 30 日至 2019 年 7 月 12 日期间，对 429 名成年人进行了资格评估，其中 251 人（59%）被随机分配。在随机分配到 mavacamten 的 123 名患者中，92 名（75%）在基线和第 30 周完成了 KCCQ，在随机分配到安慰剂的 128 名患者中，88 名（69%）在基线和第 30 周完成了 KCCQ。在 30 周时，变化mavacamten 组的 KCCQ-OS 评分高于安慰剂组（平均评分 14·9 [SD 15·8] vs5·4 [13·7]；差异 +9·1 [95% CI 5·5–12·8]；p<0·0001)，在所有 KCCQ 分量表中具有相似的益处。mavacamten 组发生非常大变化（KCCQ-OS ≥20 分）的患者比例为 36%（92 人中的 33 人），安慰剂组为 15%（88 人中的 13 人），估计绝对差异为 21% (95% CI 8·8–33·4) 和需要治疗的人数为 5 (95% CI 3–11)。这些收益在治疗停止后恢复到基线。

解释

与安慰剂相比，Mavacamten 显着改善了有症状的梗阻性肥厚型心肌病患者的健康状况，而显着改善所需治疗的人数较少。鉴于治疗的主要目标是改善症状、身体和社会功能以及生活质量，mavacamten 代表了实现这些目标的新的潜在策略。

资金

MyoKardia，百时美施贵宝公司。