意大利卡雷吉大学医院Iacopo Olivotto团队研究了Mavacamten治疗梗阻性肥厚型心肌病的疗效和安全性。2020年8月29日，该研究发表在《柳叶刀》杂志上。

心肌过度收缩是肥厚型心肌病的关键病理生理异常，并且是动态左心室流道（LVOT）梗阻的主要决定因素。肥厚型心肌病的可用药理学选择有限或耐受性差，且疾病特异性低。

为了评估一级心肌肌球蛋白抑制剂Mavacamten治疗症状性梗阻性肥厚型心肌病的疗效和安全性，研究组在13个国家/地区的68个临床心血管中心进行了一项临床3期、双盲、安慰剂对照试验，2018年5月30日至2019年7月12日，研究组招募了251位LVOT梯度≥50 mmHg、纽约心脏协会（NYHA）II-III级的肥厚型心肌病患者。

将其按1：1随机分组，其中123例接受Mavacamten治疗，128例接受安慰剂治疗，为期30周。每2-4周进行一次随访以评估患者的状况。主要终点为峰值耗氧量（pVO2）每分钟增加1.5 mL/kg及以上，且NYHA分级至少降低一级；或pVO2每分钟增加3.0 mL/kg及以上，NYHA分级不下降。

Mavacamten组中有45名（37%）患者达到主要终点，显著高于安慰剂组（22名，17%）。Mavacamten组患者运动后LVOT梯度与安慰剂组相比，平均降低了36 mmHg；pVO2平均增加了1.4 mL/kg/min，症状评分亦显著增加，差异均有统计学意义。Mavacamten组NYHA至少改善1级的患者比安慰剂组多34%，差异显著，其安全性和耐受性与安慰剂组相差不大。紧急治疗中的不良反应一般较轻。安慰剂组中有一名患者猝死。

总之，Mavacamten治疗可改善梗阻性肥厚型心肌病患者的运动障碍、LVOT阻塞、NYHA功能分级和健康状况。

附：英文原文

Title: Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial

Author: Iacopo Olivotto, Artur Oreziak, Roberto Barriales-Villa, Theodore P Abraham, Ahmad Masri, Pablo Garcia-Pavia, Sara Saberi, Neal K Lakdawala, Matthew T Wheeler, Anjali Owens, Milos Kubanek, Wojciech Wojakowski, Morten K Jensen, Juan Gimeno-Blanes, Kia Afshar, Jonathan Myers, Sheila M Hegde, Scott D Solomon, Amy J Sehnert, David Zhang, Wanying Li, Mondira Bhattacharya, Jay M Edelberg, Cynthia Burstein Waldman, Steven J Lester, Andrew Wang, Carolyn Y Ho, Daniel Jacoby, Jozef Bartunek, Antoine Bondue, Emeline Van Craenenbroeck, Milos Kubanek, David Zemanek, Morten Jensen, Jens Mogensen, Jens Jakob Thune, Philippe Charron, Albert Hagege, Olivier Lairez, Jean-Nol Trochu, Christoph Axthelm, Hans-Dirk Duengen, Norbert Frey, Veselin Mitrovic, Michael Preusch, Jeanette Schulz-Menger, Tim Seidler, Michael Arad, Majdi Halabi, Amos Katz, Daniel Monakier, Offir Paz, Samuel Viskin, Donna Zwas, Iacopo Olivotto, Hans Peter Brunner-La Rocca, Michelle Michels, Dariusz Dudek, Zofia Oko-Sarnowska, Artur Oreziak, Wojciech Wojakowski, Nuno Cardim, Helder Pereira, Roberto Barriales-Villa, Pablo García Pavia, Juan Gimeno Blanes, Rafael Hidalgo Urbano, Luis Miguel Rincón Diaz, Perry Elliott, Zaheer Yousef, Theodore Abraham, Kia Afshar, Paulino Alvarez, Richard Bach, Richard Becker, Lubna Choudhury, David Fermin, Daniel Jacoby, John Jefferies, Christopher Kramer, Neal Lakdawala, Steven Lester, Ali Marian, Ahmad Masri, Mathew Maurer, Sherif Nagueh, Anjali Owens, David Owens, Florian Rader, Sara Saberi, Mark Sherrid, Jamshid Shirani, John Symanski, Aslan Turer, Andrew Wang, Omar Wever-Pinzon, Matthew Wheeler, Timothy Wong, Mohamad Yamani

Issue&Volume: 2020-08-29

Abstract: Background

Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.

Methods

In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II–III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2–4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO 2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO 2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO 2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). 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 to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (36 mm Hg, 95% CI 43·2 to 28·1; p<0·0001), greater increase in pVO 2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-So

DOI: 10.1016/S0140-6736(20)31792-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31792-X/fulltext