From Lahey Hospital and Medical Center, Burlington (M.S.M.), and the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School (B.C., S.D.S.), the Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School (J.L.J., G.D.L.), and the Baim Institute for Clinical Research (J.L.J.), Boston - all in Massachusetts; Oregon Health and Science University, Portland (A.M.); the University of Missouri Kansas City Healthcare Institute for Innovations in Quality and Saint Luke's Mid America Heart Institute, Kansas City (M.E.N., J.A.S.); Complejo Hospitalario Universitario de A Coruña, Instituto de Investigación Biomédica de A Coruña, Centro de Investigación Biomédica en Red de Enfermedades Cardiovaculares (CIBERCV)-Instituto de Salud Carlos III, A Coruña (R.B.-V.), and Hospital Universitario Puerta de Hierro de Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares, Madrid (P.G.-P.) - both in Spain; Chaim Sheba Medical Center, Ramat Gan and Tel Aviv University, Tel Aviv, Israel (M.A.); Hospital Companhia União Fabril Descobertas, Lisbon, Portugal (N.C.); Northwestern University Feinberg School of Medicine, Chicago (L.C.); the School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow (C.J.C., M.M.Y.L.), and Radcliffe Department of Medicine, University of Oxford, Oxford (H.W.) - both in the United Kingdom; Charité Campus Virchow-Klinikum, Berlin (H.-D.D.); Département de Cardiologie, Hôpital Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Paris (A.A.H.); Beijing Anzhen Hospital, Capital Medical University, Beijing (C.-S.M.); the Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam (M.M.) and Zwolle (M.S.) - both in the Netherlands; Meyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Florence, Italy (I.O.); National Institute of Cardiology, Warsaw, Poland (A.O.); University of Pennsylvania Perelman School of Medicine, Philadelphia (A.T.O.); the Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, and the Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen (J.T.-H.); the Department of Cardiology, Motol University Hospital, Prague, Czech Republic (J.V.); Cytokinetics, South San Francisco (D.L.J., S.B.H., S.K., F.I.M., L.M., A.W.), and the University of California, San Francisco, San Francisco (T.P.A.) - both in California.
N Engl J Med. 2024 May 30;390(20):1849-1861. doi: 10.1056/NEJMoa2401424. Epub 2024 May 13.
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.
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.
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.
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.).
导致梗阻性肥厚型心肌病（HCM）患者运动不耐受和限制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力升高。Aficamten 是一种口服选择性心肌肌球蛋白抑制剂，通过减轻心脏过度收缩来降低左心室流出道梯度。
在这项 3 期、双盲试验中，我们将有症状的梗阻性 HCM 成年患者随机分为接受 aficamten（起始剂量 5mg；最大剂量 20mg）或安慰剂治疗 24 周组，根据超声心动图结果调整剂量。主要终点是心肺运动试验评估的从基线到第 24 周时峰值摄氧量的变化。10 个预先指定的次要终点（按层次顺序测试）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、瓦尔萨尔瓦动作后压力梯度的变化、瓦尔萨尔瓦动作后压力梯度小于 30mmHg 的发生率以及间隔切开术治疗资格的持续时间（均在第 24 周评估）；KCCQ-CSS、NYHA 功能分级改善、瓦尔萨尔瓦动作后压力梯度变化以及瓦尔萨尔瓦动作后压力梯度小于 30mmHg 的发生率（均在第 12 周评估）；以及第 24 周心肺运动试验评估的总工作量变化。
共有 282 名患者接受了随机分组：142 名进入 aficamten 组，140 名进入安慰剂组。平均年龄为 59.1 岁，59.2%为男性，基线静息左心室流出道梯度为 55.1mmHg，左心室射血分数基线平均值为 74.8%。在 24 周时，与安慰剂组相比，aficamten 组的峰值摄氧量平均变化为 1.8ml/kg/min（95%置信区间 [CI]：1.2 至 2.3），安慰剂组为 0.0ml/kg/min（95%CI：-0.5 至 0.5）（组间最小二乘均值差异，1.7ml/kg/min；95%CI：1.0 至 2.4；P<0.001）。与安慰剂相比，所有 10 个次要终点的结果均显著改善。两组不良事件的发生率似乎相似。
在有症状的梗阻性 HCM 患者中，与安慰剂相比，aficamten 治疗可显著提高峰值摄氧量。（由 Cytokinetics 资助；SEQUOIA-HCM ClinicalTrials.gov 编号，NCT05186818.）。
