背景:梗阻性肥厚型心肌病(oHCM)的特征是左心室(LV)肥大,LV流出道阻塞,左心房扩张,这可能与进行性心力衰竭有关,心房颤动,和中风。Aficamten是一种下一代心脏肌球蛋白抑制剂,可通过调节心脏收缩力来减少流出道阻塞,具有逆转病理性重塑的潜力,反过来,减少心血管事件。
目的:本研究旨在使用心血管磁共振(CMR)研究与安慰剂相比,aficanten对心脏重塑的影响及其与SEQUOIA-HCM中关键临床终点的关联(安全性,功效,以及对HCM)CMR子研究中Aficamten的阻塞影响的定量理解。
方法:Sequoia-HCM是3期双盲,安慰剂对照试验适用于有症状的oHCM成人,随机接受1:1~24周的非康定(剂量范围:5~20mg)或安慰剂治疗.符合条件的参与者被纳入CMR子研究,在基线和第24周进行研究。由核心实验室以盲法方式进行图像分析。
结果:在282名随机患者中,57人(20%)参加了亚研究,其中,50(88%)完成了基线和第24周的CMR。CMR队列的基线特征与总体研究人群相似。在这50名患者中,21人接受了aficanten,29人接受了安慰剂。相对于安慰剂,接受aficamten的患者左心室质量指数显着降低(Δ最小二乘平均值)(-15g/m2;95%CI:-25至-6g/m2;P=0.001),左心室最大壁厚(-2.1mm;95%CI:-3.1至-1.1mm;P<0.001),左心房容积指数(-13mL/m2;95%CI:-19~-7mL/m2;P<0.001),自然T1弛豫时间(-37毫秒;95%CI:-69至-5毫秒;P=0.026),指数化的细胞外体积分数(-3.9g/m2;95%CI:-7.0至-0.9g/m2;P=0.014),和指数肌细胞质量(-14g/m2;95%CI:-23至-4g/m2;P=0.004),虽然左心室容积没有显著变化,LV替代纤维化(钆增强晚期质量-0.7g;95%CI:-2.9至1.6g;P=0.54),或胞外体积(0.7%;95%CI:-2.2%至3.6%;P=0.61)。
结论:SEQUOIA-HCM的CMR子研究表明,相对于安慰剂,使用aficanten治疗24周导致良好的心脏重塑。这些变化,特别是关于左心室质量,壁厚,左心房大小,可能导致心血管事件减少,包括心力衰竭和心房颤动。(在有症状的oHCM[SEQUOIA-HCM]的成人中评价非卡汀与安慰剂相比的功效和安全性的3期试验;NCT05186818)。
BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological
remodeling and, in turn, reduce cardiovascular events.
OBJECTIVE: This study sought to investigate the effect of aficamten on cardiac
remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy.
METHODS: SEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory.
RESULTS: Of the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (-15 g/m2; 95% CI: -25 to -6 g/m2; P = 0.001), maximal LV wall thickness (-2.1 mm; 95% CI: -3.1 to -1.1 mm; P < 0.001), left atrial volume index (-13 mL/m2; 95% CI: -19 to -7 mL/m2; P < 0.001), native T1 relaxation time (-37 ms; 95% CI: -69 to -5 ms; P = 0.026), indexed extracellular volume fraction (-3.9 g/m2; 95% CI: -7.0 to -0.9 g/m2; P = 0.014), and indexed myocyte mass (-14 g/m2; 95% CI: -23 to -4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass -0.7 g; 95% CI: -2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: -2.2% to 3.6%; P = 0.61).
CONCLUSIONS: The CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac
remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).