Oregon Health and Science University, Portland, Oregon, USA.
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
J Am Coll Cardiol. 2024 Nov 5;84(19):1839-1849. doi: 10.1016/j.jacc.2024.09.002.
Standard-of-care (SoC) medications for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are recommended as first-line therapy despite the lack of evidence from controlled clinical trials and well known off-target side effects.
We describe the impact of SoC therapy downtitration and withdrawal in patients already receiving aficamten in FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy; NCT04848506).
Patients receiving SoC therapy (beta-blocker, nondihydropyridine calcium-channel blocker, and/or disopyramide) were eligible for protocol-guided SoC downtitration and withdrawal at the discretion of the investigator and after achieving a stable dose of aficamten for ≥4 weeks. Successful SoC withdrawal was defined as at least a 50% dose-reduction in ≥1 medication. Adverse events (AEs) were prospectively evaluated 1 to 2 weeks after any SoC withdrawal.
Of 145 patients with oHCM who were followed for at least 24 weeks (mean age 60.5 ± 13.2 years; 44.8% female; 42% NYHA functional class III), 136 (93.8%) were receiving ≥1 SoC therapy; of those, 64 (47%) had an attempt at withdrawal, with 59 (92.2%) successful. Thirty-eight (64.4%) patients completely discontinued ≥1 medication, and 27 (45.8%) achieved aficamten monotherapy with 2 later restarting a SoC medication. There were no significant differences in baseline characteristics on day 1 in FOREST-HCM in those with a SoC-withdrawal vs no-withdrawal attempt. In patients who underwent successful SoC therapy withdrawal, NYHA functional class improved by ≥1 class in 79.2% from baseline, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score improved to 83.0 ± 15.8 points, and resting and Valsalva left ventricular outflow tract gradient improved to 14.3 ± 10.9 and 32.9 ± 21.4 mm Hg, respectively. N-terminal pro-B-type natriuretic peptide levels improved to a median of 220.0 pg/mL (Q1-Q3: 102.0-554.0.0 pg/mL) and high-sensitivity troponin I improved to a median of 6.0 ng/L (Q1-Q3:3.5-10.7 ng/L). Downtitration and withdrawal of SoC therapy did not impact these results (all P values for change were >0.05), and these changes were similar in patients who did not undergo SoC therapy withdrawal. There were no serious AEs attributed to SoC withdrawal and treatment emergent AEs were similar between groups.
In FOREST-HCM, one-half of the patients with oHCM attempted downtitration and withdrawal of SoC medications while receiving aficamten treatment, with infrequent instances of resumption of SoC. Stopping and dose reduction of SoC medications were well tolerated with no adverse consequences in clinical measures of efficacy (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506).
尽管缺乏对照临床试验证据且具有众所周知的非靶标副作用，但治疗梗阻性肥厚型心肌病（oHCM）的标准治疗（SoC）药物仍被推荐作为一线治疗。
我们描述了在接受阿非卡肽治疗的 FOREST-HCM 患者中（随访、开放标签、阿非卡肽治疗肥厚型心肌病的持续疗效研究；NCT04848506），SoC 治疗剂量下调和停药的影响。
正在接受 SoC 治疗（β受体阻滞剂、非二氢吡啶类钙通道阻滞剂和/或双异丙吡胺）的患者符合方案指导的 SoC 剂量下调和停药标准，由研究者酌情决定，并在接受阿非卡肽稳定剂量治疗≥4 周后进行。成功的 SoC 停药定义为至少减少≥1 种药物的 50%剂量。停药后 1 至 2 周内前瞻性评估不良事件（AE）。
在至少随访 24 周的 145 例 oHCM 患者中（平均年龄 60.5±13.2 岁；44.8%为女性；42%纽约心脏病协会[NYHA]心功能分级 III 级），136 例（93.8%）正在接受≥1 种 SoC 治疗；其中 64 例（47%）尝试停药，59 例（92.2%）成功。38 例（64.4%）患者完全停止≥1 种药物，27 例（45.8%）实现阿非卡肽单药治疗，其中 2 例后来重新开始使用 SoC 药物。在 FOREST-HCM 中，在有 SoC 停药与无停药尝试的患者中，第 1 天的基线特征无显著差异。在成功进行 SoC 治疗停药的患者中，NYHA 心功能分级较基线改善≥1 级的患者比例为 79.2%，堪萨斯城心肌病问卷临床综合评分改善至 83.0±15.8 分，静息和瓦尔萨尔瓦左心室流出道梯度分别改善至 14.3±10.9 和 32.9±21.4mmHg。N 端脑利钠肽前体水平改善中位数为 220.0pg/ml（Q1-Q3：102.0-554.0pg/ml），高敏肌钙蛋白 I 改善中位数为 6.0ng/L（Q1-Q3：3.5-10.7ng/L）。SoC 治疗剂量下调和停药未影响这些结果（所有变化的 P 值均>0.05），且在未进行 SoC 治疗停药的患者中，这些变化相似。SoC 停药无严重不良事件发生，且治疗出现的不良事件在各亚组间无差异。
在 FOREST-HCM 中，一半的 oHCM 患者在接受阿非卡肽治疗时尝试下调和停用 SoC 药物，且很少重新开始使用 SoC。SoC 药物的停药和剂量减少耐受良好，对疗效的临床评估无不良后果（随访、开放标签、阿非卡肽治疗肥厚型心肌病的持续疗效研究；NCT04848506）。
