Wheeler Matthew T, Jacoby Daniel, Elliott Perry M, Saberi Sara, Hegde Sheila M, Lakdawala Neal K, Myers Jonathan, Sehnert Amy J, Edelberg Jay M, Li Wanying, Olivotto Iacopo
Division of Cardiovascular Medicine, Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA, USA.
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT, USA.
Eur J Heart Fail. 2023 Feb;25(2):260-270. doi: 10.1002/ejhf.2737. Epub 2023 Feb 1.
In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten effects on the primary endpoint, a composite of peak oxygen consumption (VO ) and New York Heart Association (NYHA) class, were greater in patients not receiving background beta-blockers than in those receiving beta-blockers. We sought to determine if the effect of background treatment was consistent across other clinically meaningful parameters.
Subgroup analyses by beta-blocker use were performed in patients with oHCM from the EXPLORER-HCM and mavacamten long-term extension (MAVA-LTE) studies. In EXPLORER-HCM, 189 patients (75.3%) were receiving beta-blockers, and 62 (24.7%) were receiving non-dihydropyridine calcium channel blockers or no background HCM medication; 170 patients (90.4%) receiving beta-blockers had chronotropic incompetence. Improvements in peak VO at week 30 with mavacamten versus placebo were lower with beta-blockers (mean difference [95% confidence interval (CI)]: 1.04 [0.12, 1.95] ml/kg/min) than without beta-blockers (mean difference [95% CI]: 2.69 [1.29, 4.09] ml/kg/min); improvements in non-heart rate-dependent parameters (V /VCO slope) appeared unaffected by beta-blockers. Improvements in functional capacity parameters at week 30 with mavacamten versus placebo were independent of beta-blockade for post-exercise left ventricular outflow tract gradient (mean difference [95% CI]: -37.9 [-48.0, -27.9] mmHg with beta-blockers; -33.5 [-53.6, -13.3] mmHg without beta-blockers), proportion of patients with reduction of ≥1 NYHA class, Kansas City Cardiomyopathy Questionnaire clinical summary scores and N-terminal pro-B-type natriuretic peptide. Mavacamten benefits were reproduced and maintained in MAVA-LTE regardless of beta-blockade.
Mavacamten improved measures of functional capacity, left ventricular outflow tract obstruction, symptom burden and biomarkers in patients with HCM regardless of beta-blocker use. Beta-blocker use was often associated with chronotropic incompetence, affecting peak VO and other heart rate-dependent measures, but had minimal impact on heart rate-independent measures.
在EXPLORER-HCM试验中，mavacamten改善了梗阻性肥厚型心肌病（oHCM）患者的运动能力和症状。mavacamten对主要终点（峰值耗氧量[VO₂]和纽约心脏协会[NYHA]心功能分级的综合指标）的影响在未接受背景β受体阻滞剂治疗的患者中比接受β受体阻滞剂治疗的患者更大。我们试图确定背景治疗的效果在其他具有临床意义的参数中是否一致。
对来自EXPLORER-HCM和mavacamten长期扩展（MAVA-LTE）研究的oHCM患者按β受体阻滞剂使用情况进行亚组分析。在EXPLORER-HCM中，189例患者（75.3%）接受β受体阻滞剂治疗，62例（24.7%）接受非二氢吡啶类钙通道阻滞剂或未接受背景HCM药物治疗；170例接受β受体阻滞剂治疗的患者存在变时性功能不全。与安慰剂相比，mavacamten在第30周时使峰值VO₂的改善在接受β受体阻滞剂治疗的患者中较低（平均差值[95%置信区间（CI）]：1.04[0.12，1.95]ml/kg/min），而在未接受β受体阻滞剂治疗的患者中较高（平均差值[95%CI]：2.69[1.29，4.09]ml/kg/min）；非心率依赖性参数（Vₑ/VCO₂斜率）的改善似乎不受β受体阻滞剂的影响。与安慰剂相比，mavacamten在第30周时对功能能力参数的改善与β受体阻滞剂无关，包括运动后左心室流出道梯度（平均差值[95%CI]：接受β受体阻滞剂治疗的患者为-37.9[-48.0，-27.9]mmHg；未接受β受体阻滞剂治疗的患者为-33.5[-53.6，-13.3]mmHg）、NYHA心功能分级降低≥1级的患者比例、堪萨斯城心肌病问卷临床总结评分以及N末端B型利钠肽原。无论是否使用β受体阻滞剂，mavacamten的益处均在MAVA-LTE中得到重现和维持。
无论是否使用β受体阻滞剂，mavacamten均改善了HCM患者的功能能力、左心室流出道梗阻、症状负担和生物标志物指标。使用β受体阻滞剂通常与变时性功能不全相关，影响峰值VO₂和其他心率依赖性指标，但对心率非依赖性指标影响最小。
