Background

Pulmonary hypertension (PH) is a severe hemodynamic condition with high morbidity and mortality. Approved targeted therapies are limited for pediatric subjects, and treatments are widely adopted from adult algorithms. Macitentan is a safe and effective drug used for adult PH, but data on pediatric patients are limited. In this prospective single-center study, we investigated mid- and long-term effects of macitentan in children with advanced pulmonary hypertensive vascular disease.

Methods

Twenty-four patients were enrolled in the study for treatment with macitentan. Efficacy was determined by echo parameters and brain natriuretic peptide levels (BNP) at 3 months and 1 year. For detailed analysis, the entire cohort was subgrouped into patients with congenital heart disease-related PH (CHD-PH) and non-CHD-PH patients, respectively.

Results

Mean age of the patients was 10.7 ± 7.6 years; median observation period was 36 months. Twenty of 24 patients were on additional sildenafil and/or prostacyclins. Two of 24 patients discontinued because of peripheral edema.

Within the entire cohort, BNP levels and all echo measures such as right ventricular systolic pressure (RVSP), right ventricular end-diastolic diameter (RVED), tricuspid annular plane systolic excursion (TAPSE), pulmonary velocity time integral (VTI), and pulmonary artery acceleration time (PAAT) improved significantly after 3 months (p ≤ 0.01), whereas in the long term significant improvement persisted for BNP levels (−16%), VTI (+14%) and PAAT (+11%) (p < 0.05). By subgroup analysis, non-CHD PH patients showed significant improvements in BNP levels (−57%) and all echo measures (TAPSE +21%, VTI +13%, PAAT +37%, RVSP −24%, RVED −12%) at 3 months (p ≤ 0.01), whereas at 12 months, improvements persisted (p < 0.05) except for RVSP and RVED (nonsignificant). In CHD-PH patients, none of the measures changed (nonsignificant). 6-MWD (distance walked in 6 minutes) slightly increased but was not statistically evaluated.

Conclusion

Data presented herein account for the largest cohort of severely affected pediatric patients receiving macitentan. Overall, macitentan was safe and associated with significant beneficial effects and sustained positive signals after 1 year, albeit in the long term disease progression remains a major concern. Our data suggest limited efficacy in CHD-related PH, whereas favorable outcomes were mainly driven by improvements in patients with PH not related to CHD. Larger studies are needed to verify these preliminary results and to prove efficacy of this drug in different pediatric PH entities.

中文翻译：

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马西腾坦对儿科三级护理中心治疗的肺动脉高压血管疾病患者的中青年结局的影响

背景

肺动脉高压（PH）是一种严重的血流动力学疾病，发病率和死亡率很高。批准的靶向治疗仅限于儿科受试者，治疗方法广泛采用成人算法。马西腾坦是一种安全有效的药物，用于治疗成人肺动脉高压，但儿童患者的数据有限。在这项前瞻性单中心研究中，我们研究了马西腾坦对晚期肺动脉高压血管疾病儿童的中长期影响。

方法

24 名患者参加了接受马西腾坦治疗的研究。通过 3 个月和 1 年时的回声参数和脑钠尿肽水平 (BNP) 确定疗效。为了进行详细分析，整个队列分别分为先天性心脏病相关 PH 患者 (CHD-PH) 和非 CHD-PH 患者。

结果

患者的平均年龄为 10.7 ± 7.6 岁；中位观察期为 36 个月。24 名患者中有 20 名额外服用西地那非和/或前列环素。24 名患者中有 2 名因外周水肿而停药。

在整个队列中，BNP 水平和所有回波测量，例如右心室收缩压 (RVSP)、右心室舒张末期内径 (RVED)、三尖瓣环收缩期平面偏移 (TAPSE)、肺流速时间积分 (VTI) 和肺动脉血流速度时间积分 (VTI) 3 个月后动脉加速时间 (PAAT) 显着改善 ( p ≤ 0.01)，而从长远来看，BNP 水平 (−16%)、VTI (+14%) 和 PAAT (+11%) 持续显着改善 ( p  < 0.05）。通过亚组分析，非 CHD PH 患者的 BNP 水平 (−57%) 和所有回声测量值 (TAPSE +21%、VTI +13%、PAAT +37%、RVSP −24%、RVED −12%) 显着改善3 个月时 ( p  ≤ 0.01)，而 12 个月时，改善持续存在 ( p < 0.05)，RVSP 和 RVED 除外（不显着）。在 CHD-PH 患者中，所有措施均未改变（不显着）。6-MWD（6 分钟步行距离）略有增加，但未进行统计评估。

结论

本文提供的数据涵盖了接受马西替坦治疗的最大的严重受影响的儿科患者群体。总体而言，马西腾坦是安全的，并且在一年后具有显着的有益作用和持续的积极信号，尽管从长远来看，疾病进展仍然是一个主要问题。我们的数据表明，对 CHD 相关 PH 的疗效有限，而良好的结果主要是由于与 CHD 无关的 PH 患者的改善所致。需要更大规模的研究来验证这些初步结果，并证明该药物在不同儿科 PH 实体中的疗效。