临床改善时间：肺动脉高压药物试验的一个合适替代终点。
Time to clinical improvement: an appropriate surrogate endpoint for pulmonary arterial hypertension medication trials.
作者信息
Wang An, Chen Mengqi, Zhuang Qi, Guan Lihua, Xie Weiping, Wang Lan, Huang Wei, Cheng Zhaozhong, Yu Shiyong, Zhou Hongmei, Shen Jieyan
机构信息
Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, China.
出版信息
Front Cardiovasc Med. 2023 Jun 12;10:1142721. doi: 10.3389/fcvm.2023.1142721. eCollection 2023.
BACKGROUND
Many retrospective studies suggest that risk improvement may be a suitable efficacy surrogate endpoint for pulmonary arterial hypertension (PAH) medication trials. This prospective multicenter study assessed the efficacy of domestic ambrisentan in Chinese PAH patients and observed risk improvement and time to clinical improvement (TTCI) under ambrisentan treatment.
METHODS
Eligible patients with PAH were enrolled for a 24-week treatment with ambrisentan. The primary efficacy endpoint was 6-min walk distance (Δ6MWD). The exploratory endpoints were risk improvement and TTCI, defined as the time from initiation of treatment to the first occurrence of risk improvement.
RESULTS
A total of 83 subjects were enrolled. After ambrisentan treatment, Δ6MWD was significantly increased at week 12 (42.2 m, < 0.0001) and week 24 (53.4 m, < 0.0001). Within 24 weeks, risk improvement was observed in 53 (64.6%) subjects (< 0.0001), which is higher than WHO-FC (30.5%) and TAPSE/PASP (32.9%). Kaplan-Meier analysis of TTCI showed a median improvement time of 131 days and a cumulative improvement rate of 75.1%. Also, TTCI is consistent across different baseline risk status populations (log-rank = 0.51). The naive group had more risk improvement ( = 0.043) and shorter TTCI (log-rank = 0.008) than the add-on group, while Δ6MWD did not show significant differences between the two groups.
CONCLUSIONS
Domestic ambrisentan significantly improved the exercise capacity and risk status of Chinese PAH patients. TTCI has a relatively high positive event rate within 24-week treatment duration. Compared to Δ6MWD, TTCI is not affected by baseline risk status. Additionally, TTCI could identify better improvements in patients, which Δ6MWD does not detect. TTCI is an appropriate composite surrogate endpoint for PAH medication trials.
CLINICAL TRIAL REGISTRATION
NCT No. [ClinicalTrials.gov], identifier [NCT05437224].
背景
许多回顾性研究表明，风险改善可能是肺动脉高压（PAH）药物试验合适的疗效替代终点。这项前瞻性多中心研究评估了国产安立生坦在中国PAH患者中的疗效，并观察了安立生坦治疗下的风险改善情况和临床改善时间（TTCI）。
方法
符合条件的PAH患者入选接受为期24周的安立生坦治疗。主要疗效终点为6分钟步行距离（Δ6MWD）。探索性终点为风险改善和TTCI，定义为从治疗开始到首次出现风险改善的时间。
结果
共纳入83名受试者。安立生坦治疗后，第12周（42.2米，<0.0001）和第24周（53.4米，<0.0001）时Δ6MWD显著增加。在24周内，53名（64.6%）受试者出现风险改善（<0.0001），高于世界卫生组织功能分级（WHO-FC）（30.5%）和三尖瓣环平面收缩期位移/肺动脉收缩压（TAPSE/PASP）（32.9%）。TTCI的Kaplan-Meier分析显示，中位改善时间为131天，累积改善率为75.1%。此外，不同基线风险状态人群的TTCI一致（对数秩检验=0.51）。初治组比加用组有更多的风险改善（P=0.043）和更短的TTCI（对数秩检验=0.008），而两组间Δ6MWD无显著差异。
结论
国产安立生坦显著改善了中国PAH患者的运动能力和风险状态。在24周的治疗期内，TTCI有相对较高的阳性事件率。与Δ6MWD相比，TTCI不受基线风险状态的影响。此外，TTCI能发现患者更好的改善情况，而Δ6MWD无法检测到。TTCI是PAH药物试验合适的复合替代终点。
临床试验注册
NCT编号[ClinicalTrials.gov]，标识符[NCT05437224]
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