Time to clinical improvement: an appropriate surrogate endpoint for pulmonary arterial hypertension medication trials

作者全名："Wang, An; Chen, Mengqi; Zhuang, Qi; Guan, Lihua; Xie, Weiping; Wang, Lan; Huang, Wei; Cheng, Zhaozhong; Yu, Shiyong; Zhou, Hongmei; Shen, Jieyan"

作者地址："[Wang, An; Chen, Mengqi; Zhuang, Qi; Shen, Jieyan] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Cardiol, Shanghai, Peoples R China; [Guan, Lihua] Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Dept Cardiol, Shanghai, Peoples R China; [Xie, Weiping] Nanjing Med Univ, Dept Resp & Crit Care Med, Affiliated Hosp 1, Nanjing, Peoples R China; [Wang, Lan] Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Cardiopulm Circulat, Shanghai, Peoples R China; [Huang, Wei] Chongqing Med Univ, Dept Cardiol, Affiliated Hosp 1, Chongqing, Peoples R China; [Cheng, Zhaozhong] Qingdao Univ, Resp Dept, Affiliated Hosp, Qingdao, Peoples R China; [Yu, Shiyong] Army Med Univ, Mil Med Univ 3, Affiliated Hosp 2, Dept Cardiol, Chongqing, Peoples R China; [Zhou, Hongmei] Wuhan Univ Sci & Technol, Wuhan Asia Heart Hosp, Congenital Heart Dis Ctr, Wuhan, Peoples R China"

通信作者："Shen, JY (通讯作者)，Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Cardiol, Shanghai, Peoples R China."

来源：FRONTIERS IN CARDIOVASCULAR MEDICINE

ESI学科分类：　

WOS号：WOS:001019814900001

JCR分区：Q2

影响因子：2.8

年份：2023

卷号：10

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：pulmonary arterial hypertension; time to clinical improvement; efficacy; risk stratification; 6-min walk distance

摘要："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 (Delta 6MWD). 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, Delta 6MWD was significantly increased at week 12 (42.2 m, P < 0.0001) and week 24 (53.4 m, P < 0.0001). Within 24 weeks, risk improvement was observed in 53 (64.6%) subjects (P < 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 P = 0.51). The naive group had more risk improvement (P = 0.043) and shorter TTCI (log-rank P = 0.008) than the add-on group, while Delta 6MWD 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 Delta 6MWD, TTCI is not affected by baseline risk status. Additionally, TTCI could identify better improvements in patients, which Delta 6MWD does not detect. TTCI is an appropriate composite surrogate endpoint for PAH medication trials."

基金机构："National Natural Science Foundation of China [81800047]; Clinical Research Innovation and Incubation Foundation of Renji Hospital, Shanghai Jiao Tong University School of Medicine [PYII20-13]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (CN) (81800047) and the Clinical Research Innovation and Incubation Foundation of Renji Hospital, Shanghai Jiao Tong University School of Medicine (PYII20-13)."