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

An Wang; Mengqi Chen; Qi Zhuang; Lihua Guan; Weiping Xie; Lan Wang; Wei Huang; Zhaozhong Cheng; Shiyong Yu; Hongmei Zhou; Jieyan Shen

doi:10.3389/fcvm.2023.1142721

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

Front Cardiovasc Med. 2023 Jun 12:10:1142721. doi: 10.3389/fcvm.2023.1142721. eCollection 2023.

Authors

An Wang^#¹, Mengqi Chen^#¹, Qi Zhuang¹, Lihua Guan², Weiping Xie³, Lan Wang⁴, Wei Huang⁵, Zhaozhong Cheng⁶, Shiyong Yu⁷, Hongmei Zhou⁸, Jieyan Shen¹

Affiliations

¹ Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁴ Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
⁵ Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁶ Respiratory Department, The Affiliated Hospital of Qingdao University, Qingdao, China.
⁷ Department of Cardiology, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
⁸ Congenital Heart Disease Center, Wuhan Asia Heart Hospital, Wuhan University of Science and Technology, Wuhan, China.

^# Contributed equally.

Abstract

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, 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 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].

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

Associated data

ClinicalTrials.gov/NCT05437224

Grants and funding

This work was supported by the National Natural Science Foundation of China (CN) (81970047, 82270050) and the Clinical Research Innovation and Incubation Foundation of Renji Hospital, Shanghai Jiao Tong University School of Medicine (PYII20-13).