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Efficacy and Safety of Ticagrelor Versus Clopidogrel in Acute Minor Stroke or Transient Ischaemic Attack Patients with Different Intracranial Artery Stenosis Statuses: A Subgroup Analysis of CHANCE-2, A Randomized, Double-Blind, Controlled Trial

34 Pages Posted: 10 Mar 2022

See all articles by Chunjuan Wang

Chunjuan Wang

Capital Medical University - Beijing Tiantan Hospital

Jing Jing

Capital Medical University - Department of Neurology

Weili Jia

Capital Medical University - Department of Neurology

Xia Meng

Capital Medical University - Department of Neurology

Anxin Wang

Capital Medical University - Department of Neurology

Qin Xu

Capital Medical University - Department of Neurology

Xinmiao Zhang

Capital Medical University - Beijing Tiantan Hospital

Yuesong Pan

Capital Medical University - Beijing Tiantan Hospital

Xuewei Xie

Capital Medical University - Department of Neurology

S. Claiborne Johnston

University of Texas at Austin

Philip Bath

University of Nottingham - Stroke Trials Unit

Jinxi Lin

Capital Medical University - Department of Neurology

Yong Jiang

Capital Medical University - Department of Neurology

Hao Li

Capital Medical University - China National Clinical Research Center for Neurological Diseases

Yilong Wang

Capital Medical University - Department of Neurology

Xingquan Zhao

Capital Medical University - Department of Neurology

Liping Liu

Capital Medical University - Department of Neurology

Yongjun Wang

Capital Medical University - Department of Neurology

Zixiao Li

Capital Medical University - Department of Neurology

More...

Abstract

Background: Ticagrelor plus aspirin or ticagrelor alone has been demonstrated to be more effective at preventing recurrent stroke than aspirin monotherapy in patients with acute minor stroke or transient ischaemic attack (TIA) of atherosclerotic origin. However, whether ticagrelor is more efficient than clopidogrel for patients who are also carriers of CYP2C19 loss-of-function alleles remains unknown. Our aim was to investigate the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in patients with different intracranial artery stenosis (ICAS) statuses in Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events-II (CHANCE-2) trial.

Methods: CHANCE-2 was a randomized, double-blind, controlled trial exploring the use of ticagrelor-aspirin versus clopidogrel-aspirin in patients aged over 40 years with minor ischaemic stroke or high-risk TIA who were carriers of CYP2C19 loss-offunction alleles. We randomly allocated patients (1:1) within 24 hours after symptom onset to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily for days 2- 90) and placebo clopidogrel or to receive clopidogrel (300 mg on day 1 followed by 75 mg once daily for days 2-90) and placebo ticagrelor. ICAS was defined as at least 50% ipsilateral or contralateral stenosis of intracranial arteries mainly based on MR angiography and/or CT angiography, and symptomatic ICAS (sICAS) was defined as eligible ipsilateral intracranial artery stenosis according to the most recent clinical presentation. After excluding those without available imaging of the intracranial artery, all patients were classified into 3 different groups according to ICAS status: without ICAS, sICAS, or asymptomatic ICAS (asICAS). The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days. The CHANCE-2.

Findings: Of the 6412 patients enrolled from September 23, 2019 to March 22, 2021, 5920 (92·3%) had available imaging of the intracranial artery, including 3535 (59·7%) without ICAS, 1639 (27·7%) with sICAS, and 746 (12·6%) with asICAS. A total of 175 (5·0%), 172 (10·5%) and 57 (7·6%) cases of new strokes occurred within 90 days in the without ICAS, with sICAS, and with asICAS groups, respectively, and the hazard ratios (HRs) of recurrence in the sICAS and asICAS groups were 2·14 (95% CI 1·72– 2·66) and 1·57 (1·15–2·14), respectively, compared to the without ICAS group. No treatment-by-ICAS status interaction was observed (p=0·14). Among patients without ICAS, new stroke within 90 days occurred in 63 (3·6%) of the 1762 patients in the ticagrelor-aspirin group and in 112 (6·3%) of the 1773 patients in the clopidogrelaspirin group (HR 0·56 [95% CI 0·41–0·77]; p<0·001). Among the patients with sICAS, new stroke occurred in 81 (9·6%) of 841 patients in the ticagrelor-aspirin group versus 91 (11·4%) of 798 patients the clopidogrel-aspirin group (0·75 [0·55–1·04]; p=0·082), and among patients in the asICAS group, new stroke occurred in 27 (7·4%) of 366 patients in the ticagrelor-aspirin group versus 30 (7·9%) of 380 patients in the clopidogrel-aspirin group (0·77 [0·43–1·38]; p=0·375). There were no significant differences in the proportion of severe or moderate bleeding events in the ticagreloraspirin group compared with the clopidogrel-aspirin group among patients with different ICAS statuses.

Interpretation: In the subgroup analysis of the CHANCE-2 trial, both patients with sICAS and those with asICAS had a much higher risk of new stroke than those without ICAS. The efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing new stroke were similar between patients with and those without ICAS, which was consistent with the overall results of the CHANCE-2 intention-to-treat population. The without ICAS group may receive greater benefit.

Trial Registration: Trial is registered with ClinicalTrials.gov (number NCT04078737).

Funding: This trial was supported by grants from the Beijing Natural Science Foundation (Z200016), National Natural Science Foundation of China (82171270, 92046016), Ministry of Science and Technology of the People's Republic of China (National Key R&D Programme of China, 2017YFC1310901, 2016YFC0901002, 2017YFC1307905, 2015BAl12B00), Beijing Talents Project (2018000021223ZK03), Beijing Municipal Committee of Science and Technology (Z201100005620010), CAMS Innovation Fund for Medical Sciences (2019-2M-5-029).

Declaration of Interests: None.

Ethics Approval Statement: The trial was approved by the ethics committees at Beijing Tiantan Hospital, Capital Medical University, and at each participating site and was performed in accordance with Good Clinical Practice guidelines.

Keywords: Ticagrelor- aspirin, Clopidogrel- aspirin, CYP2C19 loss-of-function alleles, Intracranial artery stenosis

Suggested Citation

Wang, Chunjuan and Jing, Jing and Jia, Weili and Meng, Xia and Wang, Anxin and Xu, Qin and Zhang, Xinmiao and Pan, Yuesong and Xie, Xuewei and Johnston, S. Claiborne and Bath, Philip and Lin, Jinxi and Jiang, Yong and Li, Hao and Wang, Yilong and Zhao, Xingquan and Liu, Liping and Wang, Yongjun and Li, Zixiao, Efficacy and Safety of Ticagrelor Versus Clopidogrel in Acute Minor Stroke or Transient Ischaemic Attack Patients with Different Intracranial Artery Stenosis Statuses: A Subgroup Analysis of CHANCE-2, A Randomized, Double-Blind, Controlled Trial. Available at SSRN: https://ssrn.com/abstract=4054464 or http://dx.doi.org/10.2139/ssrn.4054464

Chunjuan Wang

Capital Medical University - Beijing Tiantan Hospital ( email )

Beijing, 100050
China

Jing Jing

Capital Medical University - Department of Neurology ( email )

Weili Jia

Capital Medical University - Department of Neurology ( email )

Xia Meng

Capital Medical University - Department of Neurology ( email )

Anxin Wang

Capital Medical University - Department of Neurology ( email )

Qin Xu

Capital Medical University - Department of Neurology ( email )

Xinmiao Zhang

Capital Medical University - Beijing Tiantan Hospital ( email )

Beijing, 100050
China

Yuesong Pan

Capital Medical University - Beijing Tiantan Hospital ( email )

Beijing, 100050
China

Xuewei Xie

Capital Medical University - Department of Neurology ( email )

S. Claiborne Johnston

University of Texas at Austin ( email )

Philip Bath

University of Nottingham - Stroke Trials Unit ( email )

Nottingham, NG5 1PB
United Kingdom

Jinxi Lin

Capital Medical University - Department of Neurology ( email )

Yong Jiang

Capital Medical University - Department of Neurology ( email )

Hao Li

Capital Medical University - China National Clinical Research Center for Neurological Diseases ( email )

Yilong Wang

Capital Medical University - Department of Neurology ( email )

Xingquan Zhao

Capital Medical University - Department of Neurology ( email )

Liping Liu

Capital Medical University - Department of Neurology ( email )

Yongjun Wang (Contact Author)

Capital Medical University - Department of Neurology ( email )

No. 119 South 4th Ring West Road
Fengtai District
Beijing, 100070
China
0086-010-67098350 (Phone)

Zixiao Li

Capital Medical University - Department of Neurology ( email )

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