Association of CYP2C19 Loss-of-Function Metabolizer Status With Stroke Risk Among Chinese Patients Treated With Ticagrelor-Aspirin vs Clopidogrel-Aspirin: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Xie, Xuewei; Johnston, S. Claiborne; Wang, Anxin; Xu, Qin; Bath, Philip M.; Pan, Yuesong; Li, Hao; Lin, Jinxi; Wang, Yilong; Zhao, Xingquan; Li, Zixiao; Jiang, Yong; Liu, Liping; Xu, Anding; Jing, Jing; Meng, Xia; Wang, Yongjun

Abstract

Importance: The Clopidogrel With Aspirin in High-Risk Patients With Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial showed that ticagrelor-aspirin combination therapy reduced the risk of stroke compared with a clopidogrel-aspirin combination among carriers of CYP2C19 loss-of-function (LOF) alleles after a transient ischemic attack (TIA) or minor ischemic stroke. However, the association between the degree of CYP2C19 LOF and ideal treatment allocation remains unknown.

Objective: To investigate whether the efficacy and safety of ticagrelor-aspirin vs clopidogrel-aspirin are consistent with the expected degree of CYP2C19 LOF after TIA or minor stroke.

Design, Setting, and Participants: CHANCE-2 was a multicenter, double-blind, double-dummy, placebo-controlled randomized clinical trial. Patients were enrolled at 202 centers in China from September 23, 2019, through March 22, 2021. Patients with at least two *2 or *3 alleles (*2/*2, *2/*3, or *3/*3) according to point-of-care genotyping were classified as “poor metabolizers,” and those with one *2 or *3 allele (*1/*2 or *1/*3) were classified as “intermediate metabolizers.”

Interventions: Patients were randomly assigned in a 1:1 ratio to receive ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for days 2-90) or clopidogrel (300-mg loading dose on day 1 followed by 75 mg/d for days 2-90). All patients received aspirin (75- to 300-mg loading dose followed by 75 mg/d for 21 days).

Main Outcomes and Measures: The primary efficacy outcome was a new ischemic or hemorrhagic stroke. The secondary efficacy outcome was a composite of new clinical vascular events and individual ischemic stroke events within 3 months. The primary safety outcome was severe or moderate bleeding. Analyses were performed according to the intention-to-treat principle.

Results: Of the 6412 patients enrolled, the median age was 64.8 years (IQR, 57.0-71.4 years), and 4242 patients (66.2%) were men. Of the 6412 patients, 5001 (78.0%) were intermediate metabolizers, and 1411 (22.0%) were poor metabolizers. The primary outcome occurred less often with ticagrelor-aspirin vs clopidogrel-aspirin, irrespective of metabolizer status (6.0% [150 of 2486] vs 7.6% [191 of 2515]; hazard ratio [HR], 0.78 [95% CI, 0.63-0.97] among intermediate metabolizers and 5.7% [41 of 719] vs 7.5% [52 of 692]; HR, 0.77 [95% CI, 0.50-1.18] among poor metabolizers; P = .88 for interaction). Patients taking ticagrelor-aspirin had a higher risk of any bleeding event compared with those taking clopidogrel-aspirin, irrespective of metabolizer status: 5.4% (134 of 2486) vs 2.6% (66 of 2512) (HR, 2.14 [95% CI, 1.59-2.89]) among intermediate metabolizers and 5.0% (36 of 719) vs 2.0% (14 of 692) (HR, 2.99 [95% CI, 1.51-5.93]) among poor metabolizers (P = .66 for interaction).

Conclusions and Relevance: This prespecified analysis of a randomized clinical trial found no difference in treatment effect between poor and intermediate CYP2C19 metabolizers. The relative clinical efficacy and safety of ticagrelor-aspirin vs clopidogrel-aspirin were consistent across CYP2C19 genotypes.

Trial Registration: ClinicalTrials.gov Identifier: NCT04078737

Citation

Xie, X., Johnston, S. C., Wang, A., Xu, Q., Bath, P. M., Pan, Y., …Wang, Y. (2023). Association of CYP2C19 Loss-of-Function Metabolizer Status With Stroke Risk Among Chinese Patients Treated With Ticagrelor-Aspirin vs Clopidogrel-Aspirin: A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open, 6(6), Article e2317037. https://doi.org/10.1001/jamanetworkopen.2023.17037

• Journal Article Type: Article
• Acceptance Date: Apr 23, 2023
• Online Publication Date: Jun 6, 2023
• Publication Date: Jun 6, 2023
• Deposit Date: Jun 12, 2023
• Publicly Available Date: Jun 12, 2023
• Journal: JAMA Network Open
• Electronic ISSN: 2574-3805
• Publisher: American Medical Association
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 6
• Article Number: e2317037
• DOI: https://doi.org/10.1001/jamanetworkopen.2023.17037
• Keywords: Middle Aged, Ischemic Attack, Transient - drug therapy, Stroke - drug therapy - prevention & control - genetics, Humans, Hemorrhage - chemically induced, Female, Ticagrelor - therapeutic use, Aged, Aspirin - therapeutic use, Platelet Aggregation Inhibitor
• Public URL: https://nottingham-repository.worktribe.com/output/21898461
• Publisher URL: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805605