Xuewei Xie
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
Authors
S. Claiborne Johnston
Anxin Wang
Qin Xu
PHILIP BATH philip.bath@nottingham.ac.uk
Stroke Association Professor of Stroke Medicine
Yuesong Pan
Hao Li
Jinxi Lin
Yilong Wang
Xingquan Zhao
Zixiao Li
Yong Jiang
Liping Liu
Anding Xu
Jing Jing
Xia Meng
Yongjun Wang
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 |
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Publisher Licence URL
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