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Randomized Controlled Trial
. 2023 Jun 1;6(6):e2317037.
doi: 10.1001/jamanetworkopen.2023.17037.

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

Xuewei Xie  1   2 , S Claiborne Johnston  3 , Anxin Wang  1   2 , Qin Xu  1   2 , Philip M Bath  4 , Yuesong Pan  1   2 , Hao Li  1   2 , Jinxi Lin  1   2 , Yilong Wang  1   2 , Xingquan Zhao  1   2 , Zixiao Li  1   2 , Yong Jiang  1   2 , Liping Liu  1   2 , Anding Xu  5 , Jing Jing  1   2 , Xia Meng  1   2 , Yongjun Wang  1   2   6
Affiliations
Randomized Controlled Trial

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

Xuewei Xie et al. JAMA Netw Open. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Johnston reported receiving grants from AstraZeneca to University of California, San Francisco outside the submitted work. Dr Bath reported receiving personal fees from DiaMedica, Phagenesis, CoMind, and Roche outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Cumulative Probability of Stroke Recurrence According to Treatment and CYP2C19 Metabolizer Status
See this image and copyright information in PMC

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