Ticagrelor Aspirin vs Clopidogrel Aspirin in CYP2C19 Loss-of-Function Carriers With Minor Stroke or TIA Stratified by Risk Profile

Anxin Wang; Xia Meng; Xue Tian; Yingting Zuo; Philip M Bath; Hao Li; Xuewei Xie; Jing Jing; Jinxi Lin; Yilong Wang; Xingquan Zhao; Liping Liu; Zixiao Li; Yong Jiang; Jie Xu; Feng Wang; Weifeng Chen; Minghua Cao; Jianhua Li; Yongjun Wang

doi:10.1212/WNL.0000000000201454

Ticagrelor Aspirin vs Clopidogrel Aspirin in CYP2C19 Loss-of-Function Carriers With Minor Stroke or TIA Stratified by Risk Profile

Neurology. 2023 Jan 31;100(5):e497-e504. doi: 10.1212/WNL.0000000000201454. Epub 2022 Dec 19.

Authors

Anxin Wang¹, Xia Meng¹, Xue Tian¹, Yingting Zuo¹, Philip M Bath¹, Hao Li¹, Xuewei Xie¹, Jing Jing¹, Jinxi Lin¹, Yilong Wang¹, Xingquan Zhao¹, Liping Liu¹, Zixiao Li¹, Yong Jiang¹, Jie Xu¹, Feng Wang¹, Weifeng Chen¹, Minghua Cao¹, Jianhua Li¹, Yongjun Wang²

Affiliations

¹ From the Department of Neurology (A.W., X.M., X.T., Y.Z., H.L., X.X., J.J., J.L., Y.W., X.Z., L.L., Z.L., Y.J., J.X., Y.W.), Beijing Tiantan Hospital, Capital Medical University, China; China National Clinical Research Center for Neurological Diseases (A.W., X.M., X.T., Y.Z., H.L., X.X., J.J., J.L., Y.W., X.Z., L.L., Z.L., Y.J., J.X., Y.W.), Beijing, China; Department of Epidemiology and Health Statistics (X.T.), School of Public Health, Capital Medical University, Beijing, China; Beijing Municipal Key Laboratory of Clinical Epidemiology (X.T.), China; Stroke Trials Unit, Mental Health & Clinical Neuroscience (P.M.B.), University of Nottingham, United Kingdom; Departments of Neurology (F.W.), Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Neurology (W.C.), Xingyang People's Hospital, Henan, China; Department of Neurology (M.C.), Jingdezheng First People's Hospital, Jiangxi, China; Department of Neurology (J.L.), The First Hospital of Fangshan District, Beijing, China; Advanced Innovation Center for Human Brain Protection (A.W., X.M., Y.W.), Beijing Tiantan Hospital, Capital Medical University, China.
² From the Department of Neurology (A.W., X.M., X.T., Y.Z., H.L., X.X., J.J., J.L., Y.W., X.Z., L.L., Z.L., Y.J., J.X., Y.W.), Beijing Tiantan Hospital, Capital Medical University, China; China National Clinical Research Center for Neurological Diseases (A.W., X.M., X.T., Y.Z., H.L., X.X., J.J., J.L., Y.W., X.Z., L.L., Z.L., Y.J., J.X., Y.W.), Beijing, China; Department of Epidemiology and Health Statistics (X.T.), School of Public Health, Capital Medical University, Beijing, China; Beijing Municipal Key Laboratory of Clinical Epidemiology (X.T.), China; Stroke Trials Unit, Mental Health & Clinical Neuroscience (P.M.B.), University of Nottingham, United Kingdom; Departments of Neurology (F.W.), Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Neurology (W.C.), Xingyang People's Hospital, Henan, China; Department of Neurology (M.C.), Jingdezheng First People's Hospital, Jiangxi, China; Department of Neurology (J.L.), The First Hospital of Fangshan District, Beijing, China; Advanced Innovation Center for Human Brain Protection (A.W., X.M., Y.W.), Beijing Tiantan Hospital, Capital Medical University, China. yongjunwang@ncrcnd.org.cn.

Abstract

Background and objective: Genotype data of the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial showed that efficacy of clopidogrel aspirin depended on CYP2C19 genotype and risk profile. A stratification of patients who carried CYP2C19 loss-of-function (LOF) alleles according to the risk of recurrent stroke may be important for selecting optimal antiplatelet therapy. We aimed to compare the efficacy and safety of ticagrelor aspirin with clopidogrel aspirin in CYP2C19 LOF carriers with minor stroke or transient ischemic attack (TIA) stratified by risk profile.

Methods: Data were obtained from Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial. Low-risk and high-risk profiles were defined by Essen Stroke Risk Score (ESRS) (<3 [low risk] and ≥3 [high risk], respectively).

Results: A total of 6,412 CYP2C19 LOF carriers were enrolled; ticagrelor aspirin was associated with a reduced risk of primary outcome (new stroke within 90-day follow-up) in patients at low risk (hazard ratio [HR], 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel aspirin (p = 0.02 for interaction). Secondary outcomes generally went in the same direction as the primary outcome. The primary safety outcome of severe or moderate bleeding did not differ based on risk profile (p = 0.24 for interaction), although the incidence of total bleeding was greater with ticagrelor aspirin than with clopidogrel aspirin among patients at low risk (p < 0.01 for interaction). Analysis in the per-protocol population yielded similar results.

Discussion: This post hoc analysis of CHANCE-2 trial showed that CYP2C19 LOF carriers with minor stroke or TIA at low risk of recurrent stroke received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin.

Classification of evidence: This study provides Class II evidence that CYP2C19 LOF carriers with minor stroke or TIA at low risk, but not at high risk, of recurrent stroke (by the ESRS) received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin.

Trial registration information: URL: www.

Clinicaltrials: gov. Unique identifier: NCT04078737.

MeSH terms

Aspirin / therapeutic use
Cerebral Infarction
Clopidogrel / therapeutic use
Cytochrome P-450 CYP2C19 / genetics
Cytochrome P-450 CYP2C19 / therapeutic use
Drug Therapy, Combination
Humans
Ischemic Attack, Transient* / drug therapy
Ischemic Attack, Transient* / genetics
Neoplasm Recurrence, Local / drug therapy
Platelet Aggregation Inhibitors / therapeutic use
Risk Factors
Stroke* / drug therapy
Stroke* / genetics
Ticagrelor / therapeutic use
Treatment Outcome

Substances

Clopidogrel
Aspirin
Ticagrelor
Platelet Aggregation Inhibitors
Cytochrome P-450 CYP2C19
CYP2C19 protein, human

Associated data

ClinicalTrials.gov/NCT04078737