Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis

Yuesong Pan; Weiqi Chen; Yun Xu; Xingyang Yi; Yan Han; Qingwu Yang; Xin Li; Li'an Huang; S Claiborne Johnston; Xingquan Zhao; Liping Liu; Qi Zhang; Guangyao Wang; Yongjun Wang; Yilong Wang

doi:10.1161/CIRCULATIONAHA.116.024913

Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis

Circulation. 2017 Jan 3;135(1):21-33. doi: 10.1161/CIRCULATIONAHA.116.024913. Epub 2016 Nov 2.

Authors

Affiliations

¹ From Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China (Y.P., W.C., X.Z., L.L., Q.Z., G.W., Yongjun Wang, Yilong Wang); China National Clinical Research Center for Neurological Diseases, Beijing (Y.P., W.C., X.Z., L.L., Q.Z., G.W., Yongjun Wang, Yilong Wang); Center of Stroke, Beijing Institute for Brain Disorders, China (Y.P., W.C., L.H., X.Z., L.L., Q.Z., G.W., Yongjun Wang, Yilong Wang); Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, China (Y.P., W.C., L.H., X.Z., L.L., Q.Z., G.W., Yongjun Wang, Yilong Wang); Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China (Y.P.); Beijing Municipal Key Laboratory of Clinical Epidemiology, China (Y.P.); Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, China (Y.X.); Department of Neurology, The People's Hospital of Deyang City, China (X.Y.); Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China (Y.H.); Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China (Q.Y.); Department of Neurology, the Second Hospital of Tianjin Medical University, China (X.L.); The First Affiliated Hospital, Jinan University, Guangzhou, China (L.H.); and Dell Medical School, University of Texas at Austin, TX (S.C.J.).
² From Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China (Y.P., W.C., X.Z., L.L., Q.Z., G.W., Yongjun Wang, Yilong Wang); China National Clinical Research Center for Neurological Diseases, Beijing (Y.P., W.C., X.Z., L.L., Q.Z., G.W., Yongjun Wang, Yilong Wang); Center of Stroke, Beijing Institute for Brain Disorders, China (Y.P., W.C., L.H., X.Z., L.L., Q.Z., G.W., Yongjun Wang, Yilong Wang); Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, China (Y.P., W.C., L.H., X.Z., L.L., Q.Z., G.W., Yongjun Wang, Yilong Wang); Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China (Y.P.); Beijing Municipal Key Laboratory of Clinical Epidemiology, China (Y.P.); Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, China (Y.X.); Department of Neurology, The People's Hospital of Deyang City, China (X.Y.); Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China (Y.H.); Department of Neurology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China (Q.Y.); Department of Neurology, the Second Hospital of Tianjin Medical University, China (X.L.); The First Affiliated Hospital, Jinan University, Guangzhou, China (L.H.); and Dell Medical School, University of Texas at Austin, TX (S.C.J.). yilong528@gmail.com yongjunwang1962@gmail.com.

PMID: 27806998
DOI: 10.1161/CIRCULATIONAHA.116.024913

Abstract

Background: The association of genetic polymorphisms and clopidogrel efficacy in patients with ischemic stroke or transient ischemic attack (TIA) remains controversial. We performed a systematic review and meta-analysis to assess the association between genetic polymorphisms, especially CYP2C19 genotype, and clopidogrel efficacy for ischemic stroke or TIA.

Methods: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to June 24, 2016. Studies that reported clopidogrel-treated patients with stroke or TIA and with information on genetic polymorphisms were included. The end points were stroke, composite vascular events, and any bleeding.

Results: Among 15 studies of 4762 patients with stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles (*2, *3, and *8) were at increased risk of stroke in comparison with noncarriers (12.0% versus 5.8%; risk ratio, 1.92, 95% confidence interval, 1.57-2.35; P<0.001). Composite vascular events were also more frequent in carriers of CYP2C19 loss-of-function alleles than in noncarriers (13.7% versus 9.4%; risk ratio, 1.51, 95% confidence interval, 1.10-2.06; P=0.01), whereas bleeding rates were similar (2.4% versus 3.1%; risk ratio, 0.89, 95% confidence interval, 0.58-1.35; P=0.59). There was no evidence of statistical heterogeneity among the included studies for stroke, but there was for composite vascular events. Genetic variants other than CYP2C19 were not associated with clinical outcomes, with the exception that significant associations of PON1, P2Y12, and COX-1 with outcomes were observed in 1 study.

Conclusions: Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel.

Keywords: clopidogrel; cytochrome P-450 CYP2C19; ischemic attack, transient; meta-analysis; stroke.

Publication types

Meta-Analysis
Review
Systematic Review

MeSH terms

Alleles
Clopidogrel
Cytochrome P-450 CYP2C19 / genetics*
Databases, Factual
Genotype
Humans
Ischemic Attack, Transient / drug therapy
Ischemic Attack, Transient / genetics*
Ischemic Attack, Transient / pathology
Polymorphism, Genetic
Risk
Stroke / drug therapy
Stroke / genetics*
Stroke / pathology
Ticlopidine / analogs & derivatives*
Ticlopidine / therapeutic use

Substances

Clopidogrel
Cytochrome P-450 CYP2C19
Ticlopidine