The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack

Abstract

Introduction Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its active metabolite by hepatic cytochrome P450-2C19 (CYP2C19) is essential for the inhibition of the P2Y12 receptor and subsequent platelet aggregation to prevent thrombotic events. CYP2C19 is highly polymorphic, with over 30 loss of function (LoF) alleles. This review considers whether there is sufficient data to support genotype guided antiplatelet therapy after stroke. Areas covered A systematic literature review retrieved articles, which describe the interaction between CYP2C19 genotype and clinical outcomes following IS or TIA when treated with clopidogrel. The review documents efforts to identify optimal antiplatelet regimens and explores the value genotype guided antiplatelet therapy. The work outlines the contemporary understanding of clopidogrel metabolism and appraises evidence linking CYP2C19 LoF variants with attenuated platelet inhibition and poorer outcomes. Expert opinion There is good evidence that CYP2C19 LoF allele carriers of Han-Chinese ancestry have increased risk for further vascular events following TIA or IS when treated with clopidogrel. The evidence base is less certain in other populations. The expansion of pharmacogenetics into routine clinical practice will facilitate further research and help tailor other aspects of secondary prevention.

Substantiation of a clopidogrel metabolism-associated gene (CYP2C19) variation among healthy individuals

“…Additionally, the frequency of rapid and poor metabolizer groups in India, which exhibit a pattern comparable to the results of the CYP2C19 genotyping in European and East Asian nations, suggests that the geographical element may also be connected to the pattern. 10 , 11 A study on Tamilians suggests the distribution of CYP2C19∗1/∗1 being lower than Caucasians, Africans, and North Indians, but a notably higher frequency of CYP2C19∗1/∗2 compared to other populations; whereas the CYP2C19∗1/∗3 allele was reported in 2.7% Tamilians, the same was not reported in North Indian and Caucasians. 12 Thus, the allele frequencies in South Indian populations were found to be distinct from Caucasians and Chinese, 13 this confirms the variable racial distribution of CYP2C19 alleles among different ethnic groups, with each ethnic group having a mate selection bias that may cater to inbreeding (either strict caste endogamy or consanguinity), rendering deviation from HWE.…”

CYP2C19 Pharmacogenetics and Clopidogrel Prescription in a University Hospital: A Descriptive Study in a Clinical Data Warehouse

“…Compared to the population prevalence of pharmacogenetics CYP2C19*2 polymorphism14, this result suggests that patients with a resistance phenotype have a higher risk of stroke on clopidogrel treatment and require special medical care. Indeed, 26% of patients of European ancestry are classified as CYP2C19 IM [13,14]. Consequently, they have a higher risk of stroke relapse due to antiplatelet resistance [14].…”

“…Recent scientific literature proposed guidelines for the interpretation of pharmacogenetics and its consequences on prescriptions [7,[18][19][20]. Level of evidence is debated according to scientific literature, in particular, in stroke for CYP2C19 genotyping [13]. In patients with pharmacogenetics resistance to clopidogrel, P2Y12 inhibitors not metabolised by CYP2C19 such as ticagrelor could be a therapeutic alternative, considering the benefit-risk balance (risk of thrombosis versus bleeding) [13].…”

Precision antiplatelet therapy

“…Although several studies have reported reduced active metabolite formation and platelet inhibition in poor and/or intermediate metabolizers vs the normal or rapid ones, the clinical impact of each CYP2C19 allele status and their multiple combinations is not fully established. Some retrospective studies and posthoc analyses of randomized clinical trials that pooled patients with intermediate- and poor-metabolizer genotypes showed a higher rate of serious vascular events or stent thrombosis as compared with extensive metabolizers [ 40 , 71 , 72 ]. Other studies have shown a lack of clopidogrel efficacy in poor but not intermediate metabolizers, as compared to extensive metabolizers [ 40 ].…”