Impact of CYP2C19 Genotype on Efficacy and Safety of Clopidogrel-based Antiplatelet Therapy in Stroke or Transient Ischemic Attack Patients: An Updated Systematic Review and Meta-analysis of Non-East Asian Studies

Abstract

Purpose Inconclusive and limited results have been reported on the clinical utility of CYP2C19 genotyping in stroke/TIA patients of non-East Asian ancestries. We herein performed an updated systematic review and meta-analysis to quantitatively estimate the association of CYP2C19 loss-of function (LOF) status with efficacy and safety of clopidogrel-based antiplatelet therapy in non-East Asian patients affected by stroke or TIA. Methods A comprehensive search was performed up to July 2023 using PubMed, Web of Knowledge, and Cochrane Library databases. The clinical outcomes investigated were stroke, composite vascular events and bleeding. Pooled estimates were calculated as risk ratios (RR) with 95% CI using the Mantel– Haenszel random-effects model. The quality of evidence was assessed using the GRADEpro tool. Results A total number of 1673 stroke/TIA patients from 8 non-East Asian studies, published between 2014 and 2022, were included in the systematic review. Clopidogrel-treated carriers of CYP2C19 LOF alleles were found at increased risk of stroke compared to non-carriers (RR: 1.68, 95%CI: 1.04–2.71, P = 0.03). However, no significant association was observed with the risk of composite vascular events (RR: 1.15, 95%CI: 0.58–2.28, P = 0.69) or bleeding (RR: 0.84, 95%CI: 0.38–1.86, P = 0.67). Similarly, European ancestry patients carrying CYP2C19 LOF alleles displayed a higher risk of stroke (RR: 2.69 (1.11–6.51, P = 0.03), but not of composite vascular events or bleeding. Conclusion The present updated meta-analysis provides moderate quality evidence of association between CYP2C19 LOF alleles and an increased risk of stroke in non-East Asian patients with stroke/TIA after receiving clopidogrel therapy. Further large pharmacogenetic studies are still warranted to corroborate these findings.

The association of CYP2C19LoF alleles with adverse clinical outcomes in stroke patients taking clopidogrel: An updated meta‐analysis

“…However, the risk of severe or moderate bleeding events did not differ between these two treatment groups (0.3% vs. 0.3%), although total bleeding events were slightly higher in ticagrelor treatment group compared with clopidogrel treatment group (5.3% vs. 2.5%). 52 It is believed that the CPIC guideline should update the prescribing recommendations including stroke patients since the robust evidence established in this analysis, along with other available evidence, 2,16 warrants this.…”

“…Another very recent meta-analysis was published to validate the associations between carriers of CYP2C19 LoF alleles and the risk of recurrent stroke in non-East Asian populations but this analysis did not consider other populations. 16 Thus, the only available well-established meta-analysis was published in 2017, which included 15 studies with 4762 stroke/TIA patients from all ethnic groups, including Asians, Europeans, Africans, and other ethnicities. 2 Although it was a well-established analysis, since then, many more studies have appeared in the literature; therefore, there is a need to update the meta-analysis of the literature.…”

Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment

“…he has only one functional CYP2C19 allele), which means that the conversion of clopidogrel to the active metabolite will be suboptimal. A recent systematic review and meta-analysis of non-East Asian studies showed that individuals carrying CYP2C19 loss-of-function alleles on clopidogrel were at an increased risk of stroke (relative risk 1.68) when compared to noncarriers [78]. This was also observed in patients of European ancestry carrying CYP2C19 loss-offunction alleles (relative risk 2.69).…”