CYP2C19 and effect of clopidogrel for secondary prevention of major ischemic events: systematic review and meta-analysis

Background Carriers of the CYP2C19 Loss of Function (LoF) allele may experience decreased efficacy of clopidogrel in secondary prevention after cardiovascular events. Randomized clinical trials of clopidogrel in patients with known CYP2C19 carrier status provided inconsistent results. Our aim was to pool the evidence on the effect of clopidogrel on outcome, according to CYP2C19 LoF status, in a meta-analysis. Methods A systematic review and meta-analysis of randomized controlled trials (RCTs) on the effect of clopidogrel according to CYP2C19 LoF status in patients with cardiovascular disease and recent TIA or stroke was performed. The primary outcomes were 1) ischemic stroke and 2) major adverse cardiac events (MACE). We used random effects analysis to estimate the effect of clopidogrel as a pooled odds ratio (OR) in carriers and non-carriers of the LoF variant and tested for interaction between clopidogrel and CYP2C19. Results We included six RCTs with a total of 15,141 participants comparing combined clopidogrel and aspirin therapy to aspirin monotherapy. The effect of clopidogrel on MACE was OR=0.70 in CYP2C19 non-variant carriers compared to OR=0.84 in CYP2C19 variant carriers (pinteraction=0.13). In patients with a recent TIA or minor ischemic stroke, the OR for the effect of clopidogrel on MACE was OR=0.52 in CYP2C19 non-variant carriers compared to OR=0.84 in CYP2C19 variant carriers (pinteraction=0.02) while in patients with cardiovascular disease the difference in effect was not evident (non-variant carriers OR=0.76, variant carriers OR= 0.84, pinteraction=0.50). Conclusion Our meta-analysis could not establish that overall, clopidogrel is less effective in patients with a recent MI, minor stroke or TIA and a CYP2C19 LoF genotype. However, the size and direction of the difference in effect warrants further research. Registration - URL https://www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42021242993.