Interaction of CYP2C19 with the effect of clopidogrel in secondary prevention of major ischemic events: Systematic review and meta-analysis.

Background and aims: Clopidogrel may be a less effective antiplatelet agent for secondary prevention after cardiovascular events in carriers of the CYP2C19 Loss of Function (LoF) allele. Randomized controlled trials (RCTs) of clopidogrel in patients with known CYP2C19 carrier status have provided inconsistent results. This meta-analysis aims to pool evidence on the effect of different antiplatelet strategies on outcomes according to CYP2C19 LoF status.

Methods: We conducted a systematic review and meta-analysis of RCTs to evaluate the interaction of CYP2C19 LoF allele on clopidogrel versus placebo or other antiplatelet agents in patients with cardiovascular disease or transient ischemic attack (TIA) or ischemic stroke. Primary outcomes were major adverse cardiovascular events (MACEs) including ischemic stroke, with major bleeding events assessed as a safety outcome. Random effects analysis estimated pooled odds ratios for LoF carriers and non-carriers.

Results: Fifteen RCTs with 35,189 participants in total were included. When all interaction effects are pooled, the occurrence of MACE was 1.29 times higher in LoF variant carriers compared to non-carriers for clopidogrel treatment (p-interaction = 0.01). Risk of MACE was 1.20 times higher in LoF carriers compared to non-carriers when clopidogrel was compared to placebo (p-interaction = 0.13). In TIA or minor stroke patients, the interaction effect was 1.63 times larger (p-interaction = 0.02). Clopidogrel was less effective than prasugrel for MACE occurrence (1.57 times higher, p-interaction = 0.02) and ticagrelor (1.21 times higher, p-interaction = 0.19) in CYP2C19 LoF variant carriers. Bleeding outcomes were similar across groups.

Conclusion: Clopidogrel is less effective in patients with CYP2C19 LoF genotype and cardiovascular disease, minor stroke, or TIA. The size and direction of the interaction warrant further research into the role of LoF genotypes and the cost-effectiveness of genetic testing. Prasugrel may be a more effective alternative for CYP2C19 LoF carriers.Registration-URL:https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021242993.