Effect of high-dose clopidogrel according to CYP2C19*2 genotype in patients undergoing percutaneous coronary intervention- a systematic review and meta-analysis

Introduction: High-dose clopidogrel has been recommended to overcome clopidogrel non-responsiveness in patients undergoing percutaneous coronary intervention (PCI), especially those with CYP2C19 loss-of-function genotypes. However, there is controversy over the pharmacodynamics and clinical effects of the strategy. This meta-analysis was conducted to evaluate the antiplatelet effects of high-dose clopidogrel according to CYP2C19* 2 alleles in patients undergoing PCI. Methods: Based on PubMed, Cochrane, and EMBASE prior to June 1st, 2014, a systematic review andmeta-analysis was conducted to evaluate the antiplatelet effects of high-dose clopidogrel on platelet reactivity and clinical outcomes in PCI treated patients according to CYP2C19*2 genotypes. The reported outcomes including on-treatment platelet reactivity (OTPR), high on-treatment platelet reactivity (HTPR), major adverse cardiovascular events (MACE), stent thrombosis and composite cardiovascular events. Results: Nineteen studies involving 10,960 patients were included. After high-dose clopidogrel administration (600/900 mg loading dose and/or 150 mg/day maintenance dose), compared with non-carriers, carriers of CYP2C19*2 genotype had significantly increased OTPR (SMD for VASP assay: 0.69, 95% CI: 0.48-0.90, p = 4 x 10(-4); for VerifyNow P2Y12 assay: 0.70, 95% CI: 0.54-0.85, p < b 10(-5); for LTA assay: 0.58, 95% CI: 0.48-0.69, p= 4x10(-4)). The incidence rate of HTPRwas higher in CYP2C19*2 carriers after high-dose clopidogrel treatment (RR: 1.21, 95% CI: 1.05-1.39, p= 0.008 for cutoff PRI N50% by VASP assay; RR: 1.69, 95% CI: 1.44-1.98, p < b 1x10(-4) for cutoff PRU N230 by VerifyNow P2Y12 assay). As for clinical outcomes, CYP2C19* 2was associated with higher risk forMACE (RR: 1.68, 95% CI: 1.19-2.37, p= 0.003), stent thrombosis (RR: 1.75, 95% CI: 1.31-2.34, p = 0.0001), as well as composite cardiovascular events (RR: 1.82, 95% CI: 1.42-2.34, p < b 10(-5)) after treated by high-dose clopidogrel. Conclusion: High-dose clopidogrel could not overcome the variability of clopidogrel antiplatelet effects between the CYP2C19*2 carriers and non-carriers in patients treated with PCI. (C) 2014 Elsevier Ltd. All rights reserved.