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

Thromb Res. 2015 Mar;135(3):449-58. doi: 10.1016/j.thromres.2014.12.007. Epub 2014 Dec 9.

Abstract

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 and meta-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 × 10(-4); for VerifyNow P2Y12 assay: 0.70, 95% CI: 0.54-0.85, p < 10(-5); for LTA assay:0.58, 95% CI: 0.48-0.69, p = 4 × 10(-4)). The incidence rate of HTPR was 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 > 50% by VASP assay; RR: 1.69, 95% CI: 1.44-1.98, p < 1 × 10(-4) for cutoff PRU > 230 by VerifyNow P2Y12 assay). As for clinical outcomes, CYP2C19*2 was associated with higher risk for MACE (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 < 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.

Keywords: CYP2C19*2; Cardiovascular events; Clopidogrel; High-dose; Platelet reactivity.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Alleles
  • Blood Platelets / drug effects
  • Clopidogrel
  • Cytochrome P-450 CYP2C19 / genetics*
  • Genotype*
  • Humans
  • Percutaneous Coronary Intervention* / methods
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / adverse effects
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Platelet Function Tests
  • Stents / adverse effects
  • Thrombosis / etiology
  • Thrombosis / genetics
  • Ticlopidine / administration & dosage
  • Ticlopidine / adverse effects
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / therapeutic use

Substances

  • Platelet Aggregation Inhibitors
  • Clopidogrel
  • Cytochrome P-450 CYP2C19
  • Ticlopidine