title: Effect of high-dose clopidogrel according to CYP2C19*2 genotype in patients undergoing percutaneous coronary intervention- a systematic review and meta-analysis.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Lanning
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Xuyun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China. Electronic address: yintong2000@yahoo.com.
authors.forename: Tong
authors.initials: T
authors.lastname: Yin
mesh_terms: D000483:Alleles; D001792:Blood Platelets / Q000187:drug effects; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D062645:Percutaneous Coronary Intervention / Q000379:methods; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010979:Platelet Function Tests; D015607:Stents / Q000009:adverse effects; D013927:Thrombosis / Q000209:etiology / Q000235:genetics; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: CYP2C19*2; Cardiovascular events; Clopidogrel; High-dose; Platelet reactivity