title: Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping.
abstract: OBJECTIVE
  The primary aim of the study was to determine the antiplatelet effects of prasugrel versus high-dose clopidogrel in patients with high on-treatment platelet reactivity (HTPR) after percutaneous coronary intervention (PCI) and, secondarily, their relation to cytochrome (CYP) 2C19*2 carriage.
  
  
  BACKGROUND
  High on-treatment platelet reactivity after clopidogrel administration after PCI is linked to the loss-of-function CYP2C19*2 allele and accompanied by an increased risk of adverse events.
  
  
  METHODS
  We performed a prospective, randomized, single-blind, crossover study of platelet inhibition by prasugrel 10 mg/day versus high-dose 150 mg/day clopidogrel in 71 (of 210 screened; 33.8%) post-PCI patients with HTPR. Platelet function was assessed by the VerifyNow assay (Accumetrics, San Diego, California), and real-time polymerase chain reaction genotyping was performed for CYP2C19*2 carriage.
  
  
  RESULTS
  The primary endpoint of platelet reactivity (measured in platelet reactivity units) at the end of the 2 treatment periods was lower after prasugrel compared with clopidogrel (least-squares estimates 129.4, 95% confidence interval [CI]: 111.1 to 147.7 versus 201.7, 95% CI: 183.2 to 220.2; p < 0.001). The least-squares mean difference between the 2 treatments was -122.9 (95% CI: -166.7 to -79.2, p < 0.001), and -47.5 (95% CI: -79.5 to -15.4, p = 0.004), in carriers and noncarriers of at least 1 mutant allele, respectively. The HTPR rates were lower for prasugrel than for clopidogrel, in all patients (7.5% vs. 35.8%, p < 0.001), in carriers (5.3% vs. 47.4%, p = 0.007), and in noncarriers (8.8% vs. 29.4%, p = 0.005), respectively.
  
  
  CONCLUSIONS
  In patients with HTPR after PCI, prasugrel is more effective compared with high clopidogrel in reducing platelet reactivity, particularly in CYP2C19*2 carriers. Genotyping guidance might be helpful only in case an increased clopidogrel maintenance dose is considered. (Prasugrel Versus High Dose Clopidogrel in Clopidogrel Resistant Patients Post Percutaneous Coronary Intervention (PCI); NCT01109784).
authors.affiliation: Department of Cardiology, Patras University Hospital, Patras, Greece. dalex@med.upatras.gr
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Alexopoulos
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Dimitropoulos
authors.forename: Periklis
authors.initials: P
authors.lastname: Davlouros
authors.forename: Ioanna
authors.initials: I
authors.lastname: Xanthopoulou
authors.forename: George
authors.initials: G
authors.lastname: Kassimis
authors.forename: Eleana F
authors.initials: EF
authors.lastname: Stavrou
authors.forename: George
authors.initials: G
authors.lastname: Hahalis
authors.forename: Aglaia
authors.initials: A
authors.lastname: Athanassiadou
mesh_terms: D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects / Q000295:instrumentation*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006115:Greece; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010979:Platelet Function Tests; D016133:Polymerase Chain Reaction; D000068799:Prasugrel Hydrochloride; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016037:Single-Blind Method; D015607:Stents; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine