title: Effect of CYP2C19*2 and *17 genetic variants on platelet response to clopidogrel and prasugrel maintenance dose and relation to bleeding complications.
abstract: The present study was performed to compare the influence of cytochrome P459 2C19 (CYP2C19) *2 and *17 genetic variants on the platelet response to clopidogrel and prasugrel maintenance therapy and to assess the relation between platelet reactivity and bleeding complications. A total of 730 patients were included (517 patients treated with clopidogrel 150 mg/day and 213 discharged with prasugrel 10 mg). Platelet reactivity was assessed at 1 month with the platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP). High on-treatment platelet reactivity was defined as PRI VASP >50% and low on-treatment platelet reactivity (LTPR) as PRI VASP <20%. The patients were classified according to their genotypes as poor metabolizers (*2/non *17), intermediate metabolizers (*2/*17 or non *2/non *17) and ultrametabolizers (non *2/*17). At 1 month, the prasugrel response was significantly better than the clopidogrel response in all groups of patients, with a lower incidence of high on-treatment platelet reactivity but a greater incidence of LTPR, regardless of the genetic variants. The genetic distribution had a significant effect on the mean PRI VASP values, the incidence of high on-treatment platelet reactivity, and LTPR with both clopidogrel and prasugrel (p <0.05 for all). LTPR identified a group of patients at a greater risk of bleeding (odds ratio 4.8, 95% confidence interval 2.7 to 8.3; p <0.0001). In conclusion, the present study showed that both clopidogrel and prasugrel have genetic modulation by CYP2C19 *2 and *17 alleles and that prasugrel provides greater platelet inhibition, regardless of the genotypes. In addition, LTPR was associated with a greater risk of bleeding.
authors: INSERM, UMR1062, Nutrition, Obesity and Risk of Thrombosis, Marseille, France.
authors: Charlotte
authors: C
authors: Grosdidier
authors: Jacques
authors: J
authors: Quilici
authors: Marie
authors: M
authors: Loosveld
authors: Laurence
authors: L
authors: Camoin
authors: Pierre Julien
authors: PJ
authors: Moro
authors: Noémie
authors: N
authors: Saut
authors: Bénédicte
authors: B
authors: Gaborit
authors: Mathieu
authors: M
authors: Pankert
authors: William
authors: W
authors: Cohen
authors: Marc
authors: M
authors: Lambert
authors: Shirley
authors: S
authors: Beguin
authors: Pierre Emmanuel
authors: PE
authors: Morange
authors: Jean-Louis
authors: JL
authors: Bonnet
authors: Marie-Christine
authors: MC
authors: Alessi
authors: Thomas
authors: T
authors: Cuisset
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects*; D015815:Cell Adhesion Molecules; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006470:Hemorrhage / Q000235:genetics*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D000068799:Prasugrel Hydrochloride; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D012307:Risk Factors; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010879:Piperazines; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine