title: Clinical impact of genetically determined platelet reactivity.
abstract: Dual antiplatelet therapy with aspirin and clopidogrel dramatically reduced the rate of major adverse cardiac events following percutaneous coronary intervention. Clopidogrel is a prodrug which requires a two-step hepatic biotransformation thanks to the cytochrome P450 (CYP450) enzyme system. Genetic polymorphism of CYP450 system (e.g., CYP2C19*2) responsible for altered clopidogrel metabolism is a major cause of high on-treatment platelet reactivity (HTPR), which translates into thrombotic events in stented patients. Studies demonstrated that HTPR could be overcome in poor metabolizers thanks to increased loading doses or maintenance doses of clopidogrel or with the use of more potent antiplatelet agents such as prasugrel. Other genetic polymorphisms have also been correlated with HTPR: ABCB1, ATP2B2, and TIAM2. Large-scale randomized trials with clinical endpoints remain necessary to determine the optimal antiplatelet therapy in patients carrying genetic polymorphism associated with HTPR and thrombotic events.
authors.affiliation: Département de Cardiologie, Centre Hospitalo-Universitaire Nord, Chemin des Bourrely, Marseille, France. lainemarc@hotmail.fr
authors.forename: Marc
authors.initials: M
authors.lastname: Laine
authors.forename: Sébastien
authors.initials: S
authors.lastname: Arméro
authors.forename: Michaël
authors.initials: M
authors.lastname: Peyrol
authors.forename: Pascal
authors.initials: P
authors.lastname: Sbragia
authors.forename: Franck
authors.initials: F
authors.lastname: Thuny
authors.forename: Franck
authors.initials: F
authors.lastname: Paganelli
authors.forename: Laurent
authors.initials: L
authors.lastname: Bonello
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D003328:Coronary Thrombosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D065731:Cytochrome P-450 CYP2C19; D004351:Drug Resistance; D005838:Genotype; D006801:Humans; D018579:Patient Selection; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects / Q000295:instrumentation; D010597:Pharmacogenetics; D010641:Phenotype; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D015607:Stents; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine