title: Pharmacogenomics of antiplatelet drugs.
abstract: Clopidogrel, a platelet P2Y12 inhibitor, is one of the most widely prescribed drugs in cardiovascular medicine because it reduces ischemic and thrombotic complications. It is a prodrug requiring biotransformation into the active metabolite by the hepatic cytochrome 450 system, especially the CYP2C19 enzyme. Candidate gene studies and genome-wide association studies have identified loss-of-function CYP2C19 variants to be associated with a diminished pharmacologic response. Specifically, compared with noncarriers, carriers of at least one copy of a loss-of-function CYP2C19 allele have ∼30% lower levels of active clopidogrel metabolite and ∼25% relatively less platelet inhibition with clopidogrel. Moreover, in patients treated with clopidogrel predominantly for percutaneous coronary intervention, carriers of 1 or 2 CYP2C19 loss-of-function alleles are at increased risk for major adverse cardiovascular outcomes, with an ∼1.5-fold increase in the risk of cardiovascular death, myocardial infarction, or stroke as well as an ∼3-fold increase in risk for stent thrombosis. Tripling the dose of clopidogrel in carriers of a CYP2C19 loss-of-function allele can achieve on-treatment platelet reactivity comparable to that seen with the standard 75 mg dose in wild-type individuals, but the impact on clinical outcomes remains unknown. Alternatively, 2 third-generation P2Y12 inhibitors are available: prasugrel and ticagrelor. These drugs are superior to clopidogrel in reducing ischemic outcomes and are unaffected by CYP2C19 loss-of-function alleles.
authors.affiliation: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.affiliation: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mega
mesh_terms: D002986:Clinical Trials as Topic; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D006801:Humans; D010597:Pharmacogenetics; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D017410:Practice Guidelines as Topic; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine