title: A prospective randomized evaluation of a pharmacogenomic approach to antiplatelet therapy among patients with ST-elevation myocardial infarction: the RAPID STEMI study.
abstract: Treatment of carriers of the CYP2C19*2 allele and ABCB1 TT genotype with clopidogrel is associated with increased ischemic complications after percutaneous coronary intervention (PCI). We sought to evaluate a pharmacogenomic strategy among patients undergoing PCI for ST-elevation myocardial infarction (STEMI), by performing a randomized trial, enrolling 102 patients. Point-of-care genetic testing for CYP2C19*2, ABCB1 TT and CYP2C19*17 was performed with carriers of either the CYP2C19*2 allele or ABCB1 TT genotype randomly assigned to a strategy of prasugrel 10 mg daily or an augmented dosing strategy of clopidogrel (150 mg daily for 6 days then 75 mg daily). The primary end point was the proportion of at-risk carriers exhibiting high on-treatment platelet reactivity (HPR), a marker associated with increased adverse cardiovascular events, after 1 month. Fifty-nine subjects (57.8%) were identified as carriers of at least one at-risk variant. Treatment with prasugrel significantly reduced HPR compared with clopidogrel by P2Y12 reaction unit (PRU) thresholds of >234 (0 vs 24.1%, P=0.0046) and PRU>208 (3.3 vs 34.5%, P=0.0025). The sensitivity of point-of-care testing was 100% (95% CI 88.0-100), 100% (86.3-100) and 96.9% (82.0-99.8) and specificity was 97.0% (88.5-99.5), 97.1% (89.0-99.5) and 98.5% (90.9-99.9) for identifying CYP2C19*2, ABCB1 TT and CYP2C19*17, respectively. Logistic regression confirmed carriers as a strong predictor of HPR (OR=6.58, 95% CI 1.24-34.92; P=0.03). We confirmed that concurrent identification of three separate genetic variants in patients with STEMI receiving PCI is feasible at the bedside. Among carriers of at-risk genotypes, treatment with prasugrel was superior to an augmented dosing strategy of clopidogrel in reducing HPR.
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: D Y F
authors: DY
authors: So
authors: Cardiovascular Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: G A
authors: GA
authors: Wells
authors: Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: R
authors: R
authors: McPherson
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: M
authors: M
authors: Labinaz
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: M R
authors: MR
authors: Le May
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: C
authors: C
authors: Glover
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: A J
authors: AJ
authors: Dick
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: M
authors: M
authors: Froeschl
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: J-F
authors: JF
authors: Marquis
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: M H
authors: MH
authors: Gollob
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: L
authors: L
authors: Tran
authors: Cardiovascular Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: J
authors: J
authors: Bernick
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: B
authors: B
authors: Hibbert
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: J D
authors: JD
authors: Roberts
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000368:Aged; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D019095:Point-of-Care Systems; D000068799:Prasugrel Hydrochloride / Q000627:therapeutic use*; D011446:Prospective Studies; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine