title: Effects of CYP2C19 allelic variants on inhibition of platelet aggregation and major adverse cardiovascular events in Japanese patients with acute coronary syndrome: The PRASFIT-ACS study.
abstract: We examined the effects of cytochrome P450 2C19 (CYP2C19) polymorphisms on the efficacy and safety of prasugrel and clopidogrel in a post hoc analysis of the PRASugrel compared with clopidogrel For Japanese patIenTs with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) (PRASFIT-ACS) study.
  
  
  
  Japanese ACS patients undergoing PCI were randomized (double-blind) to receive prasugrel (loading/maintenance dose: 20/3.75mg) or clopidogrel (300/75mg) plus aspirin for 24-48 weeks. Pharmacogenomic analyses were conducted in 773/1363 patients. P2Y12 reaction units (PRU) were determined using the VerifyNow(®) P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotypes were classified as extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM).
  
  
  
  Overall, 39.2% and 60.8% of patients in the prasugrel group and 35.2% and 64.8% of patients in the clopidogrel group were classified as EM and IM+PM, respectively. Among EM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group at 2-4 and 5-12h after the loading dose, but was similar in both groups from week 4 onwards. Among IM+PM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group throughout the study. Among EM patients, the incidence of major adverse cardiovascular events (MACE) at 24 weeks was 11.8% in the prasugrel group and 11.9% in the clopidogrel group [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.50-1.96]. Among IM+PM patients, the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78, 95% CI: 0.45-1.35). The incidences of major, minor, and clinically relevant bleeding were similar between the two groups for each genotype.
  
  
  
  Prasugrel showed more consistent antiplatelet effects than clopidogrel in Japanese ACS patients irrespective of the CYP2C19 phenotype.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; National Cerebral and Cardiovascular Center, Osaka, Japan. Electronic address: ogawah@kumamoto-u.ac.jp.
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Division of Cardiology, Ageo Central General Hospital, Saitama, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Isshiki
authors.affiliation: Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Cardiovascular Medicine Center, Fukuoka Sanno Hospital, Fukuoka, Japan; International University of Health and Welfare, Tochigi, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Yokoi
authors.affiliation: Nishinomiya Hospital Affairs, Nishinomiya Municipal Central Hospital, Hyogo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Nanto
authors.affiliation: Sakakibara Heart Institute, Tokyo, Japan.
authors.forename: Morimasa
authors.initials: M
authors.lastname: Takayama
authors.affiliation: Department of Neurology, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitagawa
authors.affiliation: Clinical Research Support Center, Mie University Hospital, Mie, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Division of Cardiology, Department of Medicine, Faculty of Medicine, Kinki University, Osaka, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Miyazaki
authors.affiliation: Life Science & Medical Bioscience, Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Division of Cardiovascular Medicine, Ohashi Medical Center, Toho University, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Clinical Data & Biostatistics Department, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Division of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000235:genetics; D000368:Aged; D000483:Alleles; D001241:Aspirin / Q000494:pharmacology; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D010974:Platelet Aggregation / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine; D001241:Aspirin
keywords: CYP2C19; Clopidogrel; Major adverse cardiovascular events; Platelet aggregation; Prasugrel