title: The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study.
abstract: OBJECTIVE
  Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events.
  
  
  RESULTS
  A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints.
  
  
  CONCLUSIONS
  No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications.
  
  
  BACKGROUND
  This study is registered with ClinicalTrials.gov number, NCT00050817.
authors.affiliation: VA Boston Healthcare System,  Brigham and Women's Hospital, and Harvard Medical School, 1400 VFW Parkway, Boston, MA 02132,  USA.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
authors.forename: John W
authors.initials: JW
authors.lastname: Eikelboom
authors.forename: Katy L
authors.initials: KL
authors.lastname: Simonsen
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Emison
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: Ph Gabriel
authors.initials: PG
authors.lastname: Steg
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
authors.forename: Nihar
authors.initials: N
authors.lastname: Bhakta
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Flather
authors.forename: Koon-Hou
authors.initials: KH
authors.lastname: Mak
authors.forename: Patrice
authors.initials: P
authors.lastname: Cacoub
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
authors.forename: Peter B
authors.initials: PB
authors.lastname: Berger
authors.forename: Steven R
authors.initials: SR
authors.lastname: Steinhubl
authors.forename: Gurunathan
authors.initials: G
authors.lastname: Murugesan
authors.forename: Shamir R
authors.initials: SR
authors.lastname: Mehta
authors.forename: Kandice
authors.initials: K
authors.lastname: Kottke-Marchant
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D011110:Polymorphism, Genetic / Q000235:genetics*; D020521:Stroke / Q000235:genetics; D013927:Thrombosis / Q000188:drug therapy / Q000235:genetics*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine