Role of CYP2C19 Polymorphism in the Drug Interaction Between Clopidogrel and Omeprazole
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease
Study type: Observational [Patient Registry]

Summary: 
      Clopidogrel, an inhibitor of ADP induced platelet aggregation and activation, is one of the
      most commonly used drugs in patients with cardiovascular disease. The specific aim of the
      proposed study is to determine whether the interaction between proton-pump inhibitors (PPIs)
      and clopidogrel is dependent on CYP2C19 haplotype.
    

Detailed description: 
      Clopidogrel, an inhibitor of ADP induced platelet aggregation and activation, is one of the
      most commonly used drugs in patients with cardiovascular disease; coronary-stenting would not
      be possible without the robust anti platelet function of this drug. Clopidogrel is a pro-drug
      that is transformed through a series of hepatic cytochrome p-450 (CYP) enzymes to an active
      metabolite. One of these CYP enzymes, 2C19 is subject to competitive inhibition by commonly
      used proton-pump inhibitors (PPIs). PPIs are commonly used for gastro-esophageal protection
      in patients treated with clopidogrel. Around 63% of 3,799 patients on clopidogrel received a
      PPI at TMH in 2008.

      Recently, a series of publications indicated that clopidogrel active metabolite levels and
      platelet inhibition are lower in patients receiving PPIs. In addition, a recent survey of
      >16,690 patients in Medco database indicates that use of PPIs is associated with a 51%
      increase in the risk of death or myocardial infarction in patients receiving clopidogrel.
      Recent data have also indicated that patients with loss of function (LOF) haplotypes of the
      CYP2C19 gene have lower levels of the active metabolite after dosing with clopidogrel. These
      patients have higher rates of death, myocardial infarction, stent thrombosis and other
      ischemic complications than do patients with the wild type enzyme. Inadequate responses to
      clopidogrel therapy have been implicated as an important predictor of adverse clinical
      events. The reported prevalence of non-responsiveness to clopidogrel among patients with
      cardiovascular disease is between 4% and 34%, depending on the method and definition used to
      assess this parameter. Approximately 25% of American population carries a LOF mutation of
      CYP2C19.

      It is unclear whether the concomitant use of omeprazole (PPI) with clopidogrel would result
      in a decrease in platelet function parameters through the CYP2C19 clopidogrel activation
      pathway. The specific aim of the proposed study is to determine whether the interaction
      between PPIs and clopidogrel is dependent on CYP2C19 haplotype. We hypothesize that among
      subjects with a LOF genotype, the interaction between clopidogrel and PPIs is greater than
      that in subjects with the wild type genotype7 and is manifest in both platelet function
      parameters and in conversion of clopidogrel to its active metabolite.

      Approximately 75 randomly selected healthy volunteer subjects will be screened with the
      intent of identifying at least 16 subjects who are heterozygous for a LOF mutation of CYP2C19
      (known as *2/rs4244285, *3).

      Subjects with the LOF allele will be selected along with age and gender-matched wild type
      controls and baseline platelet function studies will be performed (n=16 for each group).
      Subjects in each stratum will then be randomly assigned to receive one week of clopidogrel in
      combination with omeprazole or clopidogrel alone. Subjects initially assigned to clopidogrel
      + omeprazole will then take clopidogrel only and subjects initially assigned to clopidogrel
      only will take both clopidogrel and omeprazole.
    

Intervention name(s): Clopidogrel 75mg, Omeprazole 20mg
Intervention type(s): Drug
Intervention description(s): Clopidogrel and or Omeprazole as applicable
Other intervention name(s): Plavix , Prilosec OTC
Intervention MeSH terms: Omeprazole; Clopidogrel
Observational model: Case-Crossover
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Healthy subjects aged 18-65.
      
Biospecimen description: 
      Cheek swabs for DNA, blood samples for drug metabolite estimation and platelet function
      study.
    
Keywords: drug resistance; gene polymorphism