Pilot Study on the Effect of High Clopidogrel Maintenance Dosing
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease
Study type: Observational

Summary: 
      This is a Scripps pilot study on the effect of high clopidogrel maintenance dosing and its
      relationship to cytochrome P450 2C19 polymorphism status [STSI/CTSA].
    

Detailed description: 
      When added to aspirin, clopidogrel at a routine dose of 75 mg daily reduces the incidence of
      thrombotic vascular adverse events in patients with acute coronary syndromes and those
      undergoing percutaneous interventions (PCI). The observation that many patients have less
      than expected platelet inhibition with clopidogrel has given rise to the concept of
      clopidogrel resistance. Clopidogrel resistance is associated with increased adverse events
      such as stent thrombosis, post-stent ischemic events and periprocedural myocardial
      infarctions. Some patients can overcome the resistance with increasing the dose of
      clopidogrel. A higher maintenance dose (150 mg daily) in patients undergoing PCI results in
      superior platelet inhibition and may reduce cardiovascular events. Clopidogrel is a
      thienopyridine prodrug, which is converted to its active metabolite by several enzymes of the
      P450 family, including CYP2C19. The loss-of-function CYP2C19*2 (681 G>A) single nucleotide
      polymorphism (SNP), occurring as either a hetero- or homozygous allele, reduces the
      conversion of clopidogrel to its active metabolite. Two recent studies have shown an
      association between CYP2C19*2 polymorphism and lack of platelet inhibition with clopidogrel.
      These studies included healthy volunteers and patients undergoing elective PCI and
      demonstrated a prevalence of the CYP2C19*2 allele of 25-30%. Platelet inhibition was not
      affected by clopidogrel in those who carried the CYP2C19*2 polymorphism.

      Our hypothesis is the following: Patients who are carriers of the loss-of-function CYP2C19*2
      allele (heterozygous 1*/2* or homozygous 2*/2*) have decreased platelet inhibition on
      clopidogrel which cannot be overcome with increasing the maintenance dose from 75 mg to 150
      mg daily.

      The specific aim will include an evaluation of the anti-platelet response of a higher
      maintenance dose of clopidogrel (150 mg /daily) in patients who are resistant to the usual
      dose (75 mg/daily) and are either carriers or non-carriers of the CYP2C19*2 allele.

      The study design will be a single center, prospective, observational pilot study. We will
      screen and enroll patients who are followed at Scripps Clinic and on chronic clopidogrel
      therapy. All patients will be eligible. A blood sample will be collected to perform DNA
      extraction and genotyping for the CYP2C19*2 polymorphism. Platelet function assays will be
      performed using VerifyNow point-of-care assay. We will recruit 60 patients with high platelet
      reactivity (PRU > 230): 30 wild-types (normal) and 30 carriers (heterozygous or homozygous)
      of the CYP2C19*2 polymorphism. These patients will be given 150 mg of clopidogrel for 1 week,
      at which time the platelet assay will be repeated. At that time, patients will be counseled
      by the study physicians regarding the potential risks and benefits of continuing to receive
      150 mg of clopidogrel per day versus returning to the FDA approved dose of 75 mg daily.

      The immediate objective is to evaluate the possibility of overcoming clopidogrel resistance
      in carriers of CYP2C19*2 with a higher maintenance dose. The long term objective is to
      improve patient care and outcomes using personalized medicine based on the individual's
      genotype.
    

Intervention name(s): Clopidogrel
Intervention type(s): Drug
Intervention description(s): 150 mg dosage of Clopidogrel for 7 to 10 days.
Other intervention name(s): Plavix
Intervention MeSH terms: Clopidogrel
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Scripps Health patients having decresed platlet inhibition on clopidogrel
      
Biospecimen description: 
      Whole Blood