Assessment of Prospective CYP2C19 Genotype Guided Dosing of Anti-Platelet Therapy in Percutaneous Coronary Intervention
Condition: Acute Coronary Syndrome; Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases; Acute Coronary Syndrome
Study type: Interventional

Summary: 
      This is a randomized, prospective, open label study to determine the cost-effectiveness of
      genotype-guided antiplatelet therapy. Patients undergoing percutaneous intervention (PCI)
      with stent implantation, will be randomized either to genotype guided dosing of antiplatelet
      therapy or usual care. The study utilizes a novel genotyping device, SpartanRx, to determine
      CYP2C19 genotypes from a buccal swab sample with 1 hour turnaround time.
    

Detailed description: 
      Clopidogrel is a thienopyridine antiplatelet agent, which inhibits the purinergic P2RY12
      receptor on platelets and prevents their aggregation. It is commonly used in patients with
      acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). CYP2C19
      is one of the principal enzymes involved in the bioactivation of clopidogrel from the
      pro-drug to its active metabolite. The most common loss of function (LOF) allele is *2
      (c.681G>A; rs4244285), with frequencies of ~15% in Caucasians and Africans and 29-35% in
      Asians. A large meta-analysis demonstrated that CYP2C19*2 carriers treated with clopidogrel
      have a higher risk for major adverse cardiac events compared to noncarriers.Therefore,
      clopidogrel is less effective in patients who are CYP2C19 poor metabolizers and alternative
      therapy is recommended. A newer-generation thienopyridine, prasugrel, was found to be
      associated with a reduction in major adverse cardiac events (death, myocardial infarction,
      stroke) compared to clopidogrel, but with an increased risk of fatal and major bleeding
      events.

      Now that clopidogrel is available in generic form, pharmacogenetic (PGx) screening could
      allow for individualized anti-platelet therapy in which patients with functional CYP2C19
      alleles could be prescribed clopidogrel, and the more expensive agent would be reserved for
      patients with poor metabolizer status. A cost-effectiveness analysis of CYP2C19 screening for
      selection of antiplatelet therapy found that genotype-guided therapy would lead to more
      cost-effective care rather than uniform usage of either clopidogrel or prasugrel.

      A more recent economic evaluation determined that genotyping and prescribing ticagrelor to
      LOF allele carriers was the most effective strategy when compared against routine clopidogrel
      or prasugrel use as well as genotyping and prescribing prasugrel to LOF carriers. However,
      these results were based on decision model of a hypothetical cohort of patients with ACS who
      underwent PCI and several assumptions were made regarding outcomes, cost and quality of life.
      True costs associated with genotype guided antiplatelet therapy are unknown. Future
      prospective studies evaluating the cost effectiveness of a genotype guided approach are
      needed. We are proposing a pilot study which will provide information necessary for planning
      a prospective study that will directly estimate events averted, costs, quality-adjust life
      years (QALYs) and cost per QALY ratios. Information to be obtained in this pilot includes
      estimates of costs and their variance, preference scores (for calculating QALYs) and their
      variance, the correlation of cost and effects (required for sample size estimation for
      cost-effectiveness ratios), event rates, and implementation metrics (to estimate likely
      penetration of testing in the trial). The results from this study will provide more accurate
      estimates of the means and variances of cost and QALYs required to plan future trials.

      OBJECTIVES

        -  To identify factors linked with successful implementation of clinical pharmacogenetic
           (PGx) testing in a large academic medical center.

        -  To conduct a prospective pilot study to determine means and variances for cost, QALYs
           and the correlation of cost and effect.

        -  To determine the rates of clinical outcomes.

      APPROACH In the genotype guided arm, a buccal swab will be obtained from subjects immediately
      following PCI/stent, to determine CYP2C19 genotype with the SpartanRx system. Subject with
      slow metabolizer status [1 or 2 loss-of-function (LOF) mutations (*2 or *3) in CYP2C19] will
      be recommended to initiate therapy with prasugrel or ticagrelor in place of clopidogrel.
      Subjects with normal metabolizer status (homozygous for the *1 allele in CYP2C19) will be
      recommended to initiate therapy with clopidogrel. Antiplatelet choice is ultimately decided
      by physician judgment incorporating all clinical factors.

      In the control arm, choice of antiplatelet therapy will be decided by treating physician as
      per usual care. DNA will be collected via a saliva sample to assess CYP2C19 genotype at the
      conclusion of the study.

      Subjects in both groups will complete a baseline health related quality of life questionnaire
      (HrQoL) and additional clinical data pertaining to cardiac history will be collected from
      medical records. Subjects will be contacted every three months for medical services
      utilization, clinical information, and HrQoL assessments for a total of one year.
    

Intervention name(s): CYP2C19 genotyping
Intervention type(s): Genetic
Intervention description(s): The study utilizes a genotyping device, SpartanRx™ (Spartan Bioscience, Ottawa, Canada) that provides identification of a patient's CYP2C19 *2, *3, and *17 genotypes determined from genomic DNA from a buccal swab sample with 1 hour turnaround time
Other intervention name(s): SpartanRx
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients undergoing PCI are randomized to genotype guided antiplatelet therapy vs. usual care.
Masking: None (Open Label)
Primary purpose: Other
Keywords: pharmacogenetics; clopidogrel; genotype