Assessment of Prospective CYP2C19 Genotype Guided Dosing of Anti-Platelet Therapy in Percutaneous Coronary Intervention

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.

Inclusion Criteria:

1. Male and female subjects, ≥18 to ≤80 years at time of study

2. Status post PCI with stent implantation requiring antiplatelet therapy

3. Willingness to comply with all study-related procedures

Exclusion Criteria:

1. Pending imminent surgery placing patients at increased risk for bleeding with
prasugrel or ticagrelor.

2. History of intracranial hemorrhage, TIA, and stroke

3. Active bleeding

4. Need for long-term anticoagulation (i.e. warfarin, dabigatran, rivaroxaban, apixaban,
edoxaban, or lovenox).

5. Current or prior (within the past four weeks) treatment with voraxapar (Zontivity).

6. Severe renal or hepatic impairment

7. Treating physician does not want subject to participate

8. Drug allergy to clopidogrel, prasugrel or ticagrelor.