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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Assessment of Prospective CYP2C19 Genotype Guided Dosing of Anti-Platelet Therapy in Percutaneous Coronary Intervention (ADAPT)

Conditions
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Acute Coronary Syndrome, Cardiovascular Diseases

Intervention / Treatment
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* Genetic: CYP2C19 genotyping


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects, ≥18 to ≤80 years at time of study Status post PCI with stent implantation requiring antiplatelet therapy Willingness to comply with all study-related procedures Exclusion Criteria: Pending imminent surgery placing patients at increased risk for bleeding with prasugrel or ticagrelor. History of intracranial hemorrhage, TIA, and stroke Active bleeding Need for long-term anticoagulation (i.e. warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, or lovenox). Current or prior (within the past four weeks) treatment with voraxapar (Zontivity). Severe renal or hepatic impairment Treating physician does not want subject to participate Drug allergy to clopidogrel, prasugrel or ticagrelor.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients undergoing PCI are randomized to genotype guided antiplatelet therapy vs. usual care.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYP2C19 Genotype guided<br>Prospective CYP2C19 genotyping to decide antiplatelet therapy. | Genetic: CYP2C19 genotyping<br>* 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<br>* Other names: SpartanRx;|
| No Intervention: Control group<br>Antiplatelet therapy will be decided based on usual care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number (Percentage) of Participants Receiving Prasugrel/Ticagrelor | The number (percentage) of participants receiving prasugrel/ticagrelor in each randomized arm | for up to 7 days after PCI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Drug Orders in Agreement With the Genotype-guided Recommendations | Agreement to suggested treatment recommendations based on genotype. The agreement rate was defined as the number of participants in genotyped group with loss of function variants that received prasugrel or ticagrelor + the number of participants without these variants that received clopidogrel divided by the total number in this group. | for up to 7 days after PCI | 
| Number of Participants With Major Cardiac Events | major cardiac events defined as occurrence of first myocardial infarction, ischemic stroke, cardiovascular death, stent thrombosis, or need for urgent revascularization | 1 year | 
| Number of Participants With Bleeding Events | major bleeding events defined by the Bleeding Academic Research Consortium (BARC) type 3 or 5. Type 3= Overt bleeding requiring: blood transfusion, surgical intervention or intravenous vasoactive agents; cardiac tamponade; intracranial hemorrhage; intraocular bleeding. Type 5= fatal bleeding | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacogenetics, clopidogrel, genotype