ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy Based on GENetic Evaluation

Study Overview
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Brief Summary
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The objective of the RAPID GENE study is to evaluate the feasibility, efficacy and safety of a pharmacogenomic approach to anti-platelet therapy following coronary artery stenting using a CYP2C19*2 point-of-care genetic test.

Detailed Description
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Effective medical treatment following acute coronary syndromes and percutaneous coronary intervention (PCI) consists of dual anti-platelet therapy with aspirin and clopidogrel. Despite this treatment approach, a substantial portion of patients continue to experience an increased rate of subsequent adverse cardiovascular events including death, myocardial infarction, and stent thrombosis. This persistent vulnerability has been associated with inadequate platelet inhibition in response to clopidogrel administration, a phenomenon referred to as clopidogrel resistance. Although multiple variables have been implicated in clopidogrel resistance, mounting evidence suggests a crucial role for the loss-of-function CYP2C19*2 genetic variant. Presence of the *2 allele has been associated with a 1.5- to 6-fold increased risk of cardiovascular death, myocardial infarction, and stent thrombosis following PCI in patients treated with clopidogrel. These findings, recently bolstered by a meta-analysis, led the American Food and Drug Administration to issue a boxed warning for clopidogrel stating that poor metabolizers may not receive the full benefit of the drug. Consequently, experts have begun to advocate for routine genotyping in the context of dual anti-platelet therapy following PCI. A personalized approach to dual anti-platelet therapy following PCI is feasible given the presence of treatment alternatives such as prasugrel that are capable of overcoming clopidogrel resistance. Selective administration of prasugrel to patients at increased risk of clopidogrel resistance has the potential to successfully minimize adverse ischemic events, while simultaneously minimizing associated bleeding events and health care costs. A prospective pharmacogenomic approach to anti-platelet therapy has been previously hampered by limited access and the time-delay associated with genetic testing. The development of a point-of-care CYP2C19*2 genetic test that requires minimal training to operate carries the potential to overcome these obstacles and may facilitate the incorporation of pharmacogenomic strategies into routine clinical practice. Patients receiving percutaneous coronary intervention in the context of non-ST elevation acute coronary syndromes and stable coronary artery disease will be randomized to either a rapid genotyping strategy or standard therapy. Patients in the Rapid Genotyping arm will be screened for the presence of the CYP2C19*2 allele using a point-of-care genetic test. Carriers of the *2 allele will receive prasugrel 10 mg daily for 1 week. Non-*2 carriers in the Rapid Genotyping arm and all patients in the Standard Therapy arm will receive clopidogrel 75 mg daily. At the end of the 1 week period, efficacy of the treatment strategies will be evaluated using VerifyNow platelet function testing.

Official Title
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ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy Based on GENetic Evaluation (The RAPID GENE Study)

Conditions
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Stable Coronary Artery Disease, Acute Coronary Syndrome, Percutaneous Coronary Intervention

Intervention / Treatment
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* Genetic: Point-of-care genetic screening with subsequent prasugrel administration to CYP2C19*2 carriers


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and Females between the ages of 18 and 75 years Patients undergoing percutaneous coronary intervention in the context of a non-ST-elevation acute coronary syndrome or stable coronary artery disease Able to provide informed consent Able to comply with assigned treatment strategy and attend 1 week follow-up visit Exclusion Criteria: Receiving anti-platelet therapy other than aspirin and clopidogrel Receiving anti-coagulation with warfarin History of stroke or transient ischemic attack Platelet count < 100 000/μL Known Bleeding Diathesis Hematocrit <32% or >52% Severe Liver Dysfunction Renal Insufficiency (Creatinine Clearance < 30ml/min) Pregnant females

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rapid Genotyping<br>Patients randomized to the Rapid Genotyping arm will have their CYP2C19*2 carrier status determined at the time of percutaneous coronary intervention with subsequent alteration in anti-platelet therapy for *2 carriers. | Genetic: Point-of-care genetic screening with subsequent prasugrel administration to CYP2C19*2 carriers<br>* Patients found to carry the CYP2C19*2 allele will receive prasugrel 10 mg daily for 1 week. Non-carriers will receive clopidogrel 75 mg daily.<br>* Other names: Prasugrel (Effient);|
| No Intervention: Standard Therapy<br>Patients randomized to the Standard Therapy arm will not undergo genotyping at the time of percutaneous coronary intervention. All patients will receive clopidogrel 75 mg daily for 1 week. At the end of the 1 week period, their CYP2C19*2 carrier status will be verified. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clopidogrel response status as measured by the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) in CYP2C19*2 carriers. | Response status defined in P2Y12 Reaction Units (PRU) and percent platelet inhibition. | 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concordance of point-of-care genetic screening with laboratory based genotyping methods |  | 1 week | 
| Composite of death from cardiovascular causes, non-fatal myocardial infarction, and re-hospitalization |  | 1 week and 6 months | 
| Bleeding risk | Defined by TIMI major/minor | 1 week and 6 months | 
| Incidence of stent thrombosis | ARC definitions | 1 week and 6 months | 
| Feasibility of point-of-care genotyping in randomized setting |  | 1 week | 
| Influence of Alternate CYP2C19 variants on outcomes | CYP2C19 - functional polymorphisms | 1 week and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CYP2C19*2, Pharmacogenomics, Clopidogrel, Prasugrel, Percutaneous Coronary Intervention