Determining Genetic Role in Treatment Response to Anti-Platelet Interventions (The PAPI Study)

Study Overview
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Brief Summary
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One of the most common ways for preventing coronary heart disease (CHD) is to take aspirin or clopidogrel. However, studies have shown that not all people respond to these medications. The variance in treatment response may be linked to genetics. This study will examine the effects of aspirin and clopidogrel in a population whose genes are well known in order to determine the role that genes play in treatment responses.

Detailed Description
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CHD is the leading cause of death in the United States. Anti-platelet agents lessen platelet aggregation and are used commonly to prevent recurrent CHD events. Two of the most common anti-platelet agents are aspirin and clopidogrel. However, up to 25% to 30% of people do not respond to these medications. Evidence indicates that treatment response may be related to genetics. The purpose of this study is to determine specific gene variants that predict response to aspirin and clopidogrel therapy. This study is part of a larger group of studies called the Pharmacogenomics Research Network (PGRN). Participants will include the Old Order Amish of Lancaster, Pennsylvania. They are well suited for genetic studies because they are a homogenous, closed, founder population. Participants will receive 300 mg of clopidogrel on the first day, then 75 mg of clopidogrel per day for the next 6 days. On the last day of clopidogrel treatment, participants will take a single dose of 324 mg aspirin. Participants will undergo platelet function tests before and after clopidogrel alone, and then again after taking clopidogrel plus aspirin. Using the gene variation profiles across the genome, researchers will analyze which genes correspond to treatment response.

Official Title
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Pharmacogenomics of Anti-Platelet Interventions (The PAPI Study)

Conditions
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Platelet Aggregation Inhibitors, Coronary Heart Disease

Intervention / Treatment
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* Drug: Clopidogrel
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Of Old Order Amish descent Exclusion Criteria: Currently pregnant or less than 6 months have passed since delivery Has a history of a bleeding disorder or major spontaneous bleed, such as peptic ulcer, epistasis, or intracranial bleed Has severe hypertension, defined by a blood pressure above 160/95 mm Hg, making it unethical not to recommend prompt treatment Takes medications that would affect the outcome(s) to be measured and cannot willingly and safely, in the opinion of the treating physician and study physician, discontinue these medications for 1 week prior to protocol initiation Is taking vitamins or other supplements and is unwilling to discontinue their use for at least 1 week prior to study Has a coexisting malignancy Has a creatinine level greater than 2.0 mg/dl, aspartate transaminase (AST) or alanine transaminase (ALT) greater than two times the upper limit of normal, hematocrit less than 32%, or a thyroid-stimulating hormone (TSH) less than 0.4 or greater than 5.5 mIU/L Has a bleeding disorder or history of gastrointestinal bleeding or other major bleeding episode Is currently taking aspirin, clopidogrel, or other anti-coagulant, such as warfarin, heparin, or GPIIb/IIIa antagonists, and have conditions that might place them at increased risk from withdrawal of these medications 14 days prior to protocol initiation, including history of unstable angina, heart attack, angioplasty (including stent placement), coronary artery bypass surgery, atrial fibrillation, stroke or transient ischemic attacks, diabetes, or deep vein thrombosis or other thrombosis Has polycythemia, or thrombocytosis, defined by a platelet count greater than 500,000 Has thrombocytopenia, defined by a platelet count less than 75,000 Has had surgery within the last 6 months Has an aspirin or clopidogrel allergy Currently breast feeding

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Overall Study<br>Participants will receive clopidogrel treatment alone, followed by clopidogrel plus aspirin treatment on the last day of treatment. | Drug: Clopidogrel<br>* 300 mg on first day, then 75 mg per day for the next 6 days<br>Drug: Aspirin<br>* Single dose of 324 mg on the last day of clopidogrel treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Platelet Function in Response to Clopidogrel | Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation. | Measured at baseline, and after clopidogrel treatment | 
| Changes in Platelet Function in Response to Clopidogrel Plus Aspirin | Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation | Measured at baseline, and after clopidogrel plus aspirin treatment |