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

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.

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