CES1 Carriers in the PAPI Study
Condition: Heart Diseases; Coronary Disease; Coronary Artery Disease; Cardiovascular Diseases; Myocardial Ischemia; Artery Occlusion; Aspirin Sensitivity; Clopidogrel, Poor Metabolism of; Platelet Dysfunction; Platelet Thrombus
MeSH terms: Cardiovascular Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Heart Diseases; Ischemia
Intervention: Clopidogrel; Aspirin
Intervention description: Participants will receive 300 mg of clopidogrel on the first day, then 75 mg per day for the next 6 days. Measures of pharmacodynamics will be assessed pre- and post-drug administration.; Participants will receive a single dose of 324 mg aspirin on the last day of clopidogrel administration.
Intervention MeSH terms: Aspirin; Clopidogrel
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Intervention model description: The investigators will enroll up to 50 healthy Amish participants who have been identified through existing whole genome and exome sequencing along with bioinformatic approaches that have genetic variants that are predicted to significantly impact CES1 expression or catalytic function. Enrolled participants will undergo a two-stage intervention with clopidogrel (300 mg loading dose then 75 mg per day for the next 6 days), followed by clopidogrel (75 mg) plus aspirin 324 mg for 1 day. Platelet aggregation studies and other measures of platelet function will be performed before and after each intervention. In combination with previously collected data as part of the PAPI Study, the investigators will then characterize the impact of genetic variation in CES1 on clopidogrel and dual antiplatelet therapy response through single- and multi-variant association modeling.
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: pharmacogenetics; carboxylesterase; Personalized Medicine

Summary:

      This study builds, in part, upon preliminary results generated as part of the
      Pharmacogenomics Anti-Platelet Intervention (PAPI) Study (NCT00799396). The purpose of this
      investigation is to assess the impact of genetic variation in the carboxylesterase 1 (CES1)
      on response to clopidogrel as well as dual antiplatelet therapy (i.e. clopidogrel and
      aspirin), as assessed by ex vivo platelet aggregometry, in healthy Amish individuals. The
      investigators hypothesize that participants who carry alleles that modify the activity or
      expression of CES1 will have altered response to clopidogrel as well as dual antiplatelet
      therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age 20 years or older

          -  Of Old Order Amish descent

        Exclusion Criteria:

          -  Currently pregnant or less than 6 months have passed since delivery

          -  Currently breast feeding

          -  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

          -  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 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 anti-coagulants, such as warfarin,
             heparin, or GPIIb/IIIa antagonists, and have conditions that might place the
             participant at increased risk from withdrawal of these medications 14 days prior to
             protocol initiation

          -  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