Pharmacogenomics of Antiplatelet Response - I

Phase 4

Completed

Conditions: Coronary Artery Disease
Platelet Aggregation
Platelet Transcriptome

Brief Summary: This clinical trial is examining the role of genetic polymorphism on the effect of clopidogrel (with or without aspirin) on platelet response in persons at high-risk for myocardial infarction or stroke due to family history of early-onset coronary artery disease.

Detailed Description: The main goal of this study is to explore the impact of the PEAR1 genetic variant (rs12041331) on responsiveness to clopidogrel. The investigators will further assess the role of other genetic variants in determining the response to single or dual anti-platelet therapy. Apparently healthy subjects (N= 2108) from high-risk families are being (a) identified from a proband with early-onset CAD and (b) genotyped on the Illumina 1 million platform, with imputation to 2.5 million single nucleotide polymorphisms. The investigators plan to characterize the variance in platelet aggregation to multiple agonists (ADP, collagen, and arachidonic acid) after 1-week therapy with clopidogrel in a high-risk subset of GeneSTAR subjects (N=100). The investigators further plan to determine the extent to which variants identified in the PEAR1 gene modify platelet responsiveness to inhibition by clopidogrel in this high-risk subset. In addition, the investigators aim is to determine the extent to which variants in other recently discovered genes, by themselves, and in combination with PEAR1, modify platelet responsiveness to clopidogrel alone and with aspirin in this high-risk subset. Lastly, the investigators also want to determine what changes in platelet mRNA are produced by aspirin alone and by aspirin with clopidogrel.

Recruitment & Eligibility

Inclusion Criteria

Participants from the GeneSTAR cohort
Unaffected with no overt coronary artery disease or serious vascular event (stroke or peripheral vascular disease diagnosis
Presence of an occult coronary artery disease phenotype as defined by coronary artery calcium scores about the MESA (Multiethnic Study of Atherosclerosis) 75th percentile for age sex, and race or ≥ 1 stenoses in any of the major coronary arteries or main branches of > 50%, or coronary plaque volumetric scores above our own 75th percentile, or any combination on cardiac computed tomographic angiography (performed recently as part of the GeneSTAR study and present for all persons being recruited)/
Presence of occult cerebrovascular disease defined as presence of white matter hyperintensities (WMH) thought to represent ischemic small vessel cerebrovascular disease, and /or the presence of lacunes (old small strokes), or the presence of an Atherosclerosis Risk in Communities Study (ARIC) silent stroke score on a visual analogue scales of 4 or more (on a scale of 0-9).
Women who are postmenopausal.
Women who use a reliable contraceptive method; a reliable contraceptive method will be defined as personal history of tubal ligation, ongoing use of intra-uterine device, or ongoing use of oral contraceptive pills.

Exclusion Criteria

Presence of any CAD or stroke, transient ischemic attacks, peripheral arterial disease
Persons taking aspirin, NSAIDS, or any anti-coagulants who are medically unable to stop them for a two week pre-trial
A history of allergy to aspirin or clopidogrel
Weight < 60kg
Age < 45 and > 75 years of age
A history of recent or any active bleeding
Serious or current co-morbidity (AIDS, cancer)
Pregnant women as determined by urine dipstick pregnancy test
Any aneurysms on cranial magnetic resonance imaging/magnetic resonance angiography (obtained recently in the GeneSTAR participants)
Blood pressure above >=159/95mmHg
History of a gastric or duodenal ulcer, or significant gastrointestinal disease, like regional enteritis
Mental incompetence to make a decision to participate (developmentally disabled, and persons with diagnosed psychiatric disorders-documented in primary care records).

Arm && Interventions

Group	Intervention	Description
Clopidogrel	Clopidogrel	Clopidogrel 75 mg daily by mouth for 1 week then Clopidogrel 75 mg daily with aspirin 81 mg daily
Clopidogrel	Aspirin	Clopidogrel 75 mg daily by mouth for 1 week then Clopidogrel 75 mg daily with aspirin 81 mg daily

Primary Outcome Measures

Name	Time	Method
Difference in ADP-induced Platelet Aggregation	at baseline and at 1 week	ADP-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined. Higher impedance represent higher platelet aggregation.

Secondary Outcome Measures

Name	Time	Method
Changes in Platelet Transcriptome With Clopidogrel	At baseline and at 1 week	Platelet transcriptome will be examined before and after 1 week of therapy with clopidogrel and differences will be determined
Difference in Arachidonic Acid-induced Platelet Aggregation	At baseline and after 1-week	Arachidonic Acid-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined
Difference in Collagen-induced Platelet Aggregation	At Baseline and at 1 week	Collagen-induced platelet aggregation will be measured using impedance aggregometry in whole blood before and after 1-week of clopidogrel. The difference between the baseline and after clopidogrel therapy will be determined