Coronary Artery Disease, Platelet Aggregation, Platelet Transcriptome
Conditions
Keywords
Platelet aggregation, Clopidogrel, 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.
Interventions
DRUGClopidogrel
Clopidogrel 75 mg daily
DRUGAspirin
Aspirin 81 mg daily
Sponsors
Johns Hopkins University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
45 Years to 75 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Clopidogrel Clopidogrel 75 mg daily by mouth for 1 week then Clopidogrel 75 mg daily with aspirin 81 mg daily
Clopidogrel: Clopidogrel 75 mg daily
Aspirin: Aspirin 81 mg daily | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Clopidogrel |
|---|---|
| Age, Continuous | 45.9 years STANDARD_DEVIATION 5.2 |
| Gender Female | 6 Participants |
| Gender Male | 8 Participants |
| Race/Ethnicity, Customized African Americans | 14 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 14 |
| serious Total, serious adverse events | 0 / 14 |
Outcome results
Primary
Difference in ADP-induced Platelet Aggregation
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.
Time frame: at baseline and at 1 week
Population: Data was collected before and after one week of clopidogrel. We found it difficult to enroll patients with low risk to the combined aspirin and clopidogrel and hence study was continued for the first week only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clopidogrel | Difference in ADP-induced Platelet Aggregation | -5.2 Difference in ohms (Post-Pre) | Standard Deviation 4.1 |
Secondary
Changes in Platelet Transcriptome With Clopidogrel
Platelet transcriptome will be examined before and after 1 week of therapy with clopidogrel and differences will be determined
Time frame: At baseline and at 1 week
Population: Note: The 2nd week of the study was not performed as we could not find low risk population in our cohort who could be given both anti-platelets without increased estimated risk of bleeding. Note that the top most gene (CNOT2) with the lowest p-value is being reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clopidogrel | Changes in Platelet Transcriptome With Clopidogrel | 13.7 FPKM | Standard Error 3.55 |
Secondary
Difference in Arachidonic Acid-induced Platelet Aggregation
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
Time frame: At baseline and after 1-week
Population: Data was collected before and after one week of clopidogrel. We found it difficult to enroll patients with low risk to the combined aspirin and clopidogrel and hence study was continued for the first week only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clopidogrel | Difference in Arachidonic Acid-induced Platelet Aggregation | -5.2 Difference in ohms (Post-Pre) | Standard Deviation 4.4 |
Secondary
Difference in Collagen-induced Platelet Aggregation
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
Time frame: At Baseline and at 1 week
Population: Note: The 2nd week of the study was not performed as we could not find low risk population in our cohort who could be given both anti-platelets without increased estimated risk of bleeding.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clopidogrel | Difference in Collagen-induced Platelet Aggregation | -1.13 Difference in ohms (Post-Pre) | Standard Deviation 4.1 |