Artery Occlusion, Aspirin Sensitivity, Cardiovascular Diseases, Clopidogrel, Poor Metabolism of, Coronary Artery Disease, Coronary Disease, Heart Diseases, Myocardial Ischemia, Platelet Dysfunction, Platelet Thrombus
Conditions
Keywords
pharmacogenetics, carboxylesterase, Personalized Medicine
Brief 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.
Interventions
DRUGClopidogrel
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.
DRUGAspirin
Participants will receive a single dose of 324 mg aspirin on the last day of clopidogrel administration.
Sponsors
University of Maryland, Baltimore
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Platelet Function in Response to Clopidogrel | Measured at baseline and after 8 days of clopidogrel treatment | Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation in response to ADP (20 ug/ml) or collagen (5 ug/ml). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline (recorded as a percentage) minus the maximum platelet aggregation value obtained after clopidogrel administration but before aspirin administration (also recorded as percentage). Thus, values recorded below represent a percentage change. |
| Changes in Platelet Function in Response to Clopidogrel Plus Aspirin | Measured at baseline and after 8 days clopidogrel administration plus 1 day of aspirin treatment | Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation in response to ADP (20 ug/ml) or collagen (5 ug/ml). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline (recorded as a percentage) minus the maximum platelet aggregation value obtained after clopidogrel and aspirin administration (also recorded as percentage). Thus, values recorded below represent a percentage change. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBraxton D Mitchell, PhD
University of Maryland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Clopidogrel Alone Followed by Clopidogrel and Aspirin Treatment Participants will receive clopidogrel treatment alone (300 mg loading dose followed by 75 mg/d for 6 days), followed by clopidogrel (75 mg) plus aspirin (324 mg) treatment on day 8.
Clopidogrel: 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.
Aspirin: Participants will receive a single dose of 324 mg aspirin on the last day of clopidogrel administration. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Clopidogrel Alone Followed by Clopidogrel and Aspirin Treatment |
|---|---|
| Age, Continuous | 47.8 years STANDARD_DEVIATION 14.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Changes in Platelet Function in Response to Clopidogrel
Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation in response to ADP (20 ug/ml) or collagen (5 ug/ml). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline (recorded as a percentage) minus the maximum platelet aggregation value obtained after clopidogrel administration but before aspirin administration (also recorded as percentage). Thus, values recorded below represent a percentage change.
Time frame: Measured at baseline and after 8 days of clopidogrel treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clopidogrel Alone Followed by Clopidogrel and Aspirin Treatment | Changes in Platelet Function in Response to Clopidogrel | Change in the percentage of maximal platelet aggregation in response to 5 ug/ml collagen | 20.4 percentage of maximum aggregation change | Standard Deviation 7.9 |
| Clopidogrel Alone Followed by Clopidogrel and Aspirin Treatment | Changes in Platelet Function in Response to Clopidogrel | Change in the percentage of maximal platelet aggregation in response to 20 ug/ml ADP | 37.4 percentage of maximum aggregation change | Standard Deviation 5.5 |
Primary
Changes in Platelet Function in Response to Clopidogrel Plus Aspirin
Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation in response to ADP (20 ug/ml) or collagen (5 ug/ml). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline (recorded as a percentage) minus the maximum platelet aggregation value obtained after clopidogrel and aspirin administration (also recorded as percentage). Thus, values recorded below represent a percentage change.
Time frame: Measured at baseline and after 8 days clopidogrel administration plus 1 day of aspirin treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clopidogrel Alone Followed by Clopidogrel and Aspirin Treatment | Changes in Platelet Function in Response to Clopidogrel Plus Aspirin | Change in the percentage of maximal platelet aggregation in response to 20 ug/ml ADP | 38.0 percentage of max aggregation change | Standard Deviation 8.2 |
| Clopidogrel Alone Followed by Clopidogrel and Aspirin Treatment | Changes in Platelet Function in Response to Clopidogrel Plus Aspirin | Change in the percentage of maximal platelet aggregation in response to 5 ug/ml collagen | 55.8 percentage of max aggregation change | Standard Deviation 8.8 |