Myocardial Infarction, Platelet Dysfunction, Thrombosis
Conditions
Keywords
Pharmacogenetics, Carboxylesterase 1 (CES1), Antiplatelet therapy
Brief summary
The purpose of this investigation is to evaluate when genetic variation in the carboxylesterase 1 (CES1) gene influences antiplatelet therapy response, as assessed by ex vivo platelet aggregometry, in healthy participants treated with clopidogrel and ticagrelor. We hypothesize that genetic variation in CES1 will significantly impact on-clopidogrel platelet aggregation while having a minimal effect in ticagrelor-treated subjects. Specific Aim: To conduct a prospective randomized crossover study of clopidogrel and ticagrelor in healthy individuals stratified by CES1 genotype. Participants will be recruited by CES1 genotype into a randomized crossover study of clopidogrel (75 mg daily for 7d) and ticagrelor (90 mg twice daily for 7d) with extensive phenotyping including ex vivo platelet aggregometry performed pre- and post-drug administration in order to assess the interaction of genotype and drug choice on on-treatment platelet function.
Interventions
DRUGClopidogrel
Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
DRUGTicagrelor
Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Sponsors
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Ninety healthy Amish subjects (30 CES1 G143E allele carriers, 30 carriers of a risk variant to be determined, and 30 age/sex-matched controls) will be enrolled. We will prospectively evaluate the effect of CES1 genotype on clopidogrel and ticagrelor response, as assessed by agonist-stimulated platelet aggregation, through the completion of a randomized crossover study of clopidogrel (75 mg per day for 7 d) and ticagrelor (90 mg twice daily for 7 d) in 90 healthy Amish individuals stratified by CES1 genotype as described above, with at least a 14-day washout period between drug interventions.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Of Amish descent * Age 18 to 75 years * Participant in the Phamacogenomics of Anti-Platelet Intervention (PAPI-1) Study or other Amish Research Center study, or a family member of an Amish Research Center study participant.
Exclusion criteria
* Clopidogrel or ticagrelor allergy * Platelet count \< 100,000 mm3 or \> 500,000 mm3 * Hematocrit (Hct) \< 32% or \> 50% * Blood pressure \> 160/95 mm Hg * Co-existing malignancy * Creatinine \> 2.0 mg/dl * Aspartate transaminase (AST) or alanine transaminase (ALT) \> 2 times the upper limit of normal * Thyroid-stimulating hormone (TSH) \< 0.40 or \> 5.50 mU/L * Pregnant or breast feeding * History of gastrointestinal bleeding, a major life-threatening bleeding event, active pathological bleeding, bleeding diathesis, or coagulopathy * History of stroke or transient ischemic attack, deep vein thrombosis, or atrial fibrillation * History of myocardial infarction, coronary artery bypass surgery, unstable angina, or angioplasty * History of sick sinus syndrome, 2nd or 3rd degree atrioventricular block, or bradycardia-related syncope * Type 1 or Type 2 diabetes mellitus * Surgery in the past 3 months or planned surgery in the next 3 months * Participant cannot willingly and safely discontinue medications that, in the opinion of the study physician would affect the outcomes to be measured for at least 1 week prior to study initiation through completion of the study * Participant is unwilling to discontinue taking vitamins and/or supplements that, in the opinion of the study physician would affect the outcomes to be measured for 1 week prior to the study initiation through the the completion of the study * Any other condition that would place prospective participants at unacceptable risk or render them unable to meet the requirements of the protocol in the opinion of the site investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Maximal Platelet Aggregation in Response to Clopidogrel | 8 days of exposure to clopidogrel (change from baseline at day 8 reported) | Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of clopidogrel \[75mg/d\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after clopidogrel administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-clopidogrel visits. |
| Change in Maximal Platelet Aggregation in Response to Ticagrelor | 8 days of independent exposure to ticagrelor (change from baseline at day 8 reported) | Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of ticagrelor \[90 mg twice daily\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after ticagrelor administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-ticagrelor visits. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBraxton D Mitchell, PhD
University of Maryland
Participant flow
Pre-assignment details
In our investigation, participants discontinued all vitamins/supplements at least 7 days before their first clinic visit, which is when drug was randomly assigned. Of the 111 enrolled, 11 (3 controls, 1 G143E, and 7 CES1 rs7498748) withdrew prior to clinic visit 1, thus drug was not assigned to those individuals. As such, the number of individuals shown below do not equal 111 (total enrollment number) but instead show the number of individuals who were randomly assigned to a medication (N=100)
Participants by arm
| Arm | Count |
|---|---|
| All Participants With Wild-Type Genotype Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. | 34 |
| All Participants Who Carried the CES1 G143E Mutation Research subjects who carry the CES1 G143E allele (rs71647871) will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. | 17 |
| All Participants Who Carried the CES1 Functional Mutation Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. | 38 |
| Total | 89 |
Baseline characteristics
| Characteristic | All Participants Who Carried the CES1 G143E Mutation | Total | All Participants With Wild-Type Genotype | All Participants Who Carried the CES1 Functional Mutation |
|---|---|---|---|---|
| Age, Continuous | 44.5 years STANDARD_DEVIATION 14.2 | 49.5 years STANDARD_DEVIATION 12.5 | 49.1 years STANDARD_DEVIATION 10.6 | 52.1 years STANDARD_DEVIATION 12.9 |
| Body Mass Index | 27.6 kg/m^2 STANDARD_DEVIATION 4.7 | 28.1 kg/m^2 STANDARD_DEVIATION 4.7 | 27.4 kg/m^2 STANDARD_DEVIATION 4.4 | 29.0 kg/m^2 STANDARD_DEVIATION 4.9 |
| Diastolic Blood Pressure | 70.7 mm Hg STANDARD_DEVIATION 6.8 | 73.7 mm Hg STANDARD_DEVIATION 7.7 | 73.8 mm Hg STANDARD_DEVIATION 8 | 74.0 mm Hg STANDARD_DEVIATION 7.7 |
| High-Density Lipoprotein Cholesterol | 52.8 mg/dL STANDARD_DEVIATION 14.3 | 59.0 mg/dL STANDARD_DEVIATION 15.6 | 60.4 mg/dL STANDARD_DEVIATION 18 | 60.5 mg/dL STANDARD_DEVIATION 13.3 |
| Low-Density Lipoprotein Cholesterol | 138.7 mg/dL STANDARD_DEVIATION 49.6 | 134.4 mg/dL STANDARD_DEVIATION 40.7 | 135.0 mg/dL STANDARD_DEVIATION 38.4 | 132.0 mg/dL STANDARD_DEVIATION 39.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 89 Participants | 34 Participants | 38 Participants |
| Region of Enrollment United States | 17 participants | 89 participants | 34 participants | 38 participants |
| Sex: Female, Male Female | 6 Participants | 45 Participants | 16 Participants | 23 Participants |
| Sex: Female, Male Male | 11 Participants | 44 Participants | 18 Participants | 15 Participants |
| Systolic Blood Pressure | 117.2 mm Hg STANDARD_DEVIATION 12 | 118.9 mm Hg STANDARD_DEVIATION 13.1 | 118.2 mm Hg STANDARD_DEVIATION 12.8 | 120.2 mm Hg STANDARD_DEVIATION 13.9 |
| Total Cholesterol | 207.9 mg/dL STANDARD_DEVIATION 56.2 | 209.3 mg/dL STANDARD_DEVIATION 46.8 | 210.7 mg/dL STANDARD_DEVIATION 47 | 208.8 mg/dL STANDARD_DEVIATION 43.3 |
| Triglycerides | 71.5 mg/dL STANDARD_DEVIATION 45.4 | 66.9 mg/dL STANDARD_DEVIATION 35.7 | 61.9 mg/dL STANDARD_DEVIATION 21.1 | 69.4 mg/dL STANDARD_DEVIATION 41.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 | 0 / 19 | 0 / 21 | 0 / 41 | 0 / 39 |
| other Total, other adverse events | 0 / 35 | 0 / 35 | 1 / 19 | 1 / 21 | 0 / 41 | 0 / 39 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 | 0 / 19 | 0 / 21 | 0 / 41 | 0 / 39 |
Outcome results
Primary
Change in Maximal Platelet Aggregation in Response to Clopidogrel
Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of clopidogrel \[75mg/d\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after clopidogrel administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-clopidogrel visits.
Time frame: 8 days of exposure to clopidogrel (change from baseline at day 8 reported)
Population: All of the outcome measures in this trial were pre-specified to be analyzed by genotype. Therefore, Arm/Groups are shown by genotype group rather than per medication sequence order. This is consistent with how baseline characteristics are displayed as well.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wild-Type Genotype | Change in Maximal Platelet Aggregation in Response to Clopidogrel | 32.6 Percent Maximal Platelet Aggregation | Standard Error 2.7 |
| Carriers of the CES1 G143E Mutation | Change in Maximal Platelet Aggregation in Response to Clopidogrel | 50.8 Percent Maximal Platelet Aggregation | Standard Error 2.1 |
| Carriers of CES1 Functional Mutation | Change in Maximal Platelet Aggregation in Response to Clopidogrel | 35.0 Percent Maximal Platelet Aggregation | Standard Error 2.1 |
Comparison: Change in platelet aggregation was assessed between the wild-type group and the carriers of the CES1 G143E mutation. The null hypothesis is that, following drug intervention, there is no difference in the change in platelet aggregation between genotype groups.p-value: <0.001Regression, Linear
Comparison: Change in platelet aggregation was assessed between the wild-type group and the carriers of the CES1 functional mutation (rs7498748). The null hypothesis is that, following drug intervention, there is no difference in the change in platelet aggregation between genotype groups.p-value: 0.24Regression, Linear
Primary
Change in Maximal Platelet Aggregation in Response to Ticagrelor
Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of ticagrelor \[90 mg twice daily\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after ticagrelor administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-ticagrelor visits.
Time frame: 8 days of independent exposure to ticagrelor (change from baseline at day 8 reported)
Population: All of the outcome measures in this trial were pre-specified to be analyzed by genotype. Therefore, Arm/Groups are shown by genotype group rather than per medication sequence order. This is consistent with how baseline characteristics are displayed as well.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wild-Type Genotype | Change in Maximal Platelet Aggregation in Response to Ticagrelor | 46.1 Percent Maximal Platelet Aggregation | Standard Error 1.5 |
| Carriers of the CES1 G143E Mutation | Change in Maximal Platelet Aggregation in Response to Ticagrelor | 47.8 Percent Maximal Platelet Aggregation | Standard Error 1.8 |
| Carriers of CES1 Functional Mutation | Change in Maximal Platelet Aggregation in Response to Ticagrelor | 39.6 Percent Maximal Platelet Aggregation | Standard Error 1.9 |
Comparison: Change in platelet aggregation was assessed between the wild-type group and the carriers of the CES1 G143E mutation. The null hypothesis is that, following drug intervention, there is no difference in the change in platelet aggregation between genotype groups.p-value: 0.75Regression, Linear
Comparison: Change in platelet aggregation was assessed between the wild-type group and the carriers of the CES1 functional mutation (rs7498748). The null hypothesis is that, following drug intervention, there is no difference in the change in platelet aggregation between genotype groups.p-value: 0.011Regression, Linear