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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Wild-Type Genotype | Active Comparator | 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. |
|
| Carriers of the CES1 G143E Mutation | Experimental | 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. |
|
| Carriers of CES1 rs7498748 Mutation | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clopidogrel | Drug | Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 8 days of exposure to clopidogrel (change from baseline at day 8 reported) |
| 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. | 8 days of independent exposure to ticagrelor (change from baseline at day 8 reported) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Joshua P Lewis, PhD | University of Maryland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Amish Research Clinic | Lancaster | Pennsylvania | 17602 | United States |
It is possible that deidentified data will be deposited into large public databases as per NIH data sharing policies (e.g. database of Genotypes and Phenotypes [dbGAP], Pharmacogenomics Knowledgebase [PharmGKB]). Data to be shared would include, but not limited to, anthropometric data, study outcome data, and relevant covariate data used in statistical models of association. It is anticipated that data would be available after the completion of the trial. The data will be obtained from the participants and the study-related research procedures.
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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)
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| ID | Title | Description |
|---|---|---|
| FG000 | Wild-Type Genotype: Clopidogrel First, Then Ticagrelor | 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. This group was randomized to receive clopidogrel first followed by ticagrelor 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. |
| FG001 | Wild Type Genotype: Ticagrelor First, Then Clopidogrel | 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. This group was randomized to received ticagrelor first followed by clopidogrel 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. |
| FG002 | Carboxylesterase 1 (CES1) G143E Mutation: Clopidogrel First, Then Ticagrelor | Research subjects who carry a CES1 G143E 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. This group was randomized to clopidogrel first followed by ticagrelor. 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. |
| FG003 | Carboxylesterase 1 (CES1) G143E Mutation: Ticagrelor First, Then Clopidogrel | Research subjects who carry a CES1 G143E 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. This group was randomized to ticagrelor first followed by clopidogrel. 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. |
| FG004 | Carboxylesterase 1 (CES1) Functional Mutation: Clopidogrel First, Then Ticagrelor | 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. This group was randomized to clopidogrel first followed by ticagrelor. 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. |
| FG005 | Carboxylesterase 1 (CES1) Functional Mutation: Ticagrelor First, Then Clopidogrel | 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. This group was randomized to ticagrelor first followed by clopidogrel. 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intervention 1 (8 Days) |
|
| ||||||||||||||||||
| Washout (14 Days) |
| |||||||||||||||||||
| Intervention 2 (8 Days) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | Standard Error | Percent Maximal Platelet Aggregation | 8 days of exposure to clopidogrel (change from baseline at day 8 reported) |
During both intervention periods, the washout period, and for 30 days after the final study visit, up to 57 day
Adverse event data were collected during both intervention periods, the washout period, and for 30 days after the final study visit.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Wild-Type Genotype: Clopidogrel | 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. The data shown here are for participants who had the wild-type genotype and during the clopidogrel intervention. 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Knee Pain/Swelling | General disorders | Non-systematic Assessment | Knee pain and swelling began after participant started taking clopidogrel 75 mg daily. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Joshua P. Lewis, PhD | University of Maryland, School of Medicine | 410-706-5087 | jlewis2@som.umaryland.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 5, 2024 | Mar 6, 2024 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D009203 | Myocardial Infarction |
| D013927 | Thrombosis |
| ID | Term |
|---|---|
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D000077144 | Clopidogrel |
| D000077486 | Ticagrelor |
| ID | Term |
|---|---|
| D013988 | Ticlopidine |
| D058924 | Thienopyridines |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
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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.
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|
| Ticagrelor | Drug | Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. |
|
|
| Adverse Event |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| BG001 | 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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| Systolic Blood Pressure | Mean | Standard Deviation | mm Hg |
|
| Diastolic Blood Pressure | Mean | Standard Deviation | mm Hg |
|
| Total Cholesterol | Mean | Standard Deviation | mg/dL |
|
| Low-Density Lipoprotein Cholesterol | Mean | Standard Deviation | mg/dL |
|
| High-Density Lipoprotein Cholesterol | Mean | Standard Deviation | mg/dL |
|
| Triglycerides | Mean | Standard Deviation | mg/dL |
|
| ID | Title | Description |
|---|---|---|
| OG000 | 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. |
| OG001 | Carriers of 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. |
| OG002 | Carriers of 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. |
|
|
|
| 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. | 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. | Posted | Mean | Standard Error | Percent Maximal Platelet Aggregation | 8 days of independent exposure to ticagrelor (change from baseline at day 8 reported) |
|
|
|
|
| 0 |
| 35 |
| 0 |
| 35 |
| 0 |
| 35 |
| EG001 | Wild Type Genotype: Ticagrelor | 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. The data shown here are for participants who had the wild-type genotype and during the ticagrelor intervention. 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. | 0 | 35 | 0 | 35 | 0 | 35 |
| EG002 | Carboxylesterase 1 (CES1) G143E Mutation: Clopidogrel | Research subjects who carry a CES1 G143E 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. The data shown here are for participants who carried the G143E allele and during the clopidogrel intervention. 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. | 0 | 19 | 0 | 19 | 1 | 19 |
| EG003 | Carboxylesterase 1 (CES1) G143E Mutation: Ticagrelor | Research subjects who carry a CES1 G143E 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. The data shown here are for participants who carried the G143E allele and during the ticagrelor intervention. 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. | 0 | 21 | 0 | 21 | 1 | 21 |
| EG004 | Carboxylesterase 1 (CES1) Functional Mutation: Clopidogrel | 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. The data shown here are for participants who carried the functional mutation (rs7498748) and during the clopidogrel intervention. 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. | 0 | 41 | 0 | 41 | 0 | 41 |
| EG005 | Carboxylesterase 1 (CES1) Functional Mutation: Ticagrelor | 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. The data shown here are for participants who carried the functional mutation (rs7498748) and during the ticagrelor intervention. 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. | 0 | 39 | 0 | 39 | 0 | 39 |
|
| Dyspnea | General disorders | Non-systematic Assessment | Dyspnea occurred in 1 individual a few days after starting the ticagrelor intervention |
|
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| D007238 |
| Infarction |
| D007511 | Ischemia |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009336 | Necrosis |
| D016769 | Embolism and Thrombosis |
| D009930 |
| Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D000241 | Adenosine |
| D011684 | Purine Nucleosides |
| D011687 | Purines |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
| 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. | Regression, Linear | All analyses were adjusted for age, sex, body mass index (BMI), and relatedness among study participants. | 0.011 | Other | The effect of CES1 genotype on agonist-stimulated change in platelet aggregation was calculated using variance component method that simultaneously adjusted for age, sex, body mass index (BMI), and relatedness among study participants. Relatedness among participants were accounted for by including a polygenic component as a random effect. Please see the Study Protocol and Statistical Analysis Plan document for additional information. |