Mechanisms fo Clopidogrel Resistance in Older Adults (CEPAGE)

Study Overview
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Brief Summary
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A clopidogrel resistance rate of 40-50% has been found in the population over 70 years of age, whereas biological resistance, associated with an increased risk of cardiovascular events, is observed in about 20-30% of younger patients. One hypothesis is that the active metabolite is less available in resistant patients. Indeed, 85% of the absorbed clopidogrel undergoes inactivation by esterases. Then the remaining fraction undergoes two steps of metabolisation to the active thiol metabolite by CYP450, essentially the isoform 2C19. In older adults, increased esterase activity and/or decreased CYP450 2C19 activity may lead to a decreased concentration of the active metabolite. Multiple chronic conditions and polypharmacy encountered in older individuals are associated with basal platelet hyperactivity, and may also contribute to a poor response to clopidogrel. No data on the relationship between platelet response and circulating metabolite levels, or on the determinants of response to clopidogrel, are currently available in the geriatric population. Therefore, we propose to analyse the relationship between age and platelet and extra-platelet mechanisms potentially involved in the variability of response to clopidogrel.

Detailed Description
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This study is a prospective observational multi-centre study. The main objective is assessing the pharmacokinetics (PK) and pharmacodynamics (PD) correlation of clopidogrel action in older adults, i.e. correlation between clopidogrel active metabolite concentration (PK) and platelet response phenotype (PD). The primary outcome is the correlation between the concentration of active metabolite of clopidogrel (PK) over the percentage of maximum aggregation at 10 μM ADP (PD) as a function of age. Inclusion criteria are: age 50-100 years old, hospitalization in one of the 4 participating centres, treatment with clopidogrel 75 milligrammes per day, for at least 10 days. The statistical analysis is a multiple linear regression model with the introduction of an interaction term. The first variable of interest (explanatory) is the concentration of the metabolite. A linear regression model will be used to estimate the proportion of variance explained. The analyses will be conducted with SAS version 9.4 (SAS Institute Inc., Cary, N.C., USA). Results will be published in an international scientific review.

Official Title
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Mechanisms fo Clopidogrel Resistance in Older Adults

Conditions
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Drug Resistance

Intervention / Treatment
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* Biological: additional blood sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consecutive patients per 10-year age range, (20 patients per age range from 50 to 100 years included) : in consultation or hospitalization in one of the participating centres, treatment with clopidogrel 75 mg/d for at least 10 days for primary or secondary prevention of cardiovascular events. who have received the information and have not expressed their opposition to participate in the study and who have given their written consent for the performance of genetic examinations and the realization of a biocollection affiliated to French social security system Exclusion criteria : treatment with another antithrombotic agent, myeloproliferative syndrome, platelet count < 100 G/L, acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer, under dialysis, no participation in another clinical study, deprived of liberty

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Age Group 50 to 59<br>Inclusion criteria : age 50-100 years old, in consultation or hospitalization in one of the participating centres, treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug, myeloproliferative syndrome, platelet count < 100 gigas/liter, acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer, dialysis. | Biological: additional blood sample<br>* One sample per patient will be taken 1 to 3 hours after clopidogrel administration. Four additional tubes of 3 mL each will be collected for the study, for a total volume of 12 mL.<br>|
| Age Group 60 to 69<br>Inclusion criteria : age 50-100 years old, in consultation or hospitalization in one of the participating centres, treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug, myeloproliferative syndrome, platelet count < 100 gigas/liter, acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer, dialysis. | Biological: additional blood sample<br>* One sample per patient will be taken 1 to 3 hours after clopidogrel administration. Four additional tubes of 3 mL each will be collected for the study, for a total volume of 12 mL.<br>|
| Age Group 70 to 79<br>Inclusion criteria : age 50-100 years old, in consultation or hospitalization in one of the participating centres, treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug, myeloproliferative syndrome, platelet count < 100 gigas/liter, acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer, dialysis. | Biological: additional blood sample<br>* One sample per patient will be taken 1 to 3 hours after clopidogrel administration. Four additional tubes of 3 mL each will be collected for the study, for a total volume of 12 mL.<br>|
| Age Group 80 to 89<br>Inclusion criteria : age 50-100 years old, in consultation or hospitalization in one of the participating centres, treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug, myeloproliferative syndrome, platelet count < 100 gigas/liter, acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer, dialysis. | Biological: additional blood sample<br>* One sample per patient will be taken 1 to 3 hours after clopidogrel administration. Four additional tubes of 3 mL each will be collected for the study, for a total volume of 12 mL.<br>|
| Age Group 90 to 100<br>Inclusion criteria : age 50-100 years old, in consultation or hospitalization in one of the participating centres, treatment with clopidogrel 75 milligrammes per day, for at least 10 days, for primary or secondary prevention of cardiovascular events. Non-inclusion criteria : treatment with another antithrombotic drug, myeloproliferative syndrome, platelet count < 100 gigas/liter, acute inflammatory situation: severe sepsis, documented acute infection, chronic systemic inflammatory disease or active cancer, dialysis. | Biological: additional blood sample<br>* One sample per patient will be taken 1 to 3 hours after clopidogrel administration. Four additional tubes of 3 mL each will be collected for the study, for a total volume of 12 mL.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK/PD correlation - clopidogrel active metabolite concentration (pharmacokinetics PK in ) / platelet response phenotype(pharmacodynamics, PD) | Correlation PK (concentration of active metabolite of clopidogrel) / PD (%maximum aggregation at 10 μM ADP) as a function of age | Day 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of prodrug/active metabolite concentrations | Ratio of prodrug/active metabolite concentrations as a function of age | Day 0 | 
| Correlation between the area under the curve of aggregationat 10 μM ADP and the concentration of the active metabolite of clopidogrel | Correlation between the area under the curve of aggregation at 10μM ADP and the concentration of the active metabolite of clopidogrelas a function of age | Day 0 | 
| Correlation between the Platelet Reactivity Index of VASPphosphorylation and the concentration of the active metabolite of clopidogrel | Correlation between the Platelet Reactivity Index of VASP phosphorylation and the concentration of the active metabolite of clopidogrel in relation to age | Day 0 | 
| Determination of factors influencing PK/PD response | clinical data: gender | Day 0 | 
| Determination of factors influencing PK/PD response | clinical data: body mass index in kg/m^2 | Day 0 | 
| Determination of factors influencing PK/PD response | clinical data: Cumulative Illness Rating Scale-Geriatric | Day 0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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clopidogrel, primary or secondary prevention of cardiovascular events, older adults, clopidogrel resistance, Drug resistance, Antiplatelet resistance