Evaluation of the Biological Response to Clopidogrel in Patients With Ischemic Stroke

Study Overview
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Brief Summary
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Ischemic stroke (AIC) is the leading cause of non-traumatic disability in adults, the second leading cause of dementia and the third leading cause of death in France. Clopidogrel is one of the recommended first line in the secondary prevention of AIC non cardioembolic origin. However recurrences occur in approximately 9% of patients receiving clopidogrel. Some studies in patients with coronary artery disease have made the connection between these treatment failures and non-biological response to clopidogrel. This non-biological response is found for approximately 30% to 50% of patients. Several mechanisms may explain this non-response. The most accepted mechanism is pharmacokinetic. Indeed, clopidogrel is a prodrug that requires intestinal absorption by P-glycoprotein (PGP) and a transformation by hepatic cytochrome into active metabolites. The genetic polymorphism of proteins involved in these two steps explain the low plasma concentration of active metabolites and thus the low efficacy of clopidogrel in some patients. A new pharmacodynamic hypothesis suggests the involvement of platelet alpha 2-adrenergic receptors. The activation of these receptors potentiates signaling pathway P2Y12 receptor (channel inhibited by clopidogrel) and helps reduce platelet aggregation inhibiting response to clopidogrel.

Detailed Description
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Interest in the biological response to clopidogrel in the AIC is innovative because few data are available in this area. In addition to testing a new pharmacodynamic hypothesis, we also wish to study and compare other measures of platelet function methods in order to be able to use commonly in treatment decisions.

Official Title
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Evaluation of the Biological Response to Clopidogrel in Patients With Ischemic Stroke : Role of Platelet alpha2-adrenergic Receptors

Conditions
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Brain Ischemia, Ischemic Attack

Intervention / Treatment
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* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consent signed Patients with non-cardioembolic AIC requiring initiation of treatment with clopidogrel as usual indications normal standard biological tests Exclusion Criteria: Need to continue aspirin therapy Patients with a recurrence of clopidogrel AIC Patient already tacking clopidogrel Drugs interfering with the adrenergic system alpha blockers, alpha 2 receptor agonists (alpha-methyldopa) and alpha2 receptor inhibitors (Mianserin, Mirtazapine, yohimbine) Contra indication of clopidogrel and / or any of its excipients

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| AVC<br>Patients with non-cardioembolic AIC requiring initiation of treatment with clopidogrel as usual indications | Drug: Clopidogrel<br>* 75 mg milligrams per days of PLAVIX<br>* Other names: PLAVIX(R);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| adrenergic component of the platelet response | adrenergic component of the platelet response is estimated by the difference between the maximum percentage of platelet aggregation by light transmission aggregometry (LTA) with the addition of ADP(adenosine diphosphate) + ADP versus selective agonist (epinephrine) | 5 days after taking clopidogrel | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VASP-CMF | Platelet reactivity index (PRI) by VASP CMF (flow cytometry) method | After 5 days taking clopidogrel | 
| ELISA VASP | Platelet reactivity index (PRI-ELISA) using ELISA VASP | After 5 days taking clopidogrel | 
| active metabolite of clopidogrel | Rate of residual plasma active metabolite of clopidogrel (R-130964) | After 5 days taking clopidogrel | 
| Genotyping of MDR-1 and P450 2C19 | Genotyping of MDR-1 and P450 2C19 | After 5 days taking clopidogrel | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clopidogrel, Brain Ischemia, Ischemic attack, Biological response to clopidogrel