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

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

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.

Study Overview

• Status: Completed
• Conditions: Brain Ischemia; Ischemic Attack
• Intervention / Treatment: Drug: Clopidogrel

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 91

Contacts and Locations

Study Locations

• France
  • Saint-etienne, France, 42000
    • CHU de SAINT-ETIENNE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with non-cardioembolic AIC requiring initiation of treatment with clopidogrel as usual indications

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
AVC; Patients with non-cardioembolic AIC requiring initiation of treatment with clopidogrel as usual indications	Drug: Clopidogrel; 75 mg milligrams per days of PLAVIX; Other Names: PLAVIX(R)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Groupe de Recherche sur la Thrombose
• Investigators: Principal Investigator: Jerome VARVAT, MD, CHU de SAINT-ETIENNE

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: September 27, 2013
• First Submitted That Met QC Criteria: October 4, 2013
• First Posted (Estimate): October 7, 2013

Study Record Updates

• Last Update Posted (Estimate): December 31, 2015
• Last Update Submitted That Met QC Criteria: December 30, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Clopidogrel; Brain Ischemia; Ischemic attack; Biological response to clopidogrel
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Brain Ischemia; Ischemia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel
• Other Study ID Numbers: 1208094; 2013-000313-20 (EudraCT Number)