H2 Haplotype and CYP3As Polymorphisms and the Antiplatelet Response to Clopidogrel
Information source: University of Montreal
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Coronary Artery Disease; Elective Percutaneous Coronary Intervention
Intervention: Clopidogrel (Drug); Blood sampling - platelet aggregation (Procedure); Blood sampling - genotyping (Procedure)
Phase: Phase 4
Status: Completed
Sponsored by: University of Montreal Official(s) and/or principal investigator(s):
Jean G Diodati, MD, Principal Investigator, Affiliation: Hôpital du Sacré-Coeur de Montréal
Summary
The purpose of this study was to assess whether interpatient variability in the platelet
response to clopidogrel is partly due to polymorphisms of the hepatic cytochrome P450
(CYP450)3A and of the clopidogrel-P2Y12 receptor genes.
Clinical Details
Official title: Evaluation of the Effect of the H2 Haplotype and CYP3As Polymorphisms on the Antiplatelet Response to Clopidogrel Given Before Elective Percutaneous Coronary Intervention
Study design: Diagnostic, Randomized, Double-Blind, Dose Comparison, Parallel Assignment, Pharmacodynamics Study
Primary outcome: Effect of CYP3A5 polymorphisms and of the H2 haplotype on the inhibitory effect of clopidogrel on platelet aggregation at the time of diagnostic coronary angiography as measured by optical aggregometry with adenosine diphosphate (ADP) 20 μmol/L
Detailed description:
Clopidogrel owes its antiplatelet effect to irreversible inhibition of the purinergic
platelet receptor, P2Y12. It is estimated that approximately 4%-30% of patients treated with
conventional doses of clopidogrel do not display adequate platelet response. Moreover,
patients with low response to clopidogrel may be at higher risk for atherothrombotic events.
Clopidogrel, being a prodrug, requires oxidation by the hepatic cytochrome P450 (CYP450)3A to
generate an active metabolite. The level of CYP3A4 activity has been shown to correlate with
the inhibitory effect of clopidogrel on platelet aggregation in healthy volunteers. However,
CYP3As expression and activity vary among individuals. It is estimated that most of this
variability is caused by individual genetic makeup. Polymorphisms of the P2Y12 receptor may
also play a role in the variability in clopidogrel response. The P2Y12-H2 haplotype was
associated with higher maximal platelet aggregation in response to adenosine diphosphate
(ADP) as compared to the P2Y12-H1 haplotype probably due to an increase in the number of
receptors on the platelet surface. It has also been suggested that carriers of the H2
haplotype might be at higher risk of developing peripheral artery disease.
Comparisons: Presence of CYP3A5 polymorphism and of the H2 haplotype compared to absence of
these polymorphisms on the antiplatelet response to clopidogrel across a wide range of
clopidogrel dosing regimens in patients with suspected or demonstrated coronary artery
disease (CAD) scheduled to undergo elective percutaneous coronary intervention (PCI).
Platelet aggregation was measured by optical aggregometry with (ADP) 20 μmol/L as the agonist
in patients before clopidogrel initiation and at the time of diagnostic coronary angiography.
Genotyping was performed by standard polymerase chain reaction (PCR) method to identify
expressors of CYP3A5 and P2Y12 H2 haplotype carriers.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Documented coronary artery disease (CAD) requiring an elective diagnostic coronary
angiography with or without percutaneous coronary intervention (PCI)
Exclusion Criteria:
- Major bleeding disorders or active bleeding;
- Acute MI within 14 days of recruitment;
- Unstable angina with ST-segment changes of > or = 1 mm in at least two contiguous
electrocardiographic leads at rest, a troponin level of > 0. 06 ug/L or both within 14
days of recruitment;
- Stroke within the last 3 months;
- Platelet count < 100 x 109/L;
- Prothrombin time > 1. 5 times control;
- Hematocrit < 25% or hemoglobin level < 100 g/L;
- Alcohol or drug abuse;
- Enrolment in other investigational drug trials within the previous month;
- Use of thienopyridines, glycoprotein (GP) IIb/IIIa inhibitors, warfarin or
acenocoumarol within the prior week;
- Allergic reaction or any contraindication to clopidogrel or aspirin.
Locations and Contacts
Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec H4J 1C5, Canada
Additional Information
Starting date: September 2004
Ending date: April 2006
Last updated: June 3, 2008
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