H2 Haplotype and CYP3As Polymorphisms and the Antiplatelet Response to Clopidogrel

This study has been completed.
Sponsor:
Information provided by:
Hopital du Sacre-Coeur de Montreal
ClinicalTrials.gov Identifier:
NCT00433784
First received: February 8, 2007
Last updated: August 20, 2012
Last verified: June 2008

February 8, 2007
August 20, 2012
September 2004
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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
Same as current
Complete list of historical versions of study NCT00433784 on ClinicalTrials.gov Archive Site
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H2 Haplotype and CYP3As Polymorphisms and the Antiplatelet Response to Clopidogrel
Evaluation of the Effect of the H2 Haplotype and CYP3As Polymorphisms on the Antiplatelet Response to Clopidogrel Given Before Elective Percutaneous Coronary Intervention

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.

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Diagnostic
  • Coronary Artery Disease
  • Elective Percutaneous Coronary Intervention
  • Drug: Clopidogrel
  • Procedure: Blood sampling - platelet aggregation
  • Procedure: Blood sampling - genotyping
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
120
April 2006
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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.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Canada
 
NCT00433784
C.E.2004-06-24
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Hopital du Sacre-Coeur de Montreal
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Principal Investigator: Jean G Diodati, MD Hopital du Sacre-Coeur de Montreal
Hopital du Sacre-Coeur de Montreal
June 2008

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP