H2 Haplotype and CYP3As Polymorphisms and the Antiplatelet Response to Clopidogrel

August 20, 2012 updated by: Hopital du Sacre-Coeur de Montreal

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment

120

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Quebec
      • Montréal, Quebec, Canada, H4J 1C5
        • Hopital du Sacre-Coeur de Montreal

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hopital du Sacre-Coeur de Montreal

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2004

Study Completion

April 1, 2006

Study Registration Dates

First Submitted

February 8, 2007

First Submitted That Met QC Criteria

February 8, 2007

First Posted (Estimate)

February 12, 2007

Study Record Updates

Last Update Posted (Estimate)

August 21, 2012

Last Update Submitted That Met QC Criteria

August 20, 2012

Last Verified

June 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • C.E.2004-06-24

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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