Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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
  Purpose

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.


Condition Intervention Phase
Coronary Artery Disease
Elective Percutaneous Coronary Intervention
Drug: Clopidogrel
Procedure: Blood sampling - platelet aggregation
Procedure: Blood sampling - genotyping
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Diagnostic
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

Resource links provided by NLM:


Further study details as provided by Hopital du Sacre-Coeur de Montreal:

Primary Outcome Measures:
  • 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

Estimated Enrollment: 120
Study Start Date: September 2004
Estimated Study Completion Date: April 2006
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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00433784

Locations
Canada, Quebec
Hôpital du Sacré-Coeur de Montréal
Montréal, Quebec, Canada, H4J 1C5
Sponsors and Collaborators
Hopital du Sacre-Coeur de Montreal
Investigators
Principal Investigator: Jean G Diodati, MD Hopital du Sacre-Coeur de Montreal
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00433784     History of Changes
Other Study ID Numbers: C.E.2004-06-24
Study First Received: February 8, 2007
Last Updated: August 20, 2012
Health Authority: Canada: Ethics Review Committee

Keywords provided by Hopital du Sacre-Coeur de Montreal:
clopidogrel
platelet aggregation
CYP3A
H2 haplotype
polymorphisms

Additional relevant MeSH terms:
Coronary Artery Disease
Coronary Disease
Myocardial Ischemia
Arterial Occlusive Diseases
Arteriosclerosis
Cardiovascular Diseases
Heart Diseases
Vascular Diseases
Clopidogrel
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Platelet Aggregation Inhibitors
Purinergic Agents
Purinergic Antagonists
Purinergic P2 Receptor Antagonists
Purinergic P2Y Receptor Antagonists
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014