Escalating Clopidogrel by Involving a Genetic Strategy - Thrombolysis In Myocardial Infarction 56

Study Overview
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Brief Summary
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To determine whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele.

Detailed Description
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Clopidogrel blocks the P2Y12 ADP receptor on platelets and has been shown to reduce cardiovascular events in acute coronary syndrome (ACS) patients.However, inter-patient variability in the pharmacodynamic response to clopidogrel is well recognized, and patients with lesser degrees of platelet inhibition in response to clopidogrel have been shown to be at increased risk of cardiovascular events. One potential source of this variability is the metabolism of clopidogrel, which is a pro-drug requiring biotransformation to become an active antiplatelet compound. Cytochrome P-450 (CYP) enzymes play a role in the metabolism, and carriers of reduced-function genetic variants in CYP2C19 ( 30% of the population) have lower active clopidogrel metabolite levels, diminished platelet inhibition, and higher rates of adverse cardiovascular events as compared with non-carriers in the setting of treatment with standard maintenance doses of clopidogrel. Aim: To determine whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele. Hypotheses: The primary hypothesis is that subjects who carry a reduced-function CYP2C19 allele will have improvement in platelet inhibition with higher maintenance doses of clopidogrel.The secondary hypothesis is that higher maintenance doses of clopidogrel in carriers of a reduced-function CYP2C19 allele will result in similar platelet inhibition as compared to a standard maintenance dose of clopidogrel in non-carriers.

Official Title
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Escalating Clopidogrel by Involving a Genetic Strategy - Thrombolysis In Myocardial Infarction 56

Conditions
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Myocardial Infarction, Percutaneous Coronary Intervention

Intervention / Treatment
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* Drug: Clopidogrel
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (major): Between 18 and 75 years of age, inclusive. Have an indication for the use of clopidogrel defined as either spontaneous MI [hospitalized with final diagnosis of MI, excluding periprocedural or definite secondary MI (e.g., due to anemia or hypertensive emergency)] or PCI within the past 6 months. Clinically stable and at least 4 weeks following the MI or PCI. Exclusion Criteria (major): Conditions that alter platelet function. Conditions that increase bleeding risk.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Clopidogrel - for CYP2C19*2 carriers<br>Clopidogrel for CYP2C19*2 gene carriers | Drug: Clopidogrel<br>* Clopidogrel 75 mg daily, 150 mg daily, 225 mg daily, and 300 mg daily based on genotype<br>|
| Active Comparator: Clopidogrel - for CYP2C19*2 non-carriers<br>Clopidogrel for CYP2C19*2 gene NON-carriers | Drug: Clopidogrel<br>* Clopidogrel 75 mg daily, 150 mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparisons of Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation Platelet Reactivity Index (PRI) | The outcome measurement was on-treatment PRI determined through flow cytometric assessment of phosphorylation status of VASP. | Approximately every 2 weeks for 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocardial infarction, Percutaneous coronary intervention, Clopidogrel, Genetics, Platelet Function