Comparison of Platelet Inhibition With Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel According to Hepatic Cytochrome 2C19 Allele (CYP2C19) Polymorphism

Study Overview
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Brief Summary
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The purpose of this study was to determine the impact of adjunctive cilostazol on platelet inhibition in carriers and non-carriers of the loss-of-function CYP2C19 allele.

Detailed Description
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The additional platelet inhibition with clopidogrel, a thienopyridine inhibitor of the platelet P2Y12 adenosine diphosphate (ADP) receptor, has reduced the risk of ischemic events after coronary stent implantation. Because of inter-individual variability in platelet response to clopidogrel, a significant proportion of suboptimal platelet inhibition has been reported. In addition, persistent residual platelet reactivity measured with platelet function testing has shown the association with the cardiovascular outcomes after percutaneous coronary intervention(PCI). Various clinical factors and genetic polymorphisms have been studied to predict the degree of antiplatelet response to clopidogrel. Interestingly, recent studies found that carriers of the loss-of-function hepatic cytochrome (CYP) 2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events than did non-carriers, in the setting of PCI and acute coronary syndrome(ACS). These findings raise the need of solutions to overcome enhanced post-clopidogrel platelet reactivity by the influence of the loss-of-function CYP2C19 allele. Increasing the dose of clopidogrel and new potent P2Y12 antagonists(such as prasugrel) may be alternative antiplatelet regimens in patients with the loss-of-function CYP variant. Cilostazol reversibly induces platelet inhibition via its blockade of phosphodiesterase (PDE) type 3 and is catalysed mainly by CYP3A. A recent study demonstrated that adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) intensified platelet inhibition as compared with a high maintenance-dose (MD) of 150 mg/day. Therefore, triple antiplatelet therapy could also be an alternative antiplatelet therapy to improve platelet inhibition and clinical outcomes in carriers of CYP2C19 mutant allele.

Official Title
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Validation of Adjunctive Cilostazol According to CYP2C19 Polymorphism: Prospective, Randomized, Single-Center Trial:

Conditions
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Coronary Artery Stenosis, Maximal Platelet Aggregation, Late Platelet Aggregation, High Post-Treatment Platelet Reactivity

Intervention / Treatment
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* Drug: cilostazol
* Drug: clopidogrel
* Drug: aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must be at least 18 years of age Significant coronary artery stenosis (> 70% by visual estimate) Elective coronary stent implantation Exclusion Criteria: Acute myocardial infarction Hemodynamic instability active bleeding and bleeding diatheses Oral anticoagulation therapy with warfarin,use of peri-procedural glycoprotein IIb/IIIa inhibitors Contraindication to antiplatelet therapy Left ventricular ejection fraction < 30% Leukocyte count < 3,000/mm3, platelet count < 100,000/mm3 AST or ALT ≥ 3 times upper normal Serum creatinine level ≥ 2.5 mg/dL stroke within 3 months Noncardiac disease with a life expectancy < 1 year Inability to follow the protocol

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: triple group<br>received cilostazol 100 mg twice daily in addition to aspirin 100mg and clopidogrel 75mg once daily | Drug: cilostazol<br>* 100mg twice daily for at least 1 month<br>* Other names: pletaal;Drug: aspirin<br>* aspirin 100mg<br>|
| Active Comparator: high maintenance dose group<br>received clopidogrel 150 mg/day with aspirin 100mg once daily | Drug: clopidogrel<br>* 75mg once daily (triple group arm) 150mg once daily (high maintenance dose group arm)<br>* Other names: plavix;Drug: aspirin<br>* aspirin 100mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of maximal platelet aggregation |  | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of high post-clopidogrel platelet reactivity |  | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CYP2C19 polymorphism, platelet, Adjunctive cilostazol, high maintenance dose clopidogrel, P2Y12 Reaction Unit