Official Title: “CYP 2C19 Polymorphism and Response to Adjunctive Cilostazol and High Maintenance-dose Clopidogrel in Patients Undergoing Elective Percutaneous Coronary Intervention”

The purpose of this study is to determine the impact of adjunctive cilostazol versus high maintenance-dose clopidogrel on platelet inhibition in carriers and non-carriers of the loss-of-function CYP2C19 mutant allele.

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind (Investigator), Active Control, Parallel Assignment, Pharmacokinetics/Dynamics Study

Study Primary Completion Date: July 2009

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.

We compared the enhanced inhibition of platelet aggregation by adjunctive cilostazol 100 mg twice daily versus high-MD clopidogrel 150 mg/day in patients treated with elective coronary stenting, according to the CYP2C19 polymorphism.

Intervention(s) in this Clinical Trial

• Drug: cilostazol 100mg bid or clopidogrel 150-mg daily
  • Adjunctive cilostazol: cilostazol 100-mg bid +clopidogrel 75mg daily+aspirin 200mg daily High-MD clopidogrel: clopidogrel 150mg daly +aspirin 200mg daily

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: adjunctive cilostazol
  • adjunctive cilostazol 100mg bid to dual antiplatelet therapy
• Active Comparator: high maintenance-dose clopidogrel
  • double dose of clopidogrel 150mg/day

Primary Measures

• Reduction of maximal platelet aggregation according to CYP 2C19 polymorphism
  • Time Frame: 30-day therapy
    Safety Issue?: No

Secondary Measures

• Reduction of late platelet aggregation, reduction of P2Y12 reaction unit, and the rate of high post-clopidogrel platelet reactivity according to CYP 2C19 polymorphism
  • Time Frame: 30-day therapy
    Safety Issue?: No

Inclusion Criteria:

• Significant coronary artery stenosis (>70% by visual estimate)
• Elective coronary stent implantation

Exclusion Criteria:

• Acute myocardial infarction
• Active bleeding and bleeding diatheses
• Hemodynamic instability
• 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 ≥ 3 mg/dL
• Stroke within 3 months
• Noncardiac disease with a life expectancy < 1 year
• Inability to follow the protocol

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Gyeongsang National University Hospital

Overall Clinical Trial Officials and Contacts

Young-Hoon Jeong, MD, PhD Principal Investigator Gyeongsang National University Hospital  

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01012193

Study ID Number: GNUHIRB-2009-24

ClinicalTrials.gov Identifier: NCT01012193

Health Authority: Korea: Food and Drug Administration