Adjunctive Cilostazol Versus High Maintenance-dose Clopidogrel According to Cytochrome 2C19 Polymorphism

Phase 4

Completed

• Conditions: Coronary Artery Disease; Percutaneous Coronary Intervention
• Interventions: Drug: cilostazol 100mg bid or clopidogrel 150-mg daily

• Registration Number: NCT01012193
• Lead Sponsor: Gyeongsang National University Hospital

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 2008-01
• Primary Completion: 2009-07
• Study Completion: 2009-09
• Study First Submitted: 2009-11-10
• Study First Submitted QC: 2009-11-10
• Study First Posted: 2009-11-11
• Status Verified: 2011-05
• Last Update Submitted: 2011-05-15
• Last Update Posted: 2011-05-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 134

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
adjunctive cilostazol	cilostazol 100mg bid or clopidogrel 150-mg daily	adjunctive cilostazol 100mg bid to dual antiplatelet therapy
high maintenance-dose clopidogrel	cilostazol 100mg bid or clopidogrel 150-mg daily	double dose of clopidogrel 150mg/day

Primary Outcome Measures

Name	Time	Method
Reduction of maximal platelet aggregation according to CYP 2C19 polymorphism	30-day therapy

Secondary Outcome Measures

Name	Time	Method
Reduction of late platelet aggregation, reduction of P2Y12 reaction unit, and the rate of high post-clopidogrel platelet reactivity according to CYP 2C19 polymorphism	30-day therapy

Trial Locations

Locations (1)

Gyeongsang National University Hospital; 🇰🇷 Jinju, Gyeongsangnam-do, Korea, Republic of