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

Coronary Artery Disease Clinical Trial

— ACCEL-2C19  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01012193
• Other study ID #: GNUHIRB-2009-24
• Status: Completed
• Phase: Phase 4
• First received: November 10, 2009
• Last updated: May 15, 2011
• Start date: January 2008
• Est. completion date: September 2009

Study information

• Verified date: May 2011
• Source: Gyeongsang National University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Korea: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 134
• Est. completion date: September 2009
• Est. primary completion date: July 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia
• Percutaneous Coronary Intervention

Intervention

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

Locations

Country	Name	City	State
Korea, Republic of	Gyeongsang National University Hospital	Jinju	Gyeongsangnam-do

Sponsors (1)

Lead Sponsor	Collaborator
Gyeongsang National University Hospital

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Reduction of maximal platelet aggregation according to CYP 2C19 polymorphism		30-day therapy	No
Secondary	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	No

External Links

•   Pubmed release of ACCEL study