Comparison of Platelet Inhibition With Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel According to Hepatic Cytochrome 2C19 Allele (CYP2C19) Polymorphism (ACCEL2C19)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Stenosis; Maximal Platelet Aggregation; Late Platelet Aggregation; High Post-Treatment Platelet Reactivity	Drug: cilostazol; Drug: clopidogrel; Drug: aspirin	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	80 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Validation of Adjunctive Cilostazol According to CYP2C19 Polymorphism: Prospective, Randomized, Single-Center Trial:
Study Start Date :	May 2009
Estimated Primary Completion Date :	June 2009
Estimated Study Completion Date :	July 2009

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: triple group; received cilostazol 100 mg twice daily in addition to aspirin 100mg and clopidogrel 75mg once daily	Drug: cilostazol; 100mg twice daily for at least 1 month; Other Name: pletaal Drug: aspirin; aspirin 100mg
Active Comparator: high maintenance dose group; received clopidogrel 150 mg/day with aspirin 100mg once daily	Drug: clopidogrel; 75mg once daily (triple group arm) 150mg once daily (high maintenance dose group arm); Other Name: plavix Drug: aspirin; aspirin 100mg

Outcome Measures

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Primary Outcome Measures :

1. Reduction of maximal platelet aggregation [ Time Frame: 30 days ]

Secondary Outcome Measures :

1. Rate of high post-clopidogrel platelet reactivity [ Time Frame: 30 days ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. The patient must be at least 18 years of age
2. Significant coronary artery stenosis (> 70% by visual estimate)
3. Elective coronary stent implantation

Exclusion Criteria:

1. Acute myocardial infarction
2. Hemodynamic instability active bleeding and bleeding diatheses
3. Oral anticoagulation therapy with warfarin,use of peri-procedural glycoprotein IIb/IIIa inhibitors
4. Contraindication to antiplatelet therapy
5. Left ventricular ejection fraction < 30%
6. Leukocyte count < 3,000/mm3, platelet count < 100,000/mm3
7. AST or ALT ≥ 3 times upper normal
8. Serum creatinine level ≥ 2.5 mg/dL
9. stroke within 3 months
10. Noncardiac disease with a life expectancy < 1 year
11. Inability to follow the protocol

Contacts and Locations

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Contacts

Contact: Young-Hoon Jeong, MD, phD	82-55-750-8065	goodoctor@naver.com

Locations

Korea, Republic of
Gyeong-Sang National University Hospital	Not yet recruiting
Jinju, Gyeong-Nam, Korea, Republic of, 660-702
Principal Investigator: Young-Hoon Jeong, MD, PHD

Sponsors and Collaborators

Gyeongsang National University Hospital

Investigators

Principal Investigator:	Young-Hoon Jeong, MD, phD	Gyeong-Sang Natinal University Hospital

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jeong YH, Abadilla KA, Tantry US, Park Y, Koh JS, Kwak CH, Hwang JY, Gurbel PA. Influence of CYP2C19*2 and *3 loss-of-function alleles on the pharmacodynamic effects of standard- and high-dose clopidogrel in East Asians undergoing percutaneous coronary intervention: the results of the ACCEL-DOUBLE-2N3 study. J Thromb Haemost. 2013 Jun;11(6):1194-7. doi: 10.1111/jth.12200.

Jeong YH, Kim IS, Park Y, Kang MK, Koh JS, Hwang SJ, Kwak CH, Hwang JY. Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study. JACC Cardiovasc Interv. 2010 Jul;3(7):731-41. doi: 10.1016/j.jcin.2010.05.007.

Responsible Party:	Young-Hoon Jeong, Gyeongsang National University Hospital
ClinicalTrials.gov Identifier:	NCT00891670 History of Changes
Other Study ID Numbers:	GCS-0901-D
First Posted:	May 1, 2009
Last Update Posted:	May 1, 2009
Last Verified:	April 2009

Keywords provided by Gyeongsang National University Hospital:

CYP2C19 polymorphism; platelet; Adjunctive cilostazol; high maintenance dose clopidogrel; P2Y12 Reaction Unit

Additional relevant MeSH terms:

Coronary Stenosis; Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Aspirin; Ticlopidine; Cilostazol; Clopidogrel; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents

Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neurotransmitter Agents