Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction (AMI) Patients According to CYP2C19 Polymorphism

NCT00915733 | Completed Phase 4 DMC

• 1 other identifier: ACCEL-AMI-2C19
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Percutaneous coronary intervention (PCI) with stent implantation is the preferred reperfusion strategy for treatment of acute myocardial infarction (AMI). Despite advances in both devices and pharmacological support for AMI patients undergoing PCI, the risk of recurrent ischemic events has been higher than that of elective PCI. Among therapeutic options for surmounting clopidogrel hyporesponsiveness, higher loading doses and maintenance doses of clopidogrel achieved significant enhancements in the speed of onset and intensity of inhibition and these approaches have been widely adapted in clinical practice. 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, new potent P2Y12 antagonists (such as prasugrel), or other antiplatelet drugs such as cilostazol may be alternative antiplatelet regimens in patients with the loss-of-function CYP variant. 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. 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. The investigators compared the enhanced inhibition of platelet aggregation by adjunctive cilostazol 100 mg twice daily versus high-MD clopidogrel 150 mg/day in AMI patients treated with emergent coronary stenting, according to the CYP2C19 polymorphism.

Conditions

Myocardial Infarction

Keywords

acute myocardial infarction; inhibition of platelet aggregation; triple antiplatelet therapy; high maintenance-dose clopidogrel.; CYP2C19 polymorphism; High posttreatment platelet reactivity; Platelet Aggregation Inhibitors; CYP2C19, human

Outcome Measures

Primary Outcomes (1)

• Absolute reduction of maximal platelet aggregation (Aggmax) by 5 & 20 μM ADP induced LTA

  30 days

Secondary Outcomes (3)

• Absolute reduction of late platelet aggregation (Agglate) by 5 & 20 μM ADP induced LTA

  30 days

• Absolute reduction of P2Y12 reaction unit (PRU)

  30 days

• The rate of high post-treatment platelet reactivity

  30 days

Study Arms (2)

triple group

ACTIVE COMPARATOR

Additive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) in patients with acute myocardial infarction (AMI). Received cilostazol 100 mg twice daily in addition to aspirin 100 mg and clopidogrel 75 mg once daily.

Drug: cilostazol; Drug: clopidogrel (Plavix); Genetic: CYP2C19; Drug: aspirin (Acetylsalicylic acid)

high maintenance dose group

ACTIVE COMPARATOR

High maintenance dose dual antiplatelet therapy in patients with acute myocardial infarction (AMI). Received clopidogrel 150 mg/day with aspirin 100 mg once daily.

Drug: clopidogrel (Plavix); Genetic: CYP2C19; Drug: aspirin (Acetylsalicylic acid)

Interventions

cilostazol DRUG

100 mg twice daily for at least 1 month

Also known as: Otsuka brand of cilostazol

triple group

clopidogrel (Plavix) DRUG

150 mg once daily (high maintenance dose group arm), 75 mg once daily (triple group arm)

Also known as: Plavix

high maintenance dose group; triple group

CYP2C19 GENETIC

CYP2C19 polymorphism study: Two CYP2C19 polymorphisms, CYP2C19\*2 (rs4244285, c. 681G\>A, p.P227P), and CYP2C19\*3 (rs4986893, c. 636G\>A, p. W212X), are investigated using the ABI SNaPshot reaction and the ABI 3100 automated genetic analyzer.

Also known as: Cytochrome 2C19

high maintenance dose group; triple group

aspirin (Acetylsalicylic acid) DRUG

aspirin 100 mg qd

Also known as: Acetylsalicylic acid

high maintenance dose group; triple group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient must be at least 18 years of age.
• clinical symptoms compatible with acute myocardial ischemia within 12 h before admission with a subsequently documented increase in cardiac markers.
• Measured pre-discharge platelet reactivity in case of normalized CK-MB value after coronary stenting.

You may not qualify if:

• A history of active bleeding and bleeding diatheses.
• Oral anticoagulation therapy with coumadin.
• Contraindication to antiplatelet therapy.
• LV ejection fraction \< 30% or NYHA 3/4.
• Leukocyte count \< 3,000/mm3 and/or platelet count \< 100,000/mm3.
• AST or ALT ≥ 3 times upper normal.
• Serum creatinine level ≥ 2.5 mg/dl.
• Stroke within 3 months.
• Non-cardiac disease with a life expectancy \< 1 year.
• Inability to follow the protocol.

Sponsors & Collaborators

• Gyeongsang National University Hospital: lead

Study Sites (1)

Gyeongsang National University Hospital

Jinju, 660-702, South Korea

Location

Related Publications (15)

• Jeong YH, Lee SW, Choi BR, Kim IS, Seo MK, Kwak CH, Hwang JY, Park SW. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol. 2009 Mar 31;53(13):1101-9. doi: 10.1016/j.jacc.2008.12.025.

  PMID: 19324253 RESULT

• Kim IS, Choi BR, Jeong YH, Kwak CH, Kim S. The CYP2C19*2 and CYP2C19*3 polymorphisms are associated with high post-treatment platelet reactivity in Asian patients with acute coronary syndrome. J Thromb Haemost. 2009 May;7(5):897-9. doi: 10.1111/j.1538-7836.2009.03319.x. Epub 2009 Feb 12. No abstract available.

  PMID: 19220726 RESULT

• Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009 May 19;119(19):2553-60. doi: 10.1161/CIRCULATIONAHA.109.851949. Epub 2009 May 4.

  PMID: 19414633 RESULT

• Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009 Jan 24;373(9660):309-17. doi: 10.1016/S0140-6736(08)61845-0. Epub 2008 Dec 26.

  PMID: 19108880 RESULT

• Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. doi: 10.1056/NEJMoa0809171. Epub 2008 Dec 22.

  PMID: 19106084 RESULT

• Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Kim HS, Ko JK, Park JH, Lee JH, Choi SW, Seong IW, Cho YH, Lee NH, Kim JH, Chun KJ, Park SJ. Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Diabetic Patients). J Am Coll Cardiol. 2008 Mar 25;51(12):1181-7. doi: 10.1016/j.jacc.2007.11.049.

  PMID: 18355656 RESULT

• Lee BK, Lee SW, Park SW, Lee SW, Park DW, Kim YH, Lee CW, Hong MK, Kim JJ, Jang S, Chi HS, Park SJ. Effects of triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) on platelet aggregation and P-selectin expression in patients undergoing coronary artery stent implantation. Am J Cardiol. 2007 Aug 15;100(4):610-4. doi: 10.1016/j.amjcard.2007.03.070. Epub 2007 Jun 29.

  PMID: 17697815 RESULT

• Lee SW, Park SW, Hong MK, Kim YH, Lee BK, Song JM, Han KH, Lee CW, Kang DH, Song JK, Kim JJ, Park SJ. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol. 2005 Nov 15;46(10):1833-7. doi: 10.1016/j.jacc.2005.07.048. Epub 2005 Oct 19.

  PMID: 16286167 RESULT

• Angiolillo DJ, Capranzano P, Goto S, Aslam M, Desai B, Charlton RK, Suzuki Y, Box LC, Shoemaker SB, Zenni MM, Guzman LA, Bass TA. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Eur Heart J. 2008 Sep;29(18):2202-11. doi: 10.1093/eurheartj/ehn287. Epub 2008 Jun 21.

  PMID: 18567918 RESULT

• Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation. 2007 Feb 13;115(6):708-16. doi: 10.1161/CIRCULATIONAHA.106.667741. Epub 2007 Jan 29.

  PMID: 17261652 RESULT

• 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. No abstract available.

  PMID: 23517020 DERIVED

• Jeong YH, Tantry US, Park Y, Kwon TJ, Park JR, Hwang SJ, Bliden KP, Koh EH, Kwak CH, Hwang JY, Kim S, Gurbel PA. Pharmacodynamic effect of cilostazol plus standard clopidogrel versus double-dose clopidogrel in patients with type 2 diabetes undergoing percutaneous coronary intervention. Diabetes Care. 2012 Nov;35(11):2194-7. doi: 10.2337/dc11-2351. Epub 2012 Jul 26.

  PMID: 22837373 DERIVED

• Kim IS, Jeong YH, Park Y, Yoon SE, Kwon TJ, Park JR, Hwang SJ, Koh EH, Kwak CH, Hwang JY, Kim S. Interaction analysis between genetic polymorphisms and pharmacodynamic effect in patients treated with adjunctive cilostazol to dual antiplatelet therapy: results of the ACCEL-TRIPLE (Accelerated Platelet Inhibition by Triple Antiplatelet Therapy According to Gene Polymorphism) study. Br J Clin Pharmacol. 2012 Apr;73(4):629-40. doi: 10.1111/j.1365-2125.2011.04131.x.

  PMID: 22007612 DERIVED

• Kim IS, Jeong YH, Park Y, Park KS, Yun SE, Park JR, Hwang SJ, Koh EH, Kwak CH, Hwang JY, Kim S. Platelet inhibition by adjunctive cilostazol versus high maintenance-dose clopidogrel in patients with acute myocardial infarction according to cytochrome P450 2C19 genotype. JACC Cardiovasc Interv. 2011 Apr;4(4):381-91. doi: 10.1016/j.jcin.2010.12.010.

  PMID: 21511217 DERIVED

• 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.

  PMID: 20650435 DERIVED

MeSH Terms

Conditions

Myocardial Infarction

Interventions

Cilostazol; Clopidogrel; Cytochrome P-450 CYP2C19; CYP2C19 protein, human; Aspirin

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Limonene Hydroxylases; Cytochrome P450 Family 2; Cytochrome P-450 Enzyme System; Cytochromes; Enzymes and Coenzymes; Mixed Function Oxygenases; Oxygenases; Oxidoreductases; Enzymes; Hemeproteins; Proteins; Amino Acids, Peptides, and Proteins; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• In-Suk Kim, MD.PhD.

  Gyeongsang National University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: June 5, 2009
• First Posted: June 8, 2009
• Study Start: May 1, 2009
• Primary Completion: October 1, 2009
• Study Completion: November 1, 2009
• Last Updated: November 10, 2009

Record last verified: 2009-11

Locations

KR (1)