Genotype Guided Versus Conventional Approach in Selection of Oral P2Y12 Receptor Blocker in Chinese Patients Suffering From Acute Coronary Syndrome

Acute Coronary Syndrome Clinical Trial

Official title:

Genotype Guided Versus Conventional Approach in Selection of Oral P2Y12 Receptor Blocker in Chinese Patients Suffering From Acute Coronary Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01994941
• Other study ID #: UW 13-402
• Status: Completed
• Phase: Phase 4
• First received: November 20, 2013
• Last updated: November 30, 2015
• Start date: August 2013
• Est. completion date: August 2015

Study information

• Verified date: November 2015
• Source: The University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Health authority: Hong Kong: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

This study aims to compare the outcome between genotype guided versus clinical guided approach in selection of oral P2Y12 receptor blocker in Chinese patients suffering from acute coronary syndrome.

Description:

Acute coronary syndrome (ACS) is a disease with high mortality, morbidity and economic burden. Usually, it is caused by ischemic heart disease and atherosclerotic plaque rupture in the coronary arteries causing platelet activation, aggregation and thrombus formation. For decades, antiplatelet agents are the cornerstones of management of ACS and dual antiplatelet therapy with aspirin and P2Y12 receptor blocker are standard of care for patients with ACS with or without percutaneous coronary intervention. However, increasing evidence has shown that clopidogrel, which is a type of thienopyridine, has wide inter-individual variability in pharmacokinetic and pharmacodynamic actions which lead to suboptimal antiplatelet effect especially in Asian population. Cytochrome P450 2C19 is an important enzyme for thienopyridine metabolism and genetic polymorphisms of CYP2C19 have been demonstrated to be associated with clopidogrel resistance and ischemic event post percutaneous coronary intervention (1-3). The prevalence of the LOF allele of CYP2C19 is higher in Chinese than in Caucasians (4) and it may lead to the higher degree of clopidogrel resistance in Chinese patients as documented in our previous study (5) and study from another Asian country (6)

In view of the potential limitations of clopidogrel in ACS treatment, American and European guidelines recommend use of newer P2Y12 blockers such as ticagrelor (7) for ACS patients. Though these agents have better anti-ischemic effect, they are associated with increased bleeding risk especially in Chinese patients whom are considered to be more prone to bleeding complications. As a result, local physicians are reluctant in using these potent antiplatelet agents despite their proven clinical efficacy in Caucasian studies. Evidence has shown the correlation between CYP2C19 genotype, platelet reactivity, clinical outcome and currently CYP2C19 genotype is an emerging target in the pharmacogenomic approach in guiding the use of antiplatelet agents. With the advent of rapid genotyping technologies (8), it is anticipated that the appropriate drug can be given to the appropriate patient.

Verigene (Nanosphere, Northbrook, IL) is an FDA approved microarray-based genotyping assay for the rapid detection of cytochrome P450 2C19 polymorphisms from whole blood using nanoparticle probes. It utilises whole blood for detection of single nucleotide polymorphism and the results will be available in 2-4 hours. With proper training and handling, the accuracy is expected to be >99%. (9, 10)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 133
• Est. completion date: August 2015
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age of 18 years or above

• Diagnosis of Acute Coronary Syndrome

• P2Y12 receptor blocker naïve and planning for a loading dose of P2Y12 receptor blocker

Exclusion Criteria:

• Chronic renal failure on dialysis or plan for dialysis within 1 year

• Serious hepatic disease

• Active bleeding disorder

• Contraindicated or allergic to Clopidogrel or ticagrelor

• History of intracranial bleeding

• Women who are pregnant or who are of childbearing potential who do not use adequate contraception

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Syndrome

Intervention

Drug:
• Clopidogrel
A platelet aggregation inhibitor. Also a P2Y12 Receptor Blocker of a drug class Thienopyridine. Increasing evidence has shown that clopidogrel has wide inter-individual variability in pharmacokinetic and pharmacodynamic actions which lead to suboptimal antiplatelet effect especially in Asian population. A standard loading dose of 300mg or 600mg(according to clinical protocol) will be given to patients.
• Ticagrelor
A platelet aggregation inhibitor. Though this agent has better anti-ischemic effects, it is associated with increased bleeding risk especially in Chinese patients whom are considered to be more prone to bleeding complications. A loading dose of 180mg will be used.

Locations

Country	Name	City	State
Hong Kong	Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hospital Authority	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
The University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

References & Publications (8)

Bernlochner I, Mayer K, Morath T, Orban M, Schulz S, Schömig A, Braun S, Kastrati A, Sibbing D. Antiplatelet efficacy of prasugrel in patients with high on-clopidogrel treatment platelet reactivity and a history of coronary stenting. Thromb Haemost. 2013 Mar;109(3):517-24. doi: 10.1160/TH12-08-0552. Epub 2013 Jan 17. — View Citation

Buchan BW, Peterson JF, Cogbill CH, Anderson DK, Ledford JS, White MN, Quigley NB, Jannetto PJ, Ledeboer NA. Evaluation of a microarray-based genotyping assay for the rapid detection of cytochrome P450 2C19 *2 and *3 polymorphisms from whole blood using nanoparticle probes. Am J Clin Pathol. 2011 Oct;136(4):604-8. doi: 10.1309/AJCPCPU9Q2IRNYXC. — View Citation

Chae H, Kim M, Koh YS, Hwang BH, Kang MK, Kim Y, Park HI, Chang K. Feasibility of a microarray-based point-of-care CYP2C19 genotyping test for predicting clopidogrel on-treatment platelet reactivity. Biomed Res Int. 2013;2013:154073. doi: 10.1155/2013/154073. Epub 2013 Mar 28. — View Citation

Chan MY, Tan K, Tan HC, Huan PT, Li B, Phua QH, Lee HK, Lee CH, Low A, Becker RC, Ong WC, Richards MA, Salim A, Tai ES, Koay E. CYP2C19 and PON1 polymorphisms regulating clopidogrel bioactivation in Chinese, Malay and Indian subjects. Pharmacogenomics. 2012 Apr;13(5):533-42. doi: 10.2217/pgs.12.24. — View Citation

Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010 Oct 27;304(16):1821-30. doi: 10.1001/jama.2010.1543. — View Citation

Myrand SP, Sekiguchi K, Man MZ, Lin X, Tzeng RY, Teng CH, Hee B, Garrett M, Kikkawa H, Lin CY, Eddy SM, Dostalik J, Mount J, Azuma J, Fujio Y, Jang IJ, Shin SG, Bleavins MR, Williams JA, Paulauskis JD, Wilner KD. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008 Sep;84(3):347-61. doi: 10.1038/sj.clpt.6100482. Epub 2008 Mar 19. — View Citation

Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232. — View Citation

Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009 Jan 22;360(4):363-75. doi: 10.1056/NEJMoa0808227. Epub 2008 Dec 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Platelet reactivity 24 hours after initial loading of clopidogrel measured by verifyNow P2Y12 assay	Platelet reactivity 24 hours after initial loading of clopidogrel measured by verifyNow P2Y12 assay	24 hours	No
Primary	Platelet reactivity 1 month after initial loading of clopidogrel measured by verifyNow P2Y12 assay	Platelet reactivity 1 month after initial loading of clopidogrel measured by verifyNow P2Y12 assay	1 month	No