Ann Lab Med.  2016 Jan;36(1):42-48. 10.3343/alm.2016.36.1.42.

Correlation Between the CYP2C19 Phenotype Status and the Results of Three Different Platelet Function Tests in Cardiovascular Disease Patients Receiving Antiplatelet Therapy: An Emphasis on Newly Introduced Platelet Function Analyzer-200 P2Y Test

• Li S
• Choi JL
• Guo LZ
• Goh RY
• Kim BR
• Woo KS
• Kim MH
• Han JY

• KMID: 2373496
• DOI: http://doi.org/10.3343/alm.2016.36.1.42

Abstract

BACKGROUND
An association has been reported between CYP2C19 polymorphism and the altered antiplatelet activity of clopidogrel. We investigated this association using the newly introduced platelet function analyzer (PFA)-200 (INNOVANCE PFA-200 System; Siemens Healthcare, Germany) P2Y test.
METHODS
Polymorphisms of CYP2C19*2, *3, *17 and the degree of inhibition of platelet function were determined in 83 patients. Three different platelet function tests were used to evaluate the degree of platelet inhibition and to check the association with genotype.
RESULTS
The post-procedure PFA-200 values of extensive metabolizers (EM) patients (285.3+/-38.8) were higher than those of intermediate metabolizers (IM) and poor metabolizers (PM) patients (227.7+/-98.3 and 133.7+/-99.2, respectively; P=0.024). Light transmittance aggregometry (LTA) and the VerifyNow system showed that the post-procedure values for EM patients were lower than those of IM and PM patients (LTA: 24.4+/-15.7, 34.1+/-17.6, and 42.2+/-16.9, respectively, P<0.001; VerifyNow: 133.2+/-60.5, 171.5+/-42.6, and 218.7+/-59.3, respectively, P<0.001). The high residual platelet reactivity (HPR) rates were significantly different among the EM, IM, and PM groups using PFA-200 (PM:IM:EM=82.4:40.6:11.8, P<0.001).
CONCLUSIONS
Approximately, 59.0% of Korean patients with cardiovascular disease receiving clopidogrel had CYP2C19 loss-of-function genotypes classified as IM or PM, and the frequency was similar to the data from Asian people. The PFA-200, LTA, and VerifyNow platelet function tests revealed evidence of a significant association between the efficacy of clopidogrel and CYP2C19 genotypes.

Keyword

CYP2C19; Clopidogrel; PFA-200; LTA; VerifyNow

MeSH Terms

Aged
Cardiovascular Diseases/blood/*drug therapy
Cytochrome P-450 CYP2C19/*genetics/metabolism
Female
Genotype
Humans
Male
Middle Aged
Phenotype
Platelet Aggregation Inhibitors/*therapeutic use
Platelet Function Tests/instrumentation
Polymorphism, Genetic
Ticlopidine/*analogs & derivatives/therapeutic use
Cytochrome P-450 CYP2C19
Platelet Aggregation Inhibitors
Ticlopidine

Figure

• 

  Fig. 1 Study flow diagram.Abbreviations: PCI, percutaneous coronary intervention; EM, extensive metabolizers; IM, intermediate metabolizers; PM, poor metabolizers; LTA, light transmittance aggregometry.

• 

  Fig. 2 The platelet function test values for three different devices, measured post-percutaneous coronary intervention (PCI). (A) PFA-200 (sec); (B) Light transmittance aggregometry (LTA, %); (C) VerifyNow (PRU). Error bars indicate SD.Abbreviations: EM, extensive metabolizers; IM, intermediate metabolizers; PM, poor metabolizers; PRU, P2Y12 reaction unit.

• 

  Fig. 3 The percentage of high platelet reactivity (HPR) measured post-percutaneous coronary intervention (PCI) in different groups. (A) PFA-200; (B) Light transmittance aggregometry (LTA); (C) VerifyNow.

• 

  Fig. 4 Relationships between the results obtained by using PFA-200 (sec) and light transmittance aggregometry (LTA, %) or VerifyNow (PRU) assay systems post-percutaneous coronary intervention (PCI). Correlation coefficient (r) was calculated by using Pearson's method.Abbreviation: PRU, P2Y12 reaction unit.

Reference

1. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol. 2008; 51:1404–1411. PMID: 18387444.

2. Park KJ, Chung HS, Kim SR, Kim HJ, Han JY, Lee SY. Clinical, pharmacokinetic, and pharmacogenetic determinants of clopidogrel resistance in Korean patients with acute coronary syndrome. Korean J Lab Med. 2011; 31:91–94. PMID: 21474982.

3. Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation. 2009; 119:237–242. PMID: 19118249.

4. Ferri N, Corsini A, Bellosta S. Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties. Drugs. 2013; 73:1681–1709. PMID: 24114622.

5. Jeong YH, Tantry US, Kim IS, Koh JS, Kwon TJ, Park Y, et al. Effect of CYP2C19^*2 and ^*3 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin. Circ Cardiovasc Interv. 2011; 4:585–594. PMID: 22045970.

6. Renda G, Zurro M, Malatesta G, Ruggieri B, De Caterina R. Inconsistency of different methods for assessing ex vivo platelet function: relevance for the detection of aspirin resistance. Haematologica. 2010; 95:2095–2101. PMID: 21123440.

7. Lordkipanidzé M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J. 2007; 28:1702–1708. PMID: 17569678.

8. Hu YF, Lu TM, Wu CH, Lin YJ, Chang SL, Lo LW, et al. Differences in high on-treatment platelet reactivity between intra-coronary and peripheral blood after dual anti-platelet agents in patients with coronary artery disease. Thromb Haemost. 2013; 110:124–130. PMID: 23677387.

9. Koessler J, Kobsar AL, Rajkovic MS, Schafer A, Flierl U, Pfoertsch S, et al. The new INNOVANCE® PFA P2Y cartridge is sensitive to the detection of the P2Y12 receptor inhibition. Platelets. 2011; 22:20–27. PMID: 20873965.

10. Choi JL, Li S, Han JY. Platelet function tests: a review of progresses in clinical application. Biomed Res Int. 2014; 2014:456569. PMID: 24895576.

11. Rosiak M, Postula M, Kaplon-Cieslicka A, Kondracka A, Trzepla E, Czlonkowski A, et al. Effect of ASA dose doubling versus switching to clopidogrel on plasma inflammatory markers concentration in patients with type 2 diabetes and high platelet reactivity: the AVOCADO study. Cardiol J. 2013; 20:545–551. PMID: 24469880.

12. Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, et al. High on-treatment platelet reactivity by more than one agonist predicts 12-month follow-up cardiovascular death and non-fatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting. Thromb Haemost. 2010; 104:279–286. PMID: 20508896.

13. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol. 2013; 62:2261–2273. PMID: 24076493.

14. Stimpfle F, Karathanos A, Droppa M, Metzger J, Rath D, Müller K, et al. Impact of point-of-care testing for CYP2C19 on platelet inhibition in patients with acute coronary syndrome and early dual antiplatelet therapy in the emergency setting. Thromb Res. 2014; 134:105–110. PMID: 24856643.

15. Dawson-Saunders B, Trapp RG, editors. Basic and clinical biostatistics. 4th ed. New York: Lange Medical Books/McGraw-Hill;2004.

16. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013; 94:317–323. PMID: 23698643.

17. Nakata T, Miyahara M, Nakatani K, Wada H, Tanigawa T, Komada F, et al. Relationship between CYP2C19 loss-of-function polymorphism and platelet reactivities with clopidogrel treatment in Japanese patients undergoing coronary stent implantation. Circ J. 2013; 77:1436–1444. PMID: 23470885.

18. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360:354–362. PMID: 19106084.

19. Zhang HZ, Kim MH, Han JY, Jeong YH. Defining predictive values using three different platelet function tests for CYP2C19 phenotype status on maintenance dual antiplatelet therapy after PCI. Platelets. 2014; 25:285–291. PMID: 23971745.

20. Janssen PW. Platelet function testing and tailored antiplatelet therapy. J Cardiovasc Transl Res. 2013; 6:316–328. PMID: 23543615.

21. Wheeler GL, Braden GA, Steinhubl SR, Kereiakes DJ, Kottke-Marchant K, Michelson AD, et al. The Ultegra rapid platelet-function assay: comparison to standard platelet function assays in patients undergoing percutaneous coronary intervention with abciximab therapy. Am Heart J. 2002; 143:602–611. PMID: 11923796.

22. van Werkum JW, van der Stelt CA, Seesing TH, Hackeng CM, ten Berg JM. A head-to-head comparison between the VerifyNow P2Y12 assay and light transmittance aggregometry for monitoring the individual platelet response to clopidogrel in patients undergoing elective percutaneous coronary intervention. J Thromb Haemost. 2006; 4:2516–2518. PMID: 16938130.

23. Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010; 303:754–762. PMID: 20179285.