Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

2015, vol. 24, nr 4, July-August, p. 687–693

doi: 10.17219/acem/27922

Publication type: review article

Language: English

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Creative Commons BY-NC-ND 3.0 Open Access

Most Recent Evidence Behind Aggregometry and Genotyping Methods as Platelet Function Testing for Tailored Anti-Platelet Treatment Among PCI Patients

Sylwia N. Gajda1,A,B,C,D, Łukasz Kołtowski1,A,C,E,F, Mariusz Tomaniak1,C,E

1 1st Department of Cardiology, Public Central Teaching Hospital, Warszawa, Poland

Abstract

Aggregometry and genotyping are methods of platelet function testing, which can be beneficial for high-risk patients undergoing invasive cardiac procedures. An optimal level of platelet reactivity (PR) should be maintained. There are discrepancies between individuals and their response to clopidogrel, accounting for the incidence of poor responders from 5% to 44%. This phenomenon predisposes the patients to increased risk of ischaemic events and thereby overall poorer clinical outcome. Prasugrel and tricagrelor are newer without genetic correlation to their action, however associated with increased bleeding risk. Aggregometry methods assess platelet reactivity at the exact moment of blood sampling. They reflect “phenotype” of the patient and vary after drug administration or dose change. The most popular tests are Light Transmission Aggregometry, Vasodilator-Stimulated Protein, VerifyNow, Multiple Electrode Aggregometry and Thrombelastography. There is proven genetic correlation between some cytochrome enzymes on clopidogrel response. The most widely tested is gene CYP2C19, which produces the enzyme transforming clopidogrel into an active metabolite. The CYP2C19*2 allele carriers have higher PR which can result in more thrombotic events. The manuscript shows the most recent evidence behind platelet function testing. Aggregometry is shown to be beneficial in 5 trials and 1 meta-analysis, while one paper was of different opinion. Ten studies show a positive clinical effect of genotyping on patients’ outcome, while one does not support it. The best method of identifying high-risk individuals could be both methods and personalisation of antiplatelet therapy may decrease adverse ischaemic outcomes.

Key words

clopidogrel, platelet reactivity, aggregometry, PCI.

References (27)

  1. Campo G, Parrinello G, Ferraresi P, Lunghi B, Tebaldi M, Miccoli M, Marchesini J, Bernardi F, Ferrari R, Valgimigli M: Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011, 57, 2474–2483.
  2. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM: Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000, 84, 891–896.
  3. Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P, Pascal M, Herbert JM, Maffrand JP, Picard C: Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 2002, 30, 1288–1295.
  4. Gurbel PA, Tantry US: Clopidogrel resistance? Thromb Res 2007, 120, 311–321.
  5. Aradi D, Storey RF, Komocsi A, Trenk D, Dietrich G, Kiss RG, Husted S, Bonello L, Sibbing D, Collet J, Huber K: Expert poision paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 2014, 35, 209–215.
  6. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P: Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006, 108, 2244–2247.
  7. Siller-Matula JM, Lang I, Christ G, Jilma B: Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008, 52, 1557–1563.
  8. Varenhorst C, James S, Erlinge D, Braun OO, Brandt JT, Winters KJ, Jakubowski JA, Olofsson S, Wallentin L, Siegbahn A: Assessment of P2Y(12) inhibition with the point-of−care device VerifyNow P2Y12 in patients treated with prasugrelor clopidogrel coadministered with aspirin. Am Heart J 2009, 157, 562.e1-9.
  9. Freynhofer MK, Brozovic I, Bruno V, Farhan S, Vogt W, Schomig A, Kastrati A, von Beckerath N: Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events. Thromb Heamost 2011, 106, 230–239.
  10. Sibbing D, Braun S, Morath T, Mehilii J, Vogt W, Schomig A, Kastrati A, von Veckerath N: Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early-eluting stent thrombosis. J Am Coll Cardiol 2009, 53, 849–856.
  11. Jeong YH, Bliden KP, Antonino MJ, Park KS, Tantry US, Gurbel PA: Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogreltherapies. Am Heart J 2012, 164, 35–42.
  12. Sambu N, Radhakrishnan A, Dent H, Calver AL, Corbett S, Gray H, Simpson IA, Curzen N: Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resistance in StentThrombosis (CREST) registry. Heart 2012, 98, 706–711.
  13. Bonello L, Laine M, Baumstarck K, Fernandez J, Maillard L, Peyrol M, Bessereau J, Aradi D, Camilleri E, Roubille F, Piot C, Paganelli F, Camoin-Jau L, Dignat-George F: A randomized trial of platelet reactivity monitoring-adjusted clopidogrel therapy vs. prasugrel therapy to reduce high on-treatment platelet reactivity. Int J Cardiol 2013, 168, 4244–4248.
  14. Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, Tanguay JF, Cannon CP, Topol EJ: Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependentanalysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011, 124, 1132–1137.
  15. Aradi D, Komócsi A, Price MJ, Cuisset T, Ari H, Hazarbasanov D, Trenk D, Sibbing D, Valgimigli M, Bonello L: Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients afterpercutaneous coronary intervention: systematic review and meta-analysis. Int J Cardiol 2013, 167, 2140–2148.
  16. Collet JP, Cuisset T, Rangé G, Cayla G, Elhadad S, Pouillot C, Henry P, Motreff P, Carrié D, Boueri Z, Belle L, Van Belle E, Rousseau H, Aubry P, Monségu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Barthélémy O, Beygui F, Silvain J, Vicaut E, Montalescot G: Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012, 367, 2100–2109.
  17. Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, Wrighton SA, Ring BJ: Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006, 34, 600–607.
  18. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthélémy O, Cayla G, Beygui F, Montalescot G: Cardiovascular risk in clopidogrel treated patients according to cyrochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 2010, 56, 134–143.
  19. Harmsze A, van Werkum JW, Bouman HJ, Ruven HJ, Breet NJ, Ten Berg JM, Hackeng CM, Tjoeng MM, Klungel OH, de Boer A, Deneer VH: Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher onclopidogrel platelet reactivity inpatients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics 2010, 20, 18–25.
  20. 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, 360, 354–362.
  21. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L: Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. N Engl J Med 2009, 360, 363–375.
  22. Mega JL, Hochholzer W, Frelinger AL, Kluk MJ, Angiolillo DJ, Kereiakes DJ, Isserman S, Rogers WJ, Ruff CT, Contant C, Pencina MJ, Scirica BM, Longtine JA, Michelson AD, Sabatine MS: Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stablecardiovascular disease. JAMA 2011, 306, 2221–2228.
  23. Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, Dick A, Marguis JF, O’Brien E, Goncalves S, Druce I, Stewart A, Gollob MH, So DY: Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012, 379, 1705–1711.
  24. Grosdidier C, Quilici J, Loosveld M, Camoin L, Moro PJ, Saut N, Gaborit B, Pankert M, Cohen W, Lambert M, Beguin S, Morange PE, Bonnet JL, Alessi MC, Cuisset T: Effect of CYP2C19*2 and *17 genetic variants on platelet response to clopidogrel and prasugrel maintenance doseand relation to bleeding complications. Am J Cardiol 2013, 111, 985–990.
  25. Siller-Matula JM, Jilma B: Why have studies of tailored antiplatelet therapy failed so far? Thromb Haemost 2013, 110, 628–631.
  26. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, Van Werkum JW, Paganelli F, Price MJ, Waksman R, Gurbel PA: Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. Am J Cardiol 2010, 56, 919–933.
  27. Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, Dick A, Marguis JF, O’Brien E, Goncalves S, Druce I, Stewart A, Gollob MH, So DY: Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective,randomised, proof-of-concept trial. Lancet 2012, 379, 1705–1711.