DOI QR코드

DOI QR Code

Clopidogrel Resistance

클로피도그렐 저항성

  • Jeong, Young-Hoon (Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital)
  • 정영훈 (경상대학교 의학전문대학원 순환기내과학교실)
  • Published : 2013.07.01

Abstract

Platelet activation and aggregation play important roles in ischemic event occurrences in high-risk patients with coronary artery disease (CAD). Dual antiplatelet therapy with aspirin and a $P2Y_{12}$ receptor inhibitor is a key strategy to prevent major adverse cardiovascular events in CAD patients undergoing percutaneous coronary intervention (PCI) or those with acute coronary syndrome (ACS). Interindividual variability in response to aspirin and clopidogrel administration along with the influence of different polymorphisms on platelet reactivity has been demonstrated in healthy subjects or CAD patients. Reduced pharmacodynamic effect and reduced clinical efficacy of clopidogrel have been well documented in PCI or ACS patients carrying a loss-of-function allele of the CYP2C19 gene. In addition, accumulating data from numerous clinical studies underscore the importance of "high on-treatment platelet reactivity (HPR)" as a prognostic risk factor. However, the influence of HPR and/or genotype on clinical outcomes must be assessed in the context of the overall disease risk level (ACS vs. non-ACS, diabetes vs. non-diabetes, and old age), post-PCI time (early vs. late) and ethnicity.

Keywords

References

  1. Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004;113:340-345. https://doi.org/10.1172/JCI20986
  2. Gurbel PA, Bliden KP, DiChiara J, et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) Study. Circulation 2007;115:3156-3164. https://doi.org/10.1161/CIRCULATIONAHA.106.675587
  3. Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010;56:919-933. https://doi.org/10.1016/j.jacc.2010.04.047
  4. Jeong YH, Kim IS, Choi BR, Kwak CH, Hwang JY. The optimal threshold of high post-treatment platelet reactivity could be defined by a point-of-care VerifyNow P2Y12 assay. Eur Heart J 2008;29:2186-2187. https://doi.org/10.1093/eurheartj/ehn313
  5. Kim IS, Jeong YH, Kang MK, et al. Correlation of high post-treatment platelet reactivity assessed by light transmittance aggregometry and the VerifyNow P2Y12 assay. J Thromb Thrombolysis 2010;30:486-495. https://doi.org/10.1007/s11239-010-0484-2
  6. Park Y, Jeong YH, Kim IS, et al. The concordance and correlation of measurements by multiple electrode and light transmittance aggregometries based on the pre-defined cutoffs of high and low on-treatment platelet reactivity. Platelets 2012;23:290-298. https://doi.org/10.3109/09537104.2011.614974
  7. Kim IS, Jeong YH, Tantry US, et al. Relation between the vasodilator-stimulated phosphoprotein phosphorylation assay and light transmittance aggregometry in East Asian patients after high-dose clopidogrel loading. Am Heart J 2013 [In press]. http://dx.doi.org/10.1016/j.ahj.2013.03.030.
  8. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-2913. https://doi.org/10.1161/01.CIR.0000072771.11429.83
  9. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005;45:246-251. https://doi.org/10.1016/j.jacc.2004.09.067
  10. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 2010;38:92-99. https://doi.org/10.1124/dmd.109.029132
  11. Farid NA, Kurihara A, Wrighton SA. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol 2010;50:126-142. https://doi.org/10.1177/0091270009343005
  12. Harmsze AM, van Werkum JW, Souverein PC, et al. Combined influence of proton-pump inhibitors, calciumchannel blockers and CYP2C19*2 on on-treatment platelet reactivity and on the occurrence of atherothrombotic events after percutaneous coronary intervention. J Thromb Haemost 2011;9:1892-1901. https://doi.org/10.1111/j.1538-7836.2011.04483.x
  13. 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;7:897-899. https://doi.org/10.1111/j.1538-7836.2009.03319.x
  14. Kang MK, Jeong YH, Yoon SE, et al. Pre-procedural platelet reactivity after clopidogrel loading in korean patients undergoing scheduled percutaneous coronary intervention. J Atheroscler Thromb 2010;17:1122-1131. https://doi.org/10.5551/jat.4564
  15. Hwang SJ, Jeong YH, Kim IS, et al. The cytochrome 2C19*2 and *3 alleles attenuate response to clopidogrel similarly in East Asian patients undergoing elective percutaneous coronary intervention. Thromb Res 2011; 127:23-28. https://doi.org/10.1016/j.thromres.2010.10.021
  16. Jeong YH, Abadilla KA, Tantry US, et al. Influence of CYP2C19*2 and *3 loss-of-function alleles on 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 Mar 21 [Epub]. http://dx.doi.org/10.1111/ jth.12200.
  17. Park JJ, Park KW, Kang J, et al. Genetic determinants of clopidogrel responsiveness in Koreans treated with drugeluting stents. Int J Cardiol 2013;163:79-86. https://doi.org/10.1016/j.ijcard.2012.09.075
  18. Jeong YH, Tantry US, Kim IS, 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. https://doi.org/10.1161/CIRCINTERVENTIONS.111.962555
  19. Jeong YH, Kim IS, Park Y, et al. 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;3:731-741.
  20. Oh IY, Park KW, Kang SH, et al. Association of cytochrome P450 2C19*2 polymorphism with clopidogrel response variability and cardiovascular events in Koreans treated with drug-eluting stents. Heart 2012;98:139-144. https://doi.org/10.1136/hrt.2011.227272
  21. Aradi D, Komocsi A, Price MJ, et al. Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: systematic review and meta-analysis. Int J Cardiol 2012 Jun 15 [Epub]. http://dx.doi.org/10.1016/ j.ijcard.2012.05.100.
  22. Brar SS, ten Berg J, Marcucci R, et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: a collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011;58:1945-1954. https://doi.org/10.1016/j.jacc.2011.06.059
  23. Kirtane AJ, Parise H, Witzenbichler B, et al. Does platelet function testing add significant incremental risk stratification to unselected patients undergoing DES implantation? the ADAPT-DES Study. J Am Coll Cardiol 2012;59(13 Suppl 1):E292. https://doi.org/10.1016/S0735-1097(12)60293-9
  24. Parodi G, Marcucci R, Valenti R, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 2011;306:1215-1223. https://doi.org/10.1001/jama.2011.1332
  25. Sibbing D, Morath T, Braun S, et al. Clopidogrel response status assessed with Multiplate point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost 2010;103:151-159.
  26. Geisler T, Zurn C, Simonenko R, et al. Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions. Eur Heart J 2010;31:59-66. https://doi.org/10.1093/eurheartj/ehp402
  27. Ahn SG, Lee SH, Yoon JH, et al. Different prognostic significance of high on-treatment platelet reactivity as assessed by the VerifyNow P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction. JACC Cardiovasc Interv 2012;5:259-267. https://doi.org/10.1016/j.jcin.2011.12.009
  28. Park DW, Ahn JM, Song HG, et al. Differential prognostic impact of high on-treatment platelet reactivity among patients with acute coronary syndromes versus stable coronary artery disease undergoing percutaneous coronary intervention. Am Heart J 2013;165:34-42.e1. https://doi.org/10.1016/j.ahj.2012.10.013
  29. Mangiacapra F, Patti G, Peace A, et al. Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 2010;106:619-623. https://doi.org/10.1016/j.amjcard.2010.04.015
  30. Jeong YH, Tantry US, Gurbel PA. Platelet Focus: What is the "East Asian Paradox?" http://www.cardiosource.org/ News-Media/Publications/CardioSource-World-Interventio nal/Platelet-Focus.aspx.
  31. Jeong YH, Lee KH, Yoo SY, Park JH, Suh J, Park KH. Accelerated inhibition on platelet aggregation, inflammation and myonecrosis by adjunctive cilostazol loading in patients with acute coronary syndrome: the results of the ACCEL-LOADING-ACS multicenter randomized trial. J Am Coll Cardiol 2012;59(13 Suppl 1):E455. https://doi.org/10.1016/S0735-1097(12)60456-2
  32. Jin HY, Yang TH, Kim DI, et al. High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting. Int J Cardiol 2012 Jun 9 [Epub]. http://dx.doi.org/10.1016/j.ijcard.2012.04.154.
  33. Park KW, Jeon KH, Kang SH, et al. Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY Study). Am J Cardiol 2011;108: 1556-1563. https://doi.org/10.1016/j.amjcard.2011.07.012
  34. Ko YG, Suh JW, Kim BH, et al. Comparison of 2 point-of-care platelet function tests, VerifyNow Assay and Multiple Electrode Platelet Aggregometry, for predicting early clinical outcomes in patients undergoing percutaneous coronary intervention. Am Heart J 2011;161:383-390. https://doi.org/10.1016/j.ahj.2010.10.036
  35. Suh JW, Lee SP, Park KW, et al. Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol 2011;57:280-289. https://doi.org/10.1016/j.jacc.2010.08.631
  36. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305:1097-1105. https://doi.org/10.1001/jama.2011.290
  37. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy with Prasugrel) Study. J Am Coll Cardiol 2012;59:2159-2164. https://doi.org/10.1016/j.jacc.2012.02.026
  38. Collet JP, Cuisset T, Rangé G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367:2100-2109. https://doi.org/10.1056/NEJMoa1209979
  39. Cuisset T, Cayla G, Frere C, et al. Predictive value of post-treatment platelet reactivity for occurrence of postdischarge bleeding after non-ST elevation acute coronary syndrome: shifting from antiplatelet resistance to bleeding risk assessment? EuroIntervention 2009;5:325-329. https://doi.org/10.4244/51
  40. Sibbing D, Schulz S, Braun S, et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010;8:250-256. https://doi.org/10.1111/j.1538-7836.2009.03709.x
  41. Gurbel PA, Bliden KP, Navickas IA, et al. Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events. Am Heart J 2010;160:346-354. https://doi.org/10.1016/j.ahj.2010.05.034
  42. Bonello L, Mancini J, Pansieri M, et al. Relationship between post-treatment platelet reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving prasugrel. J Thromb Haemost 2012;10:1999-2005. https://doi.org/10.1111/j.1538-7836.2012.04875.x
  43. Mokhtar OA, Lemesle G, Armero S, et al. Relationship between platelet reactivity inhibition and non-CABG related major bleeding in patients undergoing percutaneous coronary intervention. Thromb Res 2010;126:e147-149. https://doi.org/10.1016/j.thromres.2010.01.013
  44. Patti G, Pasceri V, Vizzi V, Ricottini E, Di Sciascio G. Usefulness of platelet response to clopidogrel by pointof- care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding Study). Am J Cardiol 2011; 107:995-1000. https://doi.org/10.1016/j.amjcard.2010.11.025
  45. Tsukahara K, Kimura K, Morita S, et al. Impact of highresponsiveness to dual antiplatelet therapy on bleeding complications in patients receiving drug-eluting stents. Circ J 2010;74:679-685. https://doi.org/10.1253/circj.CJ-09-0601
  46. Parodi G, Bellandi B, Venditti F, et al. Residual platelet reactivity, bleedings, and adherence to treatment in patients having coronary stent implantation treated with prasugrel. Am J Cardiol 2012;109:214-218. https://doi.org/10.1016/j.amjcard.2011.08.034
  47. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010;303:754-762. https://doi.org/10.1001/jama.2010.181
  48. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-2747. https://doi.org/10.1161/CIRCULATIONAHA.110.009449

Cited by

  1. Pharmacotherapy for acute myocardial infarction vol.64, pp.2, 2021, https://doi.org/10.5124/jkma.2021.64.2.139