Clopidogrel Resistance: Identifying and Overcoming a Barrier to Effective Antiplatelet Treatment

Cardiovascular Therapeutics

Volumn 29, Issue 6, 2011, Pages

  Uchiyama, Shinichiro ^a  

^a TOKYO WOMEN'S MEDICAL UNIVERSITY   (Japan)

Author keywords

Clopidogrel; Clopidogrel resistance; Cytochrome P450; Drug interaction; Platelets; Polymorphism

Indexed keywords

ATORVASTATIN; CILOSTAZOL; CLOPIDOGREL; CYTOCHROME P450; FLUINDOSTATIN; OMEPRAZOLE; PRASUGREL; SIMVASTATIN; TICAGRELOR;

DRUG METABOLISM; DRUG RESISTANCE; DRUG RESPONSE; DRUG STRUCTURE; ENZYME POLYMORPHISM; EVIDENCE BASED PRACTICE; HEART INFARCTION; HUMAN; MORTALITY; PERIPHERAL OCCLUSIVE ARTERY DISEASE; POINT OF CARE TESTING; PRIORITY JOURNAL; REVIEW; THROMBOCYTE AGGREGATION INHIBITION; THROMBOSIS;

ANIMALS; CARDIOVASCULAR DISEASES; CYTOCHROME P-450 ENZYME SYSTEM; DRUG INTERACTIONS; DRUG RESISTANCE; HUMANS; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; POLYMORPHISM, GENETIC; PURINERGIC P2Y RECEPTOR ANTAGONISTS; TICLOPIDINE; TREATMENT FAILURE;

EID: 82355169717     PISSN: 17555914     EISSN: 17555922     Source Type: Journal    
DOI: 10.1111/j.1755-5922.2010.00202.x     Document Type: Review

References (89)

1. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: Response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-2913.
2. Müller I, Besta F, Schulz C, et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003;89:783-787.
3. Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006;4:542-549.
4. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: Results of the CREST Study. J Am Coll Cardiol 2005;46:1827-1832.
5. Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008;29:992-1000.
6. Patti G, Nusca A, Mangiacapra F, et al. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 2008;52:1128-1133.
7. Marcucci R, Gori AM, Paniccia R, 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.
8. Migliorini A, Valenti R, Marcucci R, et al. High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease. Circulation 2009;120:2214-2221.
9. Geisler T, Zürn 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.
10. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171-3175.
11. CAPRIE Study Investigators. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
12. Mehta SR, Yusuf S; Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study Investigators. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J 2000;21:2033-2041.
13. Steinhubl SR, Berger PB, Mann JT III, et al. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 2002;288:2411-2420.
14. Serebruany VL, Steinhubl SR, Berger PB, et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005;45:246-251.
15. Gurbel PA, Tantry US. Clopidogrel resistance? Thromb Res 2007;120:311-321.
16. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-362.
17. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: A new drug-drug interaction. Circulation 2003;107:32-37.
18. Lennon MJ, Gibbs NM, Weightman WM, et al. A comparison of Plateletworks and platelet aggregometry for the assessment of aspirin-related platelet dysfunction in cardiac surgical patients. J Cardiothorac Vasc Anesth 2004;18:136-140.
19. van Werkum JW, Kleibeuker M, Postma S, et al. A comparison between the Plateletworks-assay and light transmittance aggregometry for monitoring the inhibitory effects of clopidogrel. Int J Cardiol 2010;140:123-126.
20. Mach F, Senouf D, Fontana P, et al. Not all statins interfere with clopidogrel during antiplatelet therapy. Eur J Clin Invest 2005;35:476-481.
21. Wenaweser P, Windecker S, Billinger M, et al. Effect of atorvastatin and pravastatin on platelet inhibition by aspirin and clopidogrel treatment in patients with coronary stent thrombosis. Am J Cardiol 2007;99:353-356.
22. Mitsios JV, Papathanasiou AI, Rodis FI, et al. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation 2004;109:1335-1338.
23. Farid NA, Small DS, Payne CD, et al. Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects. Pharmacotherapy 2008;28:1483-1494.
24. Ayalasomayajula SP, Vaidyanathan S, Kemp C, et al. Effect of clopidogrel on the steady-state pharmacokinetics of fluvastatin. J Clin Pharmacol 2007;47:613-619.
25. Malmström RE, Ostergren J, Jørgensen L, et al. Influence of statin treatment on platelet inhibition by clopidogrel-A randomized comparison of rosuvastatin, atorvastatin and simvastatin co-treatment. J Intern Med 2009;266:457-466.
26. Trenk D, Hochholzer W, Frundi D, et al. Impact of cytochrome P450 3A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement. Thromb Haemost 2008;99:174-181.
27. Tan VP, Yan BP, Kiernan TJ, et al. Risk and management of upper gastrointestinal bleeding associated with prolonged dual-antiplatelet therapy after percutaneous coronary intervention. Cardiovasc Revasc Med 2009;10:36-44.
28. Ng FH, Chan P, Kwanching CP, et al. Management and outcome of peptic ulcers or erosions in patients receiving a combination of aspirin plus clopidogrel. J Gastroenterol 2008;43:679-686.
29. Ng FH, Lam KF, Wong SY, et al. Upper gastrointestinal bleeding in patients with aspirin and clopidogrel co-therapy. Digestion 2008;77:173-177.
30. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: The randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256-260.
31. Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol 2009;54:1149-1153.
32. O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet 2009;374:989-997.
33. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-718.
34. Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1-5.
35. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-944.
36. O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet 2009;374:989-997.
37. Evanchan J, Donnally MR, Binkley P, Mazzaferri E. Recurrence of acute myocardial infarction in patients discharged on clopidogrel and a proton pump inhibitor after stent placement for acute myocardial infarction. Clin Cardiol 2010;33:168-171.
38. Bhatt DL, Cryer B, Contant CF, et al.; on behalf of the COGENT Investigators. The COGENT Trial. In Proceedings of the Transcatheter Cardiovascular Therapeutics Annual Congress, San Francisco, USA, 2009.
39. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006;108:2244-2247.
40. Fontana P, Hulot JS, De Moerloose P, et al. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. J Thromb Haemost 2007;5:2153-2155.
41. Frere C, Cuisset T, Morange PE, et al. Effect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008;101:1088-1093.
42. Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 2007;17:1057-1064.
43. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008;51:1925-1934.
44. Takahiro K, Kan C, Tatsuji I. Frequency distribution of CYP2C19, CYP2D6, and CYP2C9 mutant-alleles in several different populations. Xenobiot Metab Dispos 2001;16:69-74.
45. Ozawa S, Soyama A, Saeki M, et al. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokinet 2004;19:83-95.
46. Umemura K, Furuta T, Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J Thromb Haemost 2008;6:1439-1441.
47. Hochholzer W, Trenk D, Bestehorn HP, et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006;48:1742-1750.
48. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: A cohort study. Lancet 2009;373:309-317.
49. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-375.
50. Ganter MT, Hofer CK. Coagulation monitoring: Current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008;106:1366-1375.
51. Reinhöfer M, Brauer M, Franke U, et al. The value of rotation thromboelastometry to monitor disturbed perioperative haemostasis and bleeding risk in patients with cardiopulmonary bypass. Blood Coagul Fibrinolysis 2008;19:212-219.
52. Frelinger AL 3rd, Jakubowski JA, Li Y, et al. The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities. J Thromb Haemost 2008;6:359-365.
53. Lordkipanidzé M, Pharand C, Schampaert E, et al. Evaluation of the platelet count drop method for assessment of platelet function in comparison with "gold standard" light transmission aggregometry. Thromb Res 2009;124:418-422.
54. Pinto Slottow TL, Bonello L, Gavini R, et al. Prevalence of aspirin and clopidogrel resistance among patients with and without drug-eluting stent thrombosis. Am J Cardiol 2009;104:525-530.
55. Kim H, Lee HK, Han K, et al. Prevalence and risk factors for aspirin and clopidogrel resistance in patients with coronary artery disease or ischemic cerebrovascular disease. Ann Clin Lab Sci 2009;39:289-294.
56. Blais N, Pharand C, Lordkipanidzé M, et al. Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, VerifyNow system, platelet count drop, thromboelastography (TEG) and urinary 11-dehydrothromboxane B(2). Thromb Haemost 2009;102:404-411.
57. 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.
58. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48:1339-1345.
59. L'Allier PL, Ducrocq G, Pranno N, et al. Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: Results from the PREPAIR randomized study. J Am Coll Cardiol 2008;51:1066-1072.
60. Angiolillo DJ, Bernardo E, Palazuelos J, et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions. Results of a randomized study. Thromb Haemost 2008;99:161-168.
61. von Beckerath N, Kastrati A, Wieczorek A, et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007;28:1814-1819.
62. Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: A multicenter randomized prospective study. J Am Coll Cardiol 2008;51:1404-1411.
63. Angiolillo DJ, Costa MA, Shoemaker SB, et al. Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment. Am J Cardiol 2008;101:440-445.
64. Aleil B, Jacquemin L, De Poli F, et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: Results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc Interv 2008;1:631-638.
65. Pena A, Collet JP, Hulot JS, et al. Can we override clopidogrel resistance? Circulation 2009;119:2854-2857.
66. Williams ET, Jones KO, Ponsler GD, et al. The biotransformation of prasugrel, a new thienopyri-dine prodrug, by the human carboxylesterases 1 and 2. Drug Metab Dispos 2008;36:1227-1232.
67. Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos 2007;35:1096-1104.
68. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-2015.
69. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007;116:2923-2932.
70. Tamhane U, Meier P, Chetcuti S, et al. Efficacy of Cilostazol in reducing restenosis in patients undergoing contemporary stent based PCI: A meta-analysis of randomised controlled trials. EuroIntervention 2009;5:384-393.
71. Han Y, Li Y, Wang S, et al. Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes: A randomized, controlled study. Am Heart J 2009;157:733-739.
72. Jeong YH, Lee SW, Choi BR, et al. 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;53:1101-1109.
73. Van Giezen JJ, Nilsson L, Berntsson P, et al. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009;7:1556-1565.
74. Storey RF, Melissa Thornton S, Lawrance R, et al. Ticagrelor yields consistent dose-dependent inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in P2RY12, P2RY1, and ITGB3. Platelets 2009;20:341-348.
75. Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): A randomised double-blind study. Lancet 2010;375:283-293.
76. Chen KY, Rha SW, Li YJ, et al. Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 2009;119:3207-3214.
77. Lee SW, Park SW, Hong MK, et al. Triple versus dual antiplatelet therapy after coronary stenting: Impact on stent thrombosis. J Am Coll Cardiol 2005;46:1833-1837.
78. Lee SW, Park SW, Kim YH, et al. Comparison of triple versus dual antiplatelet therapy after drug-eluting stent implantation (from the DECLARE-Long trial). Am J Cardiol 2007;100:1103-1108.
79. Lee SW, Park SW, Kim YH, et al. 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;51:1181-1187.
80. Shim CY, Yoon SJ, Park S, et al. The clopidogrel resistance can be attenuated with triple antiplatelet therapy in patients undergoing drug-eluting stents implantation. Int J Cardiol 2009;134:351-355.
81. Jaremo P, Lindahl TL, Fransson SG, et al. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002;252:233-238.
82. Mobley JE, Bresee SJ, Wortham DC, et al. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol 2004;93:456-458.
83. Lepantalo A, Virtanen KS, Heikkila J, et al. Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J 2004;25:476-483.
84. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 2005;115:101-108.
85. Dziewierz A, Dudek D, Heba G, et al. Inter-individual variability in response to clopidogrel in patients with coronary artery disease. Kardiol Pol 2005;62:108-117.
86. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: The role of dual drug resistance. J Am Coll Cardiol 2006;47:27-33.
87. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005;54:2430-2435.
88. Gurbel PA, Bliden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45:1392-1396.
89. Angiolillo DJ, Capranzano P, Goto S, et al. 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;29:2202-2211.