Comparative pharmacokinetics and pharmacodynamics of platelet adenosine diphosphate receptor antagonists and their clinical implications

Clinical Pharmacokinetics

Volumn 51, Issue 7, 2012, Pages 429-442

  Floyd, Christopher N ^a   Passacquale, Gabriella ^a   Ferro, Albert ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

acute coronary syndromes; clopidogrel; pharmacokinetics; pharmacology; platelet ADP receptor antagonists; prasugrel; ticagrelor

Indexed keywords

ACETYLSALICYLIC ACID; ATORVASTATIN; CLOPIDOGREL; CYTOCHROME P450 2C19; DRUG METABOLITE; GLYCOPROTEIN P; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; KETOCONAZOLE; LANSOPRAZOLE; MULTIDRUG RESISTANCE PROTEIN 1; OMEPRAZOLE; PLACEBO; PRASUGREL; PROTON PUMP INHIBITOR; PURINERGIC P2Y12 RECEPTOR; TICAGRELOR;

ACUTE CORONARY SYNDROME; AREA UNDER THE CURVE; BLEEDING; BODY WEIGHT; COMBINATION CHEMOTHERAPY; CORONARY ARTERY DISEASE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG HALF LIFE; DRUG HYDROLYSIS; DRUG INHIBITION; DRUG METABOLISM; DRUG PROTEIN BINDING; DYSPNEA; GENE EXPRESSION; GENETIC POLYMORPHISM; GENETIC VARIABILITY; GENOTYPE; HEART INFARCTION; HUMAN; INTESTINE CELL; KIDNEY FAILURE; LIVER FAILURE; LOADING DRUG DOSE; MAXIMUM PLASMA CONCENTRATION; MONOTHERAPY; OUTCOME ASSESSMENT; PERCUTANEOUS CORONARY INTERVENTION; PRIORITY JOURNAL; REVIEW; THROMBOCYTE ACTIVATION; THROMBOCYTE AGGREGATION INHIBITION; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT RESPONSE;

ADENOSINE; CARDIOVASCULAR DISEASES; HUMANS; PIPERAZINES; PLATELET AGGREGATION INHIBITORS; PURINERGIC P2Y RECEPTOR ANTAGONISTS; THIOPHENES; TICLOPIDINE;

EID: 84861708719     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.2165/11630740-000000000-00000     Document Type: Review

References (93)

1. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 2 (8607): 349-60
2. Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004; 113 (3): 340-5 (Pubitemid 38544175)
3. Kim S, Kunapuli SP. P2Y12 receptor in platelet activation. Platelets 2011; 22 (1): 54-8
4. Zakarija A, Kwaan HC, Moake JL, et al. Ticlopidine-and clopidogrelassociated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008). Kidney Int Suppl 2009; (112): S20-4
5. 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 (2): 126-42
6. Combescure C, Fontana P, Mallouk N, et al. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and metaanalysis. J Thromb Haemost 2010; 8 (5): 923-33
7. 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 (7): 2244-7 (Pubitemid 44497506)
8. Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther 2008; 84 (2): 236-42
9. Giusti B, Gori AM, Marcucci R, et al., Relation of cytochrome P450 2C19 lossof-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 2009; 103 (6): 806-11
10. Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30 (8): 916-22
11. Farid NA, Payne CD, Small DS, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 2007; 81 (5): 735-41 (Pubitemid 46625113)
12. Yun KH, Rhee SJ, Park HY, et al. Effects of omeprazole on the antiplatelet activity of clopidogrel. Int Heart J 2010; 51 (1): 13-6
13. Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008; 48 (4): 475-84 (Pubitemid 351389118)
14. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, doubleblind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51 (3): 256-60
15. Springthorpe B, Bailey A, Barton P, et al. From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett 2007; 17 (21): 6013-8 (Pubitemid 47446193)
16. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent STsegment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 32 (23): 2999-3054
17. National Institute for Health and Clinical Excellence. Technology appraisals TA210: clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of technology appraisal guidance 90). London: NICE, 2010 Dec
18. von Kugelgen I, Harden TK. Molecular pharmacology, physiology, and structure of the P2Y receptors. Adv Pharmacol 2011; 61: 373-415
19. Sanofi-Aventis. Plavix-(clopidogrel bisulphate): package insert [online]. Available from URL: http://products.sanofi.us/plavix/plavix.html [Accessed 2011 Oct 27]
20. Taubert D, von Beckerath N, Grimberg G, et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80 (5): 486-501 (Pubitemid 44767878)
21. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376 (9749): 1312-9
22. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360 (4): 363-75
23. Tang M, Mukundan M, Yang J, et al. Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J Pharmacol Exp Ther 2006; 319 (3): 1467-76
24. 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 (1): 92-9
25. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009; 302 (8): 849-57
26. Holmes Jr DR, Dehmer GJ, Kaul S, et al. ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2010; 56 (4): 321-41
27. Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos 2003; 31 (1): 53-9 (Pubitemid 36735258)
28. 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 (12): 1483-94
29. 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 (9694): 989-97
30. Hsiao FY, Mullins CD, Wen YW, et al. Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome. Pharmacoepidemiol Drug Saf 2011; 20 (10): 1043-9
31. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363 (20): 1909-17
32. Small DS, Farid NA, Li YG, et al. Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Curr Med Res Opin 2008; 24 (8): 2251-7
33. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) trial. Circulation 2005; 112 (19): 2946-50 (Pubitemid 41612296)
34. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358 (9281): 527-33 (Pubitemid 32772726)
35. Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions: the Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005; 26 (8): 804-47
36. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111 (20): 2560-4 (Pubitemid 40740853)
37. 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 (23): 2908-13 (Pubitemid 36736631)
38. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010; 121 (10): 1188-99
39. 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(11): 1215-23
40. Sugunaraj JP, Palaniswamy C, Selvaraj DR, et al. Clopidogrel resistance.AmJ Ther 2010; 17 (2): 210-5
41. Committee CS. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348 (9038): 1329-39
42. Mehta SR, Yusuf S. 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 (24): 2033-41 (Pubitemid 32006217)
43. Steinhubl SR, Berger PB, Mann 3rd JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288 (19): 2411-20 (Pubitemid 35340537)
44. Sofi F, Marcucci R, Gori AM, et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity: an updated meta-analysis. Thromb Haemost 2010; 103 (4): 841-8
45. 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 (25): 3171-5
46. Snoep JD, Hovens MM, Eikenboom JC, et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154 (2): 221-31 (Pubitemid 47069129)
47. Aleil B, Jacquemin L, De Poli F, et al. Clopidogrel 150mg/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 (6): 631-8
48. Mehta SR, Bassand JP, Chrolavicius S, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.NEngl J Med 2010; 363 (10): 930-42
49. Algaier I, Jakubowski JA, Asai F, et al. Interaction of the active metabolite of prasugrel, R-138727, with cysteine 97 and cysteine 175 of the human P2Y12 receptor. J Thromb Haemost 2008; 6 (11): 1908-14
50. Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos 2007; 35 (7): 1096-104 (Pubitemid 46956429)
51. Williams ET, Jones KO, Ponsler GD, et al. The biotransformation of prasugrel, a new thienopyridine prodrug, by the human carboxylesterases 1 and 2. Drug Metab Dispos 2008; 36 (7): 1227-32 (Pubitemid 351929304)
52. Rehmel JL, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006; 34 (4): 600-7
53. Paine MF, Hart HL, Ludington SS, et al. The human intestinal cytochrome P450 "pie". Drug Metab Dispos 2006; 34 (5): 880-6
54. Daiichi Sankyo and Lilly. Effient (prasugrel) box insert [online]. Available from URL: http://pi.lilly.com/us/effient.pdf [Accessed 2011 Oct 28]
55. Kelly RP, Close SL, Farid NA, et al. Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants. Br J Clin Pharmacol 2012; 73 (1): 93-105
56. Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5 (12): 2429-36 (Pubitemid 350154353)
57. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119 (19): 2553-60
58. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20): 2001-15 (Pubitemid 350106708)
59. Small DS, Wrishko RE, Ernest 2nd CS, et al. Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease. J Clin Pharm Ther 2009; 34 (5): 585-94
60. Small DS, Farid NA, Li YG, et al. Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver disease. J Clin Pharm Ther, 2009; 34 (5): 575-83
61. Asai F, Jakubowski JA, Naganuma H, et al. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a single ascending dose study in healthy humans. Platelets 2006; 17 (4): 209-17 (Pubitemid 43890792)
62. Matsushima N, Jakubowski JA, Asai F, et al. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a multiple-dose study in healthy humans. Platelets 2006; 17 (4): 218-26 (Pubitemid 43890793)
63. Small DS, Wrishko RE, Ernest 2nd CS, et al. Effect of age on the pharmacokinetics and pharmacodynamics of prasugrel during multiple dosing: an open-label, single-sequence, clinical trial. Drugs Aging 2009; 26 (9): 781-90
64. AstraZeneca. Brilinta (tigacrelor): package insert [online]. Available from URL: http://www1.astrazeneca-us.com/pi/brilinta.pdf [Accessed 2011 Oct 4]
65. TengR, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 2010; 66 (5): 487-96
66. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 2010; 70 (1): 65-77
67. Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153 (1): 66.e9-16
68. Payne CD, Li YG, Brandt JT, et al. Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects. Platelets 2008; 19 (4): 275-81 (Pubitemid 351874155)
69. Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27 (10): 1166-73
70. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29 (1): 21-30
71. Jakubowski JA, Matsushima N, Asai F, et al. A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharmacol 2007; 63 (4): 421-30 (Pubitemid 46426638)
72. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120 (25): 2577-85
73. Payne CD, Li YG, Small DS, et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007; 50 (5): 555-62 (Pubitemid 350146459)
74. Sugidachi A, Ogawa T, Kurihara A, et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite. J Thromb Haemost 2007; 5 (7): 1545-51 (Pubitemid 46965386)
75. van Giezen J, Berntsson P. AZD6140 displays over 100-fold higher affinity for the P2Y12 receptor vs AZ11702105, a compound indistinguishable from the active metabolite of prasugrel, and is a more potent inhibitor of ADP-induced platelet aggregation [abstract]. Arterioscler Thromb Vasc Biol 2008; 28: 139-40
76. Angiolillo DJ, Badimon JJ, Saucedo JF, et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 trial. Eur Heart J 2011; 32 (7): 838-46
77. van Giezen J, 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 (9): 1556-65
78. Teng R, Oliver S, Hayes MA, et al. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 2010; 38 (9): 1514-21
79. Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet 2010; 3 (6): 556-66
80. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376 (9749): 1320-8
81. Wallentin L, Becker RC, BudajA, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11): 1045-57
82. Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27 (9): 1038-47
83. James SK, Roe MT, Cannon CP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ 2011; 342: d3527
84. 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 (9711): 283-93
85. Steg PG, James S, Harrington RA, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation 2010; 122 (21): 2131-41
86. Mahaffey KW, Wojdyla DM, Carroll K, et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2011; 124 (5): 544-54
87. Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011; 32 (23): 2945-53
88. Storey RF, Becker RC, Harrington RA, et al. Pulmonary function in patients with acute coronary syndrome treated with ticagrelor or clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] Pulmonary Function substudy). Am J Cardiol 2011; 108 (11): 1542-6
89. James S, BudajA, Aylward P, et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2010; 122 (11): 1056-67
90. James S, AngiolilloDJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy fromthe PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010; 31 (24): 3006-16
91. Chernoguz A, Telem DA, Chu E, et al. Cessation of clopidogrel before major abdominal procedures. Arch Surg 2011; 146 (3): 334-9
92. Latib A, Morici N, Cosgrave J, et al. Incidence of bleeding and compliance on prolonged dual antiplatelet therapy (aspirin+thienopyridine) following drugeluting stent implantation. Am J Cardiol 2008; 102 (11): 1477-81
93. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001; 23 (8): 1296-310 (Pubitemid 32804122)