Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

Clinical Pharmacokinetics

Volumn 54, Issue 2, 2015, Pages 147-166

  Jiang, Xi Ling ^a   Samant, Snehal ^a   Lesko, Lawrence J ^a   Schmidt, Stephan ^a  

^a UNIVERSITY OF FLORIDA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; ARYLDIALKYLPHOSPHATASE 1; CALCIUM CHANNEL BLOCKING AGENT; CLOPIDOGREL; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; PROTON PUMP INHIBITOR; SEROTONIN UPTAKE INHIBITOR; CYP2C19 PROTEIN, HUMAN; CYTOCHROME P-450 CYP2C19; PURINERGIC P2Y RECEPTOR ANTAGONISTS; TICLOPIDINE;

AGE; ANTICOAGULANT THERAPY; AREA UNDER THE CURVE; BODY WEIGHT; CHRONIC KIDNEY DISEASE; CLINICAL ASSESSMENT; CLINICAL TRIAL (TOPIC); CONCENTRATION RESPONSE; DIABETES MELLITUS; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG TRANSFORMATION; GENE FREQUENCY; GENETIC POLYMORPHISM; GENETIC VARIABILITY; HOMOZYGOTE; HUMAN; MAXIMUM PLASMA CONCENTRATION; META ANALYSIS (TOPIC); PATIENT COMPLIANCE; PHARMACODYNAMICS; PHARMACOKINETICS; PLASMA CONCENTRATION-TIME CURVE; PLATELET REACTIVITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RACE; REVIEW; SIGNAL TRANSDUCTION; THROMBOCYTE ACTIVATION; THROMBOCYTE AGGREGATION; THROMBOCYTE FUNCTION; TREATMENT RESPONSE; ACUTE CORONARY SYNDROME; ANALOGS AND DERIVATIVES; DOSE-RESPONSE RELATIONSHIP, DRUG; GENETICS; HUMANS; INDIVIDUALIZED MEDICINE; METABOLISM; POLYMORPHISM, GENETIC;

ACUTE CORONARY SYNDROME; CYTOCHROME P-450 CYP2C19; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; INDIVIDUALIZED MEDICINE; POLYMORPHISM, GENETIC; PURINERGIC P2Y RECEPTOR ANTAGONISTS; TICLOPIDINE;

EID: 84925488457     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.1007/s40262-014-0230-6     Document Type: Review

References (200)

1. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment 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.
2. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Executive summary: heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125(1):188–97.
3. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49(14):1505–16.
4. Kelly RP, Close SL, Farid NA, Winters KJ, Shen L, Natanegara F, 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.
5. Boggon R, van Staa TP, Timmis A, Hemingway H, Ray KK, Begg A, et al. Clopidogrel discontinuation after acute coronary syndromes: frequency, predictors and associations with death and myocardial infarction—a hospital registry-primary care linked cohort (MINAP-GPRD). Eur Heart J. 2011;32(19):2376–86.
6. Eshaghian S, Kaul S, Amin S, Shah PK, Diamond GA. Role of clopidogrel in managing atherothrombotic cardiovascular disease. Ann Intern Med. 2007;146(6):434–41.
7. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494–502.
8. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60(7):645–81.
9. American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78–140.
10. Perry CG, Shuldiner AR. Pharmacogenomics of anti-platelet therapy: how much evidence is enough for clinical implementation? J Hum Genet. 2013;58(6):339–45.
11. Gurbel PA, Tantry US. Clopidogrel resistance? Thromb Res. 2007;120(3):311–21.
12. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, 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.
13. US Food and Drug Administration (FDA). FDA drug safety communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. Rockville: FDA; 2010.
14. Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302(8):849–57.
15. Siller-Matula JM, Delle-Karth G, Lang IM, Neunteufl T, Kozinski M, Kubica J, et al. Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. J Thromb Haemost. 2012;10(4):529–42.
16. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363–75.
17. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, 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.
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(4):354–62.
19. Frelinger AL 3rd, Bhatt DL, Lee RD, Mulford DJ, Wu J, Nudurupati S, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;61(8):872–9.
20. Sanofi Pharmaceuticals. Plavix® US Prescribing Information [CLO-FPLR-SL-DEC13]. 2013. http://products.sanofi.us/plavix/plavix.html. Accessed 23 Dec 2014.
21. Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N, Goeser T, et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006;80(5):486–501.
22. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker 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(12):919–33.
23. Zhu HJ, Wang X, Gawronski BE, Brinda BJ, Angiolillo DJ, Markowitz JS. Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation. J Pharmacol Exp Ther. 2013;344(3):665–72.
24. Bouman HJ, Schomig E, van Werkum JW, Velder J, Hackeng CM, Hirschhauser C, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2011;17(1):110–6.
25. Peer CJ, Spencer SD, VanDenBerg DA, Pacanowski MA, Horenstein RB, Figg WD. A sensitive and rapid ultra HPLC–MS/MS method for the simultaneous detection of clopidogrel and its derivatized active thiol metabolite in human plasma. J Chromatogr B Anal Technol Biomed Life Sci. 2012;880(1):132–9.
26. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig A. 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.
27. Caplain H, Donat F, Gaud C, Necciari J. Pharmacokinetics of clopidogrel. Semin Thromb Hemost. 1999;25(Suppl 2):25–8.
28. Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA, et al. Prasugrel achieves greater and faster P2Y12 receptor-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.
29. Collet JP, Hulot JS, Anzaha G, Pena A, Chastre T, Caron C, et al. High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2). JACC Cardiovasc Interv. 2011;4(4):392–402.
30. Horenstein RB, Madabushi R, Zineh I, Yerges-Armstrong LM, Peer CJ, Schuck RN, et al. Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers. J Clin Pharmacol. 2014;54(8):865–73.
31. Small DS, Farid NA, Payne CD, Konkoy CS, Jakubowski JA, Winters KJ, et al. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of prasugrel. Clinical Pharmacokinetics. 2010;49(12):777–98.
32. Linden MD, Tran H, Woods R, Tonkin A. High platelet reactivity and antiplatelet therapy resistance. Semin Thromb Hemost. 2012;38(2):200–12.
33. Ait-Mokhtar O, Bonello L, Benamara S, Paganelli F. High on treatment platelet reactivity. Heart Lung Circ. 2012;21(1):12–21.
34. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol. 2007;50(19):1822–34.
35. Cattaneo M, Hayward CP, Moffat KA, Pugliano MT, Liu Y, Michelson AD. Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: a report from the Platelet Physiology Subcommittee of the SSC of the ISTH. J Thromb Haemost. 2009;7(6):1029.
36. Sibbing D, Byrne RA, Bernlochner I, Kastrati A. High platelet reactivity and clinical outcome—fact and fiction. Thromb Haemost. 2011;106(2):191–202.
37. Cuisset T, Frere C, Quilici J, Gaborit B, Castelli C, Poyet R, et al. Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients. Am J Cardiol. 2009;104(8):1078–82.
38. Hochholzer W, Ruff CT, Mesa RA, Mattimore JF, Cyr JF, Lei L, et al. Variability of individual platelet reactivity over time in patients treated with clopidogrel: insights from the ELEVATE-TIMI 56 trial. J Am Coll Cardiol. 2014;64(4):361–8.
39. Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL, et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol. 2012;59(22):1928–37.
40. Park JJ, Park KW, Kang J, Jeon KH, Kang SH, Ahn HS, et al. Genetic determinants of clopidogrel responsiveness in Koreans treated with drug-eluting stents. Int J Cardiol. 2013;163(1):79–86.
41. Hochholzer W, Trenk D, Fromm MF, Valina CM, Stratz C, Bestehorn HP, et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol. 2010;55(22):2427–34.
42. Carlquist JF, Knight S, Horne BD, Huntinghouse JA, Rollo JS, Muhlestein JB, et al. Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes. Thromb Haemost. 2013;109(4):744–54.
43. Roth GA, Morden NE, Zhou W, Malenka DJ, Skinner J. Clopidogrel use and early outcomes among older patients receiving a drug-eluting coronary artery stent. Circ Cardiovasc Qual Outcomes. 2012;5(1):103–12.
44. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):2126–30.
45. Iijima R, Ndrepepa G, Mehilli J, Byrne RA, Schulz S, Neumann FJ, et al. Profile of bleeding and ischaemic complications with bivalirudin and unfractionated heparin after percutaneous coronary intervention. Eur Heart J. 2009;30(3):290–6.
46. Cay S, Cagirci G, Aydogdu S, Balbay Y, Sen N, Maden O, et al. Safety of clopidogrel in older patients: a nonrandomized, parallel-group, controlled, two-centre study. Drugs Aging. 2011;28(2):119–29.
47. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Barrera Ramirez C, Sabate M, Fernandez C, et al. Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted? J Invasive Cardiol. 2004;16(4):169–74.
48. Wagner H, Angiolillo DJ, Ten Berg JM, Bergmeijer TO, Jakubowski JA, Small DS, et al. Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients. J Thromb Thrombolysis. 2014;38(2):127–36.
49. Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet. 2012;51(5):277–304.
50. Jernas M, Olsson B, Arner P, Jacobson P, Sjostrom L, Walley A, et al. Regulation of carboxylesterase 1 (CES1) in human adipose tissue. Biochem Biophys Res Commun. 2009;383(1):63–7.
51. Nagashima S, Yagyu H, Takahashi N, Kurashina T, Takahashi M, Tsuchita T, et al. Depot-specific expression of lipolytic genes in human adipose tissues—association among CES1 expression, triglyceride lipase activity and adiposity. J Atheroscler Thromb. 2011;18(3):190–9.
52. Lancefield T, Clark DJ, Andrianopoulos N, Brennan AL, Reid CM, Johns J, et al. Is there an obesity paradox after percutaneous coronary intervention in the contemporary era? An analysis from a multicenter Australian registry. JACC Cardiovasc Interv. 2010;3(6):660–8.
53. Mak KH, Bhatt DL, Shao M, Haffner SM, Hamm CW, Hankey GJ, et al. The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease. Eur Heart J. 2009;30(7):857–65.
54. Sarno G, Garg S, Onuma Y, Buszman P, Linke A, Ischinger T, et al. The impact of body mass index on the one year outcomes of patients treated by percutaneous coronary intervention with biolimus- and sirolimus-eluting stents (from the LEADERS trial). Am J Cardiol. 2010;105(4):475–9.
55. Ang L, Palakodeti V, Khalid A, Tsimikas S, Idrees Z, Tran P, et al. Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel. J Am Coll Cardiol. 2008;52(13):1052–9.
56. Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy SA, Cannon CP, et al. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298(7):765–75.
57. Kassimis G, Davlouros P, Xanthopoulou I, Stavrou EF, Athanassiadou A, Alexopoulos D. CYP2C19*2 and other genetic variants affecting platelet response to clopidogrel in patients undergoing percutaneous coronary intervention. Thromb Res. 2012;129(4):441–6.
58. Bouman HJ, Harmsze AM, van Werkum JW, Breet NJ, Bergmeijer TO, Ten Cate H, et al. Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting. Heart. 2011;97(15):1239–44.
59. Feit F, Voeltz MD, Attubato MJ, Lincoff AM, Chew DP, Bittl JA, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 trial. Am J Cardiol. 2007;100(9):1364–9.
60. Jaitner J, Morath T, Byrne RA, Braun S, Gebhard D, Bernlochner I, et al. No association of ABCB1 C3435T genotype with clopidogrel response or risk of stent thrombosis in patients undergoing coronary stenting. Circ Cardiovasc Interv. 2012;5(1):82–8 (S1–2).
61. Harmsze AM, van Werkum JW, Ten Berg JM, Zwart B, Bouman HJ, Breet NJ, et al. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J. 2010;31(24):3046–53.
62. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315(5811):525–8.
63. Harmsze AM, Robijns K, van Werkum JW, Breet NJ, Hackeng CM, Ten Berg JM, et al. The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response. Thromb Haemost. 2010;103(5):920–5.
64. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, 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.
65. Delaney JT, Ramirez AH, Bowton E, Pulley JM, Basford MA, Schildcrout JS, et al. Predicting clopidogrel response using DNA samples linked to an electronic health record. Clin Pharmacol Ther. 2012;91(2):257–63.
66. Su J, Xu J, Li X, Zhang H, Hu J, Fang R, et al. ABCB1 C3435T polymorphism and response to clopidogrel treatment in coronary artery disease (CAD) patients: a meta-analysis. PLoS One. 2012;7(10):e46366.
67. Luo M, Li J, Xu X, Sun X, Sheng W. ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: a meta-analysis. Thromb Res. 2012;129(6):754–9.
68. Lewis JP, Horenstein RB, Ryan K, O’Connell JR, Gibson Q, Mitchell BD, et al. The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. Pharmacogenet Genomics. 2013;23(1):1–8.
69. Geshi E, Kimura T, Yoshimura M, Suzuki H, Koba S, Sakai T, et al. A single nucleotide polymorphism in the carboxylesterase gene is associated with the responsiveness to imidapril medication and the promoter activity. Hypertens Res. 2005;28(9):719–25.
70. Xie C, Ding X, Gao J, Wang H, Hang Y, Zhang H, et al. The effects of CES1A2 A(−816)C and CYP2C19 loss-of-function polymorphisms on clopidogrel response variability among Chinese patients with coronary heart disease. Pharmacogenet Genomics. 2014;24(4):204–10.
71. Zou JJ, Chen SL, Fan HW, Tan J, He BS, Xie HG. CES1A—816C as a genetic marker to predict greater platelet clopidogrel response in patients with percutaneous coronary intervention. J Cardiovasc Pharmacol. 2014;63(2):178–83.
72. Martis S, Peter I, Hulot JS, Kornreich R, Desnick RJ, Scott SA. Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes. Pharmacogenomics J. 2013;13(4):369–77.
73. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002;41(12):913–58.
74. Pare G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010;363(18):1704–14.
75. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, 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.
76. Gong IY, Crown N, Suen CM, Schwarz UI, Dresser GK, Knauer MJ, et al. Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response. Eur Heart J. 2012;33(22):2856–64.
77. Lewis J, Stephens S, Horenstein R, O’Connell J, Ryan K, Peer C, et al. The CYP2C19*17 variant is not independently associated with clopidogrel response. J Thromb Haemost. 2013;11(9):1640–6.
78. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373(9660):309–17.
79. Hulot JS, Collet JP, Cayla G, Silvain J, Allanic F, Bellemain-Appaix A, et al. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv. 2011;4(5):422–8.
80. Simon T, Bhatt DL, Bergougnan L, Farenc C, Pearson K, Perrin L, et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin Pharmacol Ther. 2011;90(2):287–95.
81. Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia 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(12):1057–64.
82. Sibbing D, Koch W, Massberg S, Byrne RA, Mehilli J, Schulz S, et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J. 2011;32(13):1605–13.
83. Zabalza M, Subirana I, Sala J, Lluis-Ganella C, Lucas G, Tomas M, et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart. 2012;98(2):100–8.
84. Sorich MJ, Polasek TM, Wiese MD. Challenges and limitations in the interpretation of systematic reviews: making sense of clopidogrel and CYP2C19 pharmacogenetics. Clin Pharmacol Ther. 2013;94(3):376–82.
85. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821–30.
86. Gurbel PA, Shuldiner AR, Bliden KP, Ryan K, Pakyz RE, Tantry US. The relation between CYP2C19 genotype and phenotype in stented patients on maintenance dual antiplatelet therapy. Am Heart J. 2011;161(3):598–604.
87. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010;121(4):512–8.
88. Scott SA, Martis S, Peter I, Kasai Y, Kornreich R, Desnick RJ. Identification of CYP2C19*4B: pharmacogenetic implications for drug metabolism including clopidogrel responsiveness. Pharmacogenomics J. 2012;12(4):297–305.
89. Zhang H, Amunugama H, Ney S, Cooper N, Hollenberg PF. Mechanism-based inactivation of human cytochrome P450 2B6 by clopidogrel: involvement of both covalent modification of cysteinyl residue 475 and loss of heme. Mol Pharmacol. 2011;80(5):839–47.
90. Nishiya Y, Hagihara K, Ito T, Tajima M, Miura S, Kurihara A, et al. Mechanism-based inhibition of human cytochrome P450 2B6 by ticlopidine, clopidogrel, and the thiolactone metabolite of prasugrel. Drug Metab Dispos. 2009;37(3):589–93.
91. Turpeinen M, Tolonen A, Uusitalo J, Jalonen J, Pelkonen O, Laine K. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther. 2005;77(6):553–9.
92. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Cavallari U, Trabetti E, et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol. 2006;26(8):1895–900.
93. Suh JW, Koo BK, Zhang SY, Park KW, Cho JY, Jang IJ, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ. 2006;174(12):1715–22.
94. Park KW, Kang J, Park JJ, Yang HM, Lee HY, Kang HJ, et al. Amlodipine, clopidogrel and CYP3A5 genetic variability: effects on platelet reactivity and clinical outcomes after percutaneous coronary intervention. Heart. 2012;98(18):1366–72.
95. Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA. 2008;299(11):1265–76.
96. Park KW, Park JJ, Kang J, Jeon KH, Kang SH, Han JK, et al. Paraoxonase 1 gene polymorphism does not affect clopidogrel response variability but is associated with clinical outcome after PCI. PLoS One. 2013;8(2):e52779.
97. Reny JL, Combescure C, Daali Y, Fontana P, Group PONM-A. Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost. 2012;10(7):1242–51.
98. Kang YH, Lao HY, Wu H, Lai WH, Li XX, Yu XY, et al. Association of PON1 genotype and haplotype with susceptibility to coronary artery disease and clinical outcomes in dual antiplatelet-treated Han Chinese patients. Eur J Clin Pharmacol. 2013;69(8):1511–9.
99. Cavallari U, Trabetti E, Malerba G, Biscuola M, Girelli D, Olivieri O, et al. Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease. BMC Med Genet. 2007;8:59.
100. Fontana P, Dupont A, Gandrille S, Bachelot-Loza C, Reny JL, Aiach M, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation. 2003;108(8):989–95.
101. Staritz P, Kurz K, Stoll M, Giannitsis E, Katus HA, Ivandic BT. Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene. Int J Cardiol. 2009;133(3):341–5.
102. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Cavallari U, Trabetti E, et al. Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Thromb Res. 2005;116(6):491–7.
103. Cuisset T, Frere C, Quilici J, Morange PE, Saut N, Lambert M, et al. Role of the T744C polymorphism of the P2Y12 gene on platelet response to a 600-mg loading dose of clopidogrel in 597 patients with non-ST-segment elevation acute coronary syndrome. Thromb Res. 2007;120(6):893–9.
104. Cayla G, Hulot JS, O’Connor SA, Pathak A, Scott SA, Gruel Y, et al. Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA. 2011;306(16):1765–74.
105. Rudez G, Pons D, Leebeek F, Monraats P, Schrevel M, Zwinderman A, et al. Platelet receptor P2RY12 haplotypes predict restenosis after percutaneous coronary interventions. Hum Mutat. 2008;29(3):375–80.
106. Ziegler S, Schillinger M, Funk M, Felber K, Exner M, Mlekusch W, et al. Association of a functional polymorphism in the clopidogrel target receptor gene, P2Y12, and the risk for ischemic cerebrovascular events in patients with peripheral artery disease. Stroke. 2005;36(7):1394–9.
107. Tang XF, Zhang JH, Wang J, Han YL, Xu B, Qiao SB, et al. Effects of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and clinical outcome in patients with acute coronary syndromes undergoing stent-based coronary intervention. Chin Med J. 2013;126(6):1069–75.
108. Rudez G, Bouman HJ, van Werkum JW, Leebeek FW, Kruit A, Ruven HJ, et al. Common variation in the platelet receptor P2RY12 gene is associated with residual on-clopidogrel platelet reactivity in patients undergoing elective percutaneous coronary interventions. Circ Cardiovasc Genet. 2009;2(5):515–21.
109. Bouman HJ, van Werkum JW, Rudez G, Hackeng CM, Leebeek FW, ten Cate H, et al. The relevance of P2Y12-receptor gene variation for the outcome of clopidogrel-treated patients undergoing elective coronary stent implantation: a clinical follow-up. Thromb Haemost. 2012;107(1):189–91.
110. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Sabate M, Fernandez C, et al. PlA polymorphism and platelet reactivity following clopidogrel loading dose in patients undergoing coronary stent implantation. Blood Coagul Fibrinolysis. 2004;15(1):89–93.
111. Lev EI, Patel RT, Guthikonda S, Lopez D, Bray PF, Kleiman NS. Genetic polymorphisms of the platelet receptors P2Y12, P2Y1 and GP IIIa and response to aspirin and clopidogrel. Thromb Res. 2007;119(3):355–60.
112. Sibbing D, von Beckerath O, Schomig A, Kastrati A, von Beckerath N. P2Y1 gene A1622G dimorphism is not associated with adenosine diphosphate-induced platelet activation and aggregation after administration of a single high dose of clopidogrel. J Thromb Haemost. 2006;4(4):912–4.
113. Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther. 2008;84(3):417–23.
114. Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics. 2010;11(6):781–91.
115. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001;70(2):189–99.
116. Hasan MS, Basri HB, Hin LP, Stanslas J. Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention. Int J Neurosci. 2013;123(3):143–54.
117. Harrison RW, Mahaffey KW. Clopidogrel and PPI interaction: clinically relevant or not? Curr Cardiol Rep. 2012;14(1):49–58.
118. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol. 2010;105(12):2533–49.
119. Ohbuchi M, Noguchi K, Kawamura A, Usui T. Different effects of proton pump inhibitors and famotidine on the clopidogrel metabolic activation by recombinant CYP2B6, CYP2C19 and CYP3A4. Xenobiotica. 2012;42(7):633–40.
120. Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther. 2011;89(1):65–74.
121. Frelinger AL 3rd, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A, et al. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol. 2012;59(14):1304–11.
122. Fontes-Carvalho R, Albuquerque A, Araujo C, Pimentel-Nunes P, Ribeiro VG. Omeprazole, but not pantoprazole, reduces the antiplatelet effect of clopidogrel: a randomized clinical crossover trial in patients after myocardial infarction evaluating the clopidogrel–PPIs drug interaction. Eur J Gastroenterol Hepatol. 2011;23(5):396–404.
123. Furuta T, Iwaki T, Umemura K. Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. Br J Clin Pharmacol. 2010;70(3):383–92.
124. Small DS, Farid NA, Payne CD, Weerakkody GJ, Li YG, Brandt JT, 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.
125. Hulot JS, Wuerzner G, Bachelot-Loza C, Azizi M, Blanchard A, Peyrard S, et al. Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjects. J Thromb Haemost. 2010;8(3):610–3.
126. US Food and Drug Administration (FDA). Information for healthcare professionals: update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert heal.thcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm. Accessed 12 Sept 2014.
127. US Food and Drug Administration (FDA). Plavix (clopidogrel bisulfate) tablets labeling revision. 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020839s055lbl.pdf. Accessed 4 Aug 2013.
128. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–17.
129. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301(9):937–44.
130. Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome—a systematic review. Heart. 2013;99(8):520–7.
131. Siller-Matula JM, Jilma B, Schror K, Christ G, Huber K. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemost. 2010;8(12):2624–41.
132. Gerson LB, McMahon D, Olkin I, Stave C, Rockson SG. Lack of significant interactions between clopidogrel and proton pump inhibitor therapy: meta-analysis of existing literature. Dig Dis Sci. 2012;57(5):1304–13.
133. Feidt DM, Klein K, Hofmann U, Riedmaier S, Knobeloch D, Thasler WE, et al. Profiling induction of cytochrome p450 enzyme activity by statins using a new liquid chromatography–tandem mass spectrometry cocktail assay in human hepatocytes. Drug Metab Dispos. 2010;38(9):1589–97.
134. Howe K, Sanat F, Thumser AE, Coleman T, Plant N. The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes. Xenobiotica. 2011;41(7):519–29.
135. Farid NA, Small DS, Payne CD, Jakubowski JA, Brandt JT, Li YG, et al. Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects. Pharmacotherapy. 2008;28(12):1483–94.
136. Leoncini M, Toso A, Maioli M, Angiolillo DJ, Giusti B, Marcucci R, et al. Pharmacodynamic effects of adjunctive high dose atorvastatin on double dose clopidogrel in patients with high on-treatment platelet reactivity depending on diabetes mellitus status. J Thromb Thrombolysis. 2014;37(4):427–34.
137. Muller I, Besta F, Schulz C, Li Z, Massberg S, Gawaz M. Effects of statins on platelet inhibition by a high loading dose of clopidogrel. Circulation. 2003;108(18):2195–7.
138. Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DC, et al. Absence of interaction between atorvastatin or other statins and clopidogrel: results from the Interaction Study. Arch Intern Med. 2004;164(18):2051–7.
139. Smith SM, Judge HM, Peters G, Storey RF. Multiple antiplatelet effects of clopidogrel are not modulated by statin type in patients undergoing percutaneous coronary intervention. Platelets. 2004;15(8):465–74.
140. Trenk D, Hochholzer W, Frundi D, Stratz C, Valina CM, Bestehorn HP, 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(1):174–81.
141. Geisler T, Schaeffeler E, Dippon J, Winter S, Buse V, Bischofs C, et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics. 2008;9(9):1251–9.
142. Malmstrom RE, Ostergren J, Jorgensen L, Hjemdahl P. Influence of statin treatment on platelet inhibition by clopidogrel—a randomized comparison of rosuvastatin, atorvastatin and simvastatin co-treatment. J Intern Med. 2009;266(5):457–66.
143. Wenaweser P, Eshtehardi P, Abrecht L, Zwahlen M, Schmidlin K, Windecker S, et al. A randomised determination of the effect of fluvastatin and atorvastatin on top of dual antiplatelet treatment on platelet aggregation after implantation of coronary drug-eluting stents. The EFA-Trial. Thromb Haemost. 2010;104(3):554–62.
144. Motovska Z, Widimsky P, Petr R, Bilkova D, Marinov I, Simek S, et al. Factors influencing clopidogrel efficacy in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention: statin’s advantage and the smoking “paradox”. J Cardiovasc Pharmacol. 2009;53(5):368–72.
145. Wenaweser P, Windecker S, Billinger M, Cook S, Togni M, Meier B, 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(3):353–6.
146. Wienbergen H, Gitt AK, Schiele R, Juenger C, Heer T, Meisenzahl C, et al. Comparison of clinical benefits of clopidogrel therapy in patients with acute coronary syndromes taking atorvastatin versus other statin therapies. Am J Cardiol. 2003;92(3):285–8.
147. Lotfi A, Schweiger MJ, Giugliano GR, Murphy SA, Cannon CP. High-dose atorvastatin does not negatively influence clinical outcomes among clopidogrel treated acute coronary syndrome patients—a Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) analysis. Am Heart J. 2008;155(5):954–8.
148. Patti G, Tomai F, Melfi R, Ricottini E, Macri M, Sedati P, et al. Strategies of clopidogrel load and atorvastatin reload to prevent ischemic cerebral events in patients undergoing protected carotid stenting. Results of the randomized ARMYDA-9 CAROTID (Clopidogrel and Atorvastatin Treatment During Carotid Artery Stenting) study. J Am Coll Cardiol. 2013;61(13):1379–87.
149. Katoh M, Nakajima M, Shimada N, Yamazaki H, Yokoi T. Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug–drug interactions. Eur J Clin Pharmacol. 2000;55(11–12):843–52.
150. Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol. 2008;52(19):1557–63.
151. Sarafoff N, Neumann L, Morath T, Bernlochner I, Mehilli J, Schomig A, et al. Lack of impact of calcium-channel blockers on the pharmacodynamic effect and the clinical efficacy of clopidogrel after drug-eluting stenting. Am Heart J. 2011;161(3):605–10.
152. Schmidt M, Johansen MB, Robertson DJ, Maeng M, Kaltoft A, Jensen LO, et al. Use of clopidogrel and calcium channel blockers and risk of major adverse cardiovascular events. Eur J Clin Invest. 2012;42(3):266–74.
153. Good CW, Steinhubl SR, Brennan DM, Lincoff AM, Topol EJ, Berger PB. Is there a clinically significant interaction between calcium channel antagonists and clopidogrel? Results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Circ Cardiovasc Interv. 2012;5(1):77–81.
154. Harmsze AM, van Werkum JW, Souverein PC, Breet NJ, Bouman HJ, Hackeng CM, et al. Combined influence of proton-pump inhibitors, calcium-channel 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(10):1892–901.
155. Harmsze AM, Van Werkum JW, Moral F, Ten Berg JN, Hackeng CM, Klungel OH, et al. Sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients. Platelets. 2011;22(2):98–102.
156. Sibbing D, von Beckerath N, Morath T, Stegherr J, Mehilli J, Sarafoff N, et al. Oral anticoagulation with coumarin derivatives and antiplatelet effects of clopidogrel. Eur Heart J. 2010;31(10):1205–11.
157. Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007;81(5):735–41.
158. Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug–drug interaction. Circulation. 2003;107(1):32–7.
159. Holmberg MT, Tornio A, Neuvonen M, Neuvonen PJ, Backman JT, Niemi M. Grapefruit juice inhibits the metabolic activation of clopidogrel. Clin Pharmacol Ther. 2014;95(3):307–13.
160. Jiang XL, Gonzalez FJ, Yu AM. Drug-metabolizing enzyme, transporter, and nuclear receptor genetically modified mouse models. Drug Metab Rev. 2011;43(1):27–40.
161. Lau WC, Welch TD, Shields T, Rubenfire M, Tantry US, Gurbel PA. The effect of St John’s wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol. 2011;57(1):86–93.
162. Ueno M, Ferreiro JL, Desai B, Tomasello SD, Tello-Montoliu A, Capodanno D, et al. Cigarette smoking is associated with a dose-response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study. JACC Cardiovasc Interv. 2012;5(3):293–300.
163. Bliden KP, Baker BA, Nolin TD, Jeong YH, Bailey WL, Tantry US, et al. Thienopyridine efficacy and cigarette smoking status. Am Heart J. 2013;165(5):693–703.
164. James SH. Hematology pharmacology: anticoagulant, antiplatelet, and procoagulant agents in practice. AACN Adv Crit Care. 2009;20(2):177–92.
165. Lip GY, Huber K, Andreotti F, Arnesen H, Airaksinen JK, Cuisset T, et al. Antithrombotic management of atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing coronary stenting: executive summary—a consensus document of the European Society of Cardiology Working Group on Thrombosis, endorsed by the European Heart Rhythm Association (EHRA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2010;31(11):1311–8.
166. Gao F, Zhou YJ, Wang ZJ, Yang SW, Nie B, Liu XL, et al. Meta-analysis of the combination of warfarin and dual antiplatelet therapy after coronary stenting in patients with indications for chronic oral anticoagulation. Int J Cardiol. 2011;148(1):96–101.
167. Oldgren J, Wallentin L, Alexander JH, James S, Jonelid B, Steg G, et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J. 2013;34(22):1670–80.
168. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107–15.
169. Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ. 2011;183(16):1835–43.
170. Bismuth-Evenzal Y, Gonopolsky Y, Gurwitz D, Iancu I, Weizman A, Rehavi M. Decreased serotonin content and reduced agonist-induced aggregation in platelets of patients chronically medicated with SSRI drugs. J Affect Disord. 2012;136(1–2):99–103.
171. Serebruany VL, Glassman AH, Malinin AI, Nemeroff CB, Musselman DL, van Zyl LT, et al. Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) platelet substudy. Circulation. 2003;108(8):939–44.
172. Delavenne X, Magnin M, Basset T, Piot M, Mallouk N, Ressnikoff D, et al. Investigation of drug–drug interactions between clopidogrel and fluoxetine. Fundam Clin Pharmacol. 2013;27(6):683–9.
173. Spina E, Scordo MG, D’Arrigo C. Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol. 2003;17(5):517–38.
174. Taylor CB, Youngblood ME, Catellier D, Veith RC, Carney RM, Burg MM, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry. 2005;62(7):792–8.
175. Mortensen JK, Larsson H, Johnsen SP, Andersen G. Post stroke use of selective serotonin reuptake inhibitors and clinical outcome among patients with ischemic stroke: a nationwide propensity score-matched follow-up study. Stroke. 2013;44(2):420–6.
176. Ziegelstein RC, Meuchel J, Kim TJ, Latif M, Alvarez W, Dasgupta N, et al. Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes. Am J Med. 2007;120(6):525–30.
177. Maschino F, Hurault-Delarue C, Chebbane L, Fabry V, Montastruc JL, Bagheri H, et al. Bleeding adverse drug reactions (ADRs) in patients exposed to antiplatelet plus serotonin reuptake inhibitor drugs: analysis of the French Spontaneous Reporting Database for a controversial ADR. Eur J Clin Pharmacol. 2012;68(11):1557–60.
178. Kim DH, Daskalakis C, Whellan DJ, Whitman IR, Hohmann S, Medvedev S, et al. Safety of selective serotonin reuptake inhibitor in adults undergoing coronary artery bypass grafting. Am J Cardiol. 2009;103(10):1391–5.
179. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes. 2005;54(8):2430–5.
180. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation. 2011;123(7):798–813.
181. Angiolillo DJ, Bernardo E, Zanoni M, Vivas D, Capranzano P, Malerba G, et al. Impact of insulin receptor substrate-1 genotypes on platelet reactivity and cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol. 2011;58(1):30–9.
182. Erlinge D, Varenhorst C, Braun OO, James S, Winters KJ, Jakubowski JA, et al. Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol. 2008;52(24):1968–77.
183. Bogman K, Silkey M, Chan SP, Tomlinson B, Weber C. Influence of CYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 substrate, in healthy subjects and type 2 diabetes patients. Eur J Clin Pharmacol. 2010;66(10):1005–15.
184. Mizobe M, Hokimoto S, Akasaka T, Arima Y, Kaikita K, Morita K, Miyazaki H, Oniki K, Nakagawa K, Ogawa H. Impact of CYP2C19 polymorphism on clinical outcome following coronary stenting is more important in non-diabetic than diabetic patients. Thromb Res. 2014;134(1):72–7. doi:10.1016/j.thromres.2014.04.020.
185. Basra SS, Tsai P, Lakkis NM. Safety and efficacy of antiplatelet and antithrombotic therapy in acute coronary syndrome patients with chronic kidney disease. J Am Coll Cardiol. 2011;58(22):2263–9.
186. Leng WX, Ren JW, Cao J, Cong YL, Cui H, Hu GL, et al. Chronic kidney disease—is it a true risk factor of reduced clopidogrel efficacy in elderly patients with stable coronary artery disease? Thromb Res. 2013;131(3):218–24.
187. Voisin S, Bongard V, Tidjane MA, Lhermusier T, Carrie D, Sie P. Are P2Y12 reaction unit (PRU) and % inhibition index equivalent for the expression of P2Y12 inhibition by the VerifyNow assay? Role of haematocrit and haemoglobin levels. Thromb Haemost. 2011;106(2):227–9.
188. Tello-Montoliu A, Ferreiro JL, Kodali MK, Ueno M, Tomasello SD, Rollini F, et al. Impact of renal function on clopidogrel-induced antiplatelet effects in coronary artery disease patients without diabetes mellitus. J Thromb Thrombolysis. 2013;36(1):14–7.
189. Motovska Z, Odvodyova D, Fischerova M, Stepankova S, Maly M, Morawska P, et al. Renal function assessed using cystatin C and antiplatelet efficacy of clopidogrel assessed using the vasodilator-stimulated phosphoprotein index in patients having percutaneous coronary intervention. Am J Cardiol. 2012;109(5):620–3.
190. Cuisset T, Frere C, Moro PJ, Quilici J, Pons C, Gaborit B, et al. Lack of effect of chronic kidney disease on clopidogrel response with high loading and maintenance doses of clopidogrel after acute coronary syndrome. Thromb Res. 2010;126(5):e400–2.
191. Baber U, Bander J, Karajgikar R, Yadav K, Hadi A, Theodoropolous K, et al. Combined and independent impact of diabetes mellitus and chronic kidney disease on residual platelet reactivity. Thromb Haemost. 2013;110(1):118–23.
192. Dasgupta A, Steinhubl SR, Bhatt DL, Berger PB, Shao M, Mak KH, et al. Clinical outcomes of patients with diabetic nephropathy randomized to clopidogrel plus aspirin versus aspirin alone [a post hoc analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial]. Am J Cardiol. 2009;103(10):1359–63.
193. Best PJ, Steinhubl SR, Berger PB, Dasgupta A, Brennan DM, Szczech LA, et al. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J. 2008;155(4):687–93.
194. Keltai M, Tonelli M, Mann JF, Sitkei E, Lewis BS, Hawken S, et al. Renal function and outcomes in acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev Rehabil. 2007;14(2):312–8.
195. Morel O, El Ghannudi S, Jesel L, Radulescu B, Meyer N, Wiesel ML, et al. Cardiovascular mortality in chronic kidney disease patients undergoing percutaneous coronary intervention is mainly related to impaired P2Y12 inhibition by clopidogrel. J Am Coll Cardiol. 2011;57(4):399–408.
196. Palmer SC, Di Micco L, Razavian M, Craig JC, Perkovic V, Pellegrini F, et al. Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;156(6):445–59.
197. Bauer T, Gitt AK, Junger C, Zahn R, Koeth O, Towae F, et al. Guideline-recommended secondary prevention drug therapy after acute myocardial infarction: predictors and outcomes of nonadherence. Eur J Cardiovasc Prev Rehabil. 2010;17(5):576–81.
198. Ho PM, Tsai TT, Maddox TM, Powers JD, Carroll NM, Jackevicius C, et al. Delays in filling clopidogrel prescription after hospital discharge and adverse outcomes after drug-eluting stent implantation: implications for transitions of care. Circ Cardiovasc Qual Outcomes. 2010;3(3):261–6.
199. Krueger KP, Felkey BG, Berger BA. Improving adherence and persistence: a review and assessment of interventions and description of steps toward a national adherence initiative. J Am Pharm Assoc. 2003;43(6):668–78 (quiz 678–679).
200. Rinfret S, Rodes-Cabau J, Bagur R, Dery JP, Dorais M, Larose E, et al. Telephone contact to improve adherence to dual antiplatelet therapy after drug-eluting stent implantation. Heart. 2013;99(8):562–9.