Pharmacogenomics in cardiovascular disease: Focus on aspirin and ADP receptor antagonists

Journal of Thrombosis and Haemostasis

Volumn 11, Issue 9, 2013, Pages 1627-1639

  Wurtz M ^a   Lordkipanidze M ^b   Grove, E L ^a  

^a AARHUS UNIVERSITY HOSPITAL   (Denmark)

^b UNIVERSITY OF BIRMINGHAM   (United Kingdom)

Author keywords

ADP receptor antagonists; Aspirin; Cardiovascular disease; Clopidogrel; Pharmacogenomics

Indexed keywords

ACETYLSALICYLIC ACID; CLOPIDOGREL; PRASUGREL; TICAGRELOR;

ARTICLE; DRUG EFFICACY; DRUG METABOLISM; FIBRINOLYTIC THERAPY; GENETIC POLYMORPHISM; GENOTYPE; HUMAN; ISCHEMIC HEART DISEASE; PHARMACOGENOMICS; PRIORITY JOURNAL; RECURRENT DISEASE; THROMBOCYTE;

ADP RECEPTOR ANTAGONISTS; ASPIRIN; CARDIOVASCULAR DISEASE; CLOPIDOGREL; PHARMACOGENOMICS;

ASPIRIN; CARDIOVASCULAR DISEASES; HUMANS; PHARMACOGENETICS; PURINERGIC P2Y RECEPTOR ANTAGONISTS; TICLOPIDINE;

EID: 84883768685     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/jth.12318     Document Type: Article

References (102)

1. Grove EL, Storey RF, Wurtz M. Platelet function testing in atherothrombotic disease. Curr Pharm Des 2012; 18: 5379-91.
2. Cattaneo M. Response variability to clopidogrel: is tailored treatment, based on laboratory testing, the right solution? J Thromb Haemost 2012; 10: 327-36.
3. Wurtz M, Grove EL. Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. Curr Pharm Des 2012; 18: 5344-61.
4. O'Donnell CJ, Larson MG, Feng D, Sutherland PA, Lindpaintner K, Myers RH, D'Agostino RA, Levy D, Tofler GH. Genetic and environmental contributions to platelet aggregation: the Framingham heart study. Circulation 2001; 103: 3051-6.
5. Guttmacher AE, Collins FS. Genomic medicine-a primer. N Engl J Med 2002; 347: 1512-20.
6. Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA 2007; 297: 2018-24.
7. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-6.
8. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 2010; 38: 92-9.
9. Wurtz M, Kristensen SD, Hvas AM, Grove EL. Pharmacogenetics of the antiplatelet effect of aspirin. Curr Pharm Des 2012; 18: 5294-308.
10. Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-4.
11. Grove EL, Orntoft TF, Lassen JF, Jensen HK, Kristensen SD. The platelet polymorphism PlA2 is a genetic risk factor for myocardial infarction. J Intern Med 2004; 255: 637-44.
12. Undas A, Sanak M, Musial J, Szczeklik A. Platelet glycoprotein IIIa polymorphism, aspirin, and thrombin generation. Lancet 1999; 353: 982-3.
13. Macchi L, Christiaens L, Brabant S, Sorel N, Ragot S, Allal J, Mauco G, Brizard A. Resistance in vitro to low-dose aspirin is associated with platelet PlA1 (GP IIIa) polymorphism but not with C807T(GP Ia/IIa) and C-5T Kozak (GP Ibalpha) polymorphisms. J Am Coll Cardiol 2003; 42: 1115-19.
14. Lordkipanidze M, Diodati JG, Palisaitis DA, Schampaert E, Turgeon J, Pharand C. Genetic determinants of response to aspirin: appraisal of 4 candidate genes. Thromb Res 2011; 128: 47-53.
15. Goodman T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance: a comprehensive systematic review. Br J Clin Pharmacol 2008; 66: 222-32.
16. Halushka MK, Walker LP, Halushka PV. Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin Pharmacol Ther 2003; 73: 122-30.
17. Maree AO, Curtin RJ, Chubb A, Dolan C, Cox D, O'Brien J, Crean P, Shields DC, Fitzgerald DJ. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 2005; 3: 2340-5.
18. Gonzalez-Conejero R, Rivera J, Corral J, Acuna C, Guerrero JA, Vicente V. Biological assessment of aspirin efficacy on healthy individuals: heterogeneous response or aspirin failure? Stroke 2005; 36: 276-80.
19. Takahashi S, Ushida M, Komine R, Shimodaira A, Uchida T, Ishihara H, Shibano T, Watanabe G, Ikeda Y, Murata M. Platelet responsiveness to in vitro aspirin is independent of COX-1 and COX-2 protein levels and polymorphisms. Thromb Res 2008; 121: 509-17.
20. Higuchi W, Fuse I, Hattori A, Aizawa Y. Mutations of the platelet thromboxane A2 (TXA2) receptor in patients characterized by the absence of TXA2-induced platelet aggregation despite normal TXA2 binding activity. Thromb Haemost 1999; 82: 1528-31.
21. Fujiwara T, Ikeda M, Esumi K, Fujita TD, Kono M, Tokushige H, Hatoyama T, Maeda T, Asai T, Ogawa T, Katsumata T, Sasaki S, Suzuki E, Suzuki M, Hino F, Fujita TK, Zaima H, Shimada M, Sugawara T, Tsuzuki Y, et al. Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity. Pharmacogenomics J 2007; 7: 395-403.
22. Fontana P, Gandrille S, Remones V, Dupont A, Reny JL, Aiach M, Gaussem P. Identification of functional polymorphisms of the thromboxane A2 receptor gene in healthy volunteers. Thromb Haemost 2006; 96: 356-60.
23. Postula M, Kaplon-Cieslicka A, Rosiak M, Kondracka A, Serafin A, Filipiak KJ, Czlonkowski A, Opolski G, Janicki PK. Genetic determinants of platelet reactivity during acetylsalicylic acid therapy in diabetic patients: evaluation of 27 polymorphisms within candidate genes. J Thromb Haemost 2011; 9: 2291-301.
24. Jefferson BK, Foster JH, McCarthy JJ, Ginsburg G, Parker A, Kottke-Marchant K, Topol EJ. Aspirin resistance and a single gene. Am J Cardiol 2005; 95: 805-8.
25. Lev EI, Patel RT, Guthikonda S, Lopez D, Bray PF, Kleiman NS. Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel. Thromb Res 2007; 119: 355-60.
26. Lepantalo A, Mikkelsson J, Resendiz JC, Viiri L, Backman JT, Kankuri E, Karhunen PJ, Lassila R. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 2006; 95: 253-9.
27. Kunicki TJ, Williams SA, Nugent DJ, Harrison P, Segal HC, Syed A, Rothwell PM. Lack of association between aspirin responsiveness and seven candidate gene haplotypes in patients with symptomatic vascular disease. Thromb Haemost 2009; 101: 123-33.
28. Su G, Wang Z, Ding Y. Association of the platelet membrane glycoprotein I a C807T gene polymorphism with aspirin resistance. J Huazhong Univ Sci Technolog Med Sci 2007; 27: 664-7.
29. Douglas H, Davies GJ, Michaelides K, Gorog DA, Timlin H, Ahmed N, Tuddenham EG. Detection of functional differences between different platelet membrane glycoprotein Ibalpha variable number tandem repeat and Kozak genotypes as shown by the PFA-100 system. Heart 2006; 92: 676-8.
30. Kunicki TJ, Williams SA, Salomon DR, Harrison P, Crisler P, Nakagawa P, Mondala TS, Head SR, Nugent DJ. Genetics of platelet reactivity in normal, healthy individuals. J Thromb Haemost 2009; 7: 2116-22.
31. Lewis JP, Ryan K, O'Connell JR, Horenstein RB, Damcott CM, Gibson Q, Pollin TI, Mitchell BD, Beitelshees AL, Pakzy R, Tanner K, Parsa A, Tantry US, Bliden KP, Post WS, Faraday N, Herzog W, Gong Y, Pepine CJ, Johnson JA, et al. Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes. Circ Cardiovasc Genet 2013; 6: 184-92.
32. Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci U S A 1975; 72: 3073-6.
33. Bjornsson TD, Schneider DE, Berger H Jr. Aspirin acetylates fibrinogen and enhances fibrinolysis. Fibrinolytic effect is independent of changes in plasminogen activator levels. J Pharmacol Exp Ther 1989; 250: 154-61.
34. Ajjan RA, Standeven KF, Khanbhai M, Phoenix F, Gersh KC, Weisel JW, Kearney MT, Ariens RA, Grant PJ. Effects of aspirin on clot structure and fibrinolysis using a novel in vitro cellular system. Arterioscler Thromb Vasc Biol 2009; 29: 712-17.
35. Undas A, Sydor WJ, Brummel K, Musial J, Mann KG, Szczeklik A. Aspirin alters the cardioprotective effects of the factor XIII Val34Leu polymorphism. Circulation 2003; 107: 17-20.
36. Pamukcu B, Oflaz H, Onur I, Hancer V, Yavuz S, Nisanci Y. Impact of genetic polymorphisms on platelet function and aspirin resistance. Blood Coagul Fibrinolysis 2010; 21: 53-6.
37. Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N, Goeser T, Kastrati A, Schomig A, Schomig E. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501.
38. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. 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: 1312-19.
39. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-75.
40. Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009; 302: 849-57.
41. Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor vs. clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: 1320-8.
42. Bouman HJ, Schomig E, van Werkum JW, Velder J, Hackeng CM, Hirschhauser C, Waldmann C, Schmalz HG, ten Berg JM, Taubert D. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 2011; 17: 110-16.
43. Frelinger AL III, Bhatt DL, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A, Lampa M, Brooks JK, Barnard MR, Michelson AD. 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: 872-9.
44. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, Roden DM, Klein TE, Shuldiner AR. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011; 90: 328-32.
45. Fefer P, Matetzky S. The genetic basis of platelet responsiveness to clopidogrel. A critical review of the literature. Thromb Haemost 2011; 106: 203-10.
46. Verschuren JJ, Trompet S, Wessels JA, Guchelaar HJ, de Maat MP, Simoons ML, Jukema JW. A systematic review on pharmacogenetics in cardiovascular disease: is it ready for clinical application? Eur Heart J 2012; 33: 165-75.
47. Varenhorst C, James S, Erlinge D, Brandt JT, Braun OO, Man M, Siegbahn A, Walker J, Wallentin L, Winters KJ, Close SL. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur Heart J 2009; 30: 1744-52.
48. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS, Lachno DR, Salazar D, Winters KJ. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 2429-36.
49. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-62.
50. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-7.
51. Gladding P, Webster M, Zeng I, Farrell H, Stewart J, Ruygrok P, Ormiston J, El-Jack S, Armstrong G, Kay P, Scott D, Gunes A, Dahl ML. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv 2008; 1: 620-7.
52. Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM, Stratz C, Schmiebusch P, Bestehorn HP, Buttner HJ, Neumann FJ. 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: 1925-34.
53. Harmsze A, van Werkum JW, Bouman HJ, Ruven HJ, Breet NJ, ten Berg JM, Hackeng CM, Tjoeng MM, Klungel OH, de Boer A, Deneer VH. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics 2010; 20: 18-25.
54. Mega JL, Hochholzer W, Frelinger AL III, Kluk MJ, Angiolillo DJ, Kereiakes DJ, Isserman S, Rogers WJ, Ruff CT, Contant C, Pencina MJ, Scirica BM, Longtine JA, Michelson AD, Sabatine MS. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011; 306: 2221-8.
55. Cuisset T, Quilici J, Cohen W, Fourcade L, Saut N, Pankert M, Gaborit B, Carrieri P, Morange PE, Bonnet JL, Alessi MC. Usefulness of high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel low responders undergoing coronary stenting for non ST elevation acute coronary syndrome. Am J Cardiol 2011; 108: 760-5.
56. Food and Drug Administration. FDA drug safety communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. 2010. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm. Accessed June 7, 2013.
57. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, 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: 1821-30.
58. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O, Cayla G, Beygui F, Montalescot G. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 2010; 56: 134-43.
59. Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dorrler K, Morath T, Schomig A, Kastrati A, von Beckerath N. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30: 916-22.
60. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309-17.
61. Harmsze AM, van Werkum JW, ten Berg JM, Zwart B, Bouman HJ, Breet NJ, van 't Hof AW, Ruven HJ, Hackeng CM, Klungel OH, de Boer A, Deneer VH NJ. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J 2010; 31: 3046-53.
62. Pare G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KA, Eikelboom JW. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704-14.
63. Bhatt DL, Pare G, Eikelboom JW, Simonsen KL, Emison ES, Fox KA, Steg PG, Montalescot G, Bhakta N, Hacke W, Flather MD, Mak KH, Cacoub P, Creager MA, Berger PB, Steinhubl SR, Murugesan G, Mehta SR, Kottke-Marchant K, Lincoff AM, et al. The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study. Eur Heart J 2012; 33: 2143-50.
64. Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA 2011; 306: 2704-14.
65. Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ 2011; 343: d4588.
66. Zabalza M, Subirana I, Sala J, Lluis-Ganella C, Lucas G, Tomas M, Masia R, Marrugat J, Brugada R, Elosua R. 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: 100-8.
67. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006; 79: 103-13.
68. Frere C, Cuisset T, Gaborit B, Alessi MC, Hulot JS. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost 2009; 7: 1409-11.
69. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schomig A, von Beckerath N, Kastrati A. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010; 121: 512-18.
70. Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, von Beckerath N, Mehilli J, Schomig A, Schuster T, Kastrati A. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost 2010; 8: 1685-93.
71. Wu H, Qian J, Xu J, Sun A, Sun W, Wang Q, Ge J. Besides CYP2C19, PON1 genetic variant influences post-clopidogrel platelet reactivity in Chinese patients. Int J Cardiol 2013; 165: 204-6.
72. Sibbing D, Koch W, Massberg S, Byrne RA, Mehilli J, Schulz S, Mayer K, Bernlochner I, Schomig A, Kastrati A. 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: 1605-13.
73. Hulot JS, Collet JP, Cayla G, Silvain J, Allanic F, Bellemain-Appaix A, Scott SA, Montalescot G. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv 2011; 4: 422-8.
74. Fontana P, James R, Barazer I, Berdague P, Schved JF, Rebsamen M, Vuilleumier N, Reny JL. Relationship between paraoxonase-1 activity, its Q192R genetic variant and clopidogrel responsiveness in the ADRIE study. J Thromb Haemost 2011; 9: 1664-6.
75. Trenk D, Hochholzer W, Fromm MF, Zolk O, Valina CM, Stratz C, Neumann FJ. Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. Circ Cardiovasc Genet 2011; 4: 429-36.
76. Pare G, Ross S, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Fox KA, Eikelboom JW. Effect of PON1 Q192R genetic polymorphism on clopidogrel efficacy and cardiovascular events in the clopidogrel in the unstable angina to prevent recurrent events trial and the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events. Circ Cardiovasc Genet 2012; 5: 250-6.
77. Lewis JP, Horenstein RB, Ryan K, O'Connell JR, Gibson Q, Mitchell BD, Tanner K, Chai S, Bliden KP, Tantry US, Peer CJ, Figg WD, Spencer SD, Pacanowski MA, Gurbel PA, Shuldiner AR. The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. Pharmacogenet Genomics 2013; 23: 1-8.
78. Zhu HJ, Wang X, Gawronski B, Brinda B, Angiolillo D, Markowitz J. Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation. J Pharmacol Exp Ther 2013; 344: 665-72.
79. Fontana P, Dupont A, Gandrille S, Bachelot-Loza C, Reny JL, Aiach M, Gaussem P. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 2003; 108: 989-95.
80. Fontana P, Gaussem P, Aiach M, Fiessinger JN, Emmerich J, Reny JL. P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study. Circulation 2003; 108: 2971-3.
81. 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: 341-5.
82. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Cavallari U, Trabetti E, Sabate M, Jimenez-Quevedo P, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Pignatti PF, Macaya C. Variability in platelet aggregation following sustained aspirin and clopidogrel treatment in patients with coronary heart disease and influence of the 807 C/T polymorphism of the glycoprotein Ia gene. Am J Cardiol 2005; 96: 1095-9.
83. Cuisset T, Frere C, Quilici J, Morange PE, Saut N, Romero-Barra M, Camoin L, Lambert M, Juhan-Vague I, Bonnet JL, Alessi MC. Lack of association between the 807 C/T polymorphism of glycoprotein Ia gene and post-treatment platelet reactivity after aspirin and clopidogrel in patients with acute coronary syndrome. Thromb Haemost 2007; 97: 212-17.
84. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Sabate M, Fernandez C, Stranieri C, Trabetti E, Pignatti PF, Macaya C. PlA polymorphism and platelet reactivity following clopidogrel loading dose in patients undergoing coronary stent implantation. Blood Coagul Fibrinolysis 2004; 15: 89-93.
85. Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, Wrighton SA, Ring BJ. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006; 34: 600-7.
86. Small DS, Farid NA, Payne CD, Weerakkody GJ, Li YG, Brandt JT, Salazar DE, Winters KJ. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008; 48: 475-84.
87. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119: 2553-60.
88. Cuisset T, Loosveld M, Morange PE, Quilici J, Moro PJ, Saut N, Gaborit B, Castelli C, Beguin S, Grosdidier C, Fourcade L, Bonnet JL, Alessi MC. CYP2C19*2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome. JACC Cardiovasc Interv 2012; 5: 1280-7.
89. Bonello L, Armero S, Ait MO, Mancini J, Aldebert P, Saut N, Bonello N, Barragan P, Arques S, Giacomoni MP, Bonello-Burignat C, Bartholomei MN, Dignat-George F, Camoin-Jau L, Paganelli F. Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism. J Am Coll Cardiol 2010; 56: 1630-6.
90. Collet JP, Hulot JS, Anzaha G, Pena A, Chastre T, Caron C, Silvain J, Cayla G, Bellemain-Appaix A, Vignalou JB, Galier S, Barthelemy O, Beygui F, Gallois V, Montalescot G. 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: 392-402.
91. Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL, Schork NJ, Teirstein PS, Topol EJ. 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: 1928-37.
92. Sardella G, Calcagno S, Mancone M, Palmirotta R, Lucisano L, Canali E, Stio RE, Pennacchi M, Di Roma A, Benedetti G, Guadagni F, Biondi-Zoccai G, Fedele F. Pharmacodynamic effect of switching therapy in patients with high on-treatment platelet reactivity and genotype variation with high clopidogrel dose vs. prasugrel: the reset gene trial. Circ Cardiovasc Interv 2012; 5: 698-704.
93. Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, Dick A, Marquis JF, O'Brien E, Goncalves S, Druce I, Stewart A, Gollob MH, So DY. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012; 379: 1705-11.
94. Kim IS, Jeong YH, Park Y, Park KS, Yun SE, Park JR, Hwang SJ, Koh EH, Kwak CH, Hwang JY, Kim S. Platelet inhibition by adjunctive cilostazol vs. high maintenance-dose clopidogrel in patients with acute myocardial infarction according to cytochrome P450 2C19 genotype. JACC Cardiovasc Interv 2011; 4: 381-91.
95. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, Puri S, Robbins M, Garratt KN, Bertrand OF, Stillablower ME, Aragon JR, Kandzari DE, Stinis CT, Lee MS, Manoukian SV, Cannon CP, Schork NJ, Topol EJ. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011; 305: 1097-105.
96. Price MJ, Carson AR, Murray SS, Phillips T, Janel L, Tisch R, Topol EJ, Levy S. First pharmacogenomic analysis using whole exome sequencing to identify novel genetic determinants of clopidogrel response variability: results of the Genotype Information and Functional Testing (GIFT) EXOME study. J Am Coll Cardiol 2012; 59: E9.
97. Gurbel PA, Nolin TD, Tantry US. Clopidogrel efficacy and cigarette smoking status. JAMA 2012; 307: 2495-6.
98. Fuster V, Bhatt DL, Califf RM, Michelson AD, Sabatine MS, Angiolillo DJ, Bates ER, Cohen DJ, Coller BS, Furie B, Hulot JS, Mann KG, Mega JL, Musunuru K, O'Donnell CJ, Price MJ, Schneider DJ, Simon DI, Weitz JI, Williams MS, et al. Guided antithrombotic therapy: current status and future research direction: report on a National Heart, Lung and Blood Institute working group. Circulation 2012; 126: 1645-62.
99. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D, Bax JJ, Auricchio A, Baumgartner 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: 2999-3054.
100. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American college of cardiology foundation/American heart association task force on practice guidelines and the society for cardiovascular angiography and interventions. J Am Coll Cardiol 2011; 58: e44-122.
101. Ferraris VA, Saha SP, Oestreich JH, Song HK, Rosengart T, Reece TB, Mazer CD, Bridges CR, Despotis GJ, Jointer K, Clough ER. 2012 update to the society of thoracic surgeons guideline on use of antiplatelet drugs in patients having cardiac and noncardiac operations. Ann Thorac Surg 2012; 94: 1761-81.
102. Grove EL, Hossain R, Storey RF. Platelet function testing and prediction of procedural bleeding risk. Thromb Haemost 2013; 109: 817-24.