High on-treatment platelet reactivity and P2Y12 antagonists in clinical trials

 

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Summary

Dual antiplatelet therapy with aspirin and clopidogrel in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) has substantially decreased the rate of cardiovascular events. Within the past decade, the variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. The variability in response could be linked to genetic polymorphisms impacting on activity of cytochrome P450 enzymes as well as clinical and demographic variables, but, taken together, factors identified so far can explain only up to approximately 12% of this variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. Regulatory agencies as well as major cardiac societies suggest the use of other anti-platelet medications or alternative dosing strategies for clopidogrel in patients with reduced effectiveness of clopidogrel. This review will focus on the current status of alternate strategies for more sufficient suppression of high platelet reactivity.

• References

• 1 Lange RA, Hillis LD. Antiplatelet therapy for ischaemic heart disease. N Engl J Med 2004; 350: 277-280.
  CrossrefPubMedGoogle Scholar
• 2 Lewis Jr HD, Davis JW, Archibald DG. et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a veterans administration cooperative study. N Engl J Med 1983; 309: 396-403.
  CrossrefPubMedGoogle Scholar
• 3 Cairns JA, Gent M, Singer J. et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a canadian multicenter trial. N Engl J Med 1985; 313: 1369-1375.
  CrossrefPubMedGoogle Scholar
• 4 Theroux P, Ouimet H, McCans J. et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319: 1105-1111.
  CrossrefPubMedGoogle Scholar
• 5 Gawaz M, Neumann FJ, Ott I. et al. Platelet function in acute myocardial infarction treated with direct angioplasty. Circulation 1996; 93: 229-237.
  CrossrefPubMedGoogle Scholar
• 6 Neumann FJ, Gawaz M, Ott I. et al. Prospective evaluation of hemostatic predictors of subacute stent thrombosis after coronary palmaz-schatz stenting. J Am Coll Cardiol 1996; 27: 15-21.
  PubMedGoogle Scholar
• 7 Schömig A, Neumann FJ, Kastrati A. et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334: 1084-1089.
  CrossrefPubMedGoogle Scholar
• 8 Bertrand ME, Rupprecht HJ, Urban P. et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102: 624-629.
  CrossrefPubMedGoogle Scholar
• 9 Müller I, Seyfarth M, Rudiger S. et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001; 85: 92-93.
  CrossrefPubMedGoogle Scholar
• 10 The Clopidogrel in Unstable Angina to Prevent Recurrent Ischaemic Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
  CrossrefPubMedGoogle Scholar
• 11 Sabatine MS, Cannon CP, Gibson CM. et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
  CrossrefPubMedGoogle Scholar
• 12 Geisler T, Grass D, Bigalke B. et al. The residual platelet aggregation after deployment of intracoronary stent (PREDICT) score. J Thromb Haemost 2008; 06: 54-61.
  PubMedGoogle Scholar
• 13 von Beckerath N, Taubert D, Pogatsa-Murray G. et al. Absorption, metabolisation, 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: 2946-2950.
  PubMedGoogle Scholar
• 14 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. 66. e9-16
  PubMedGoogle Scholar
• 15 Hulot JS, Collet JP, Montalescot G. Thienopyridine-associated drug-drug interactions: Pharmacologic mechanisms and clinical relevance. Curr Cardiol Rep 2011; 13: 451-458.
  CrossrefPubMedGoogle Scholar
• 16 Geisler T, Schaeffeler E, Dippon J. et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 2008; 09: 1251-1259.
  CrossrefPubMedGoogle Scholar
• 17 Trenk D, Hochholzer W, Fromm MF. et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or baremetal stents. J Am Coll Cardiol 2008; 51: 1925-1934.
  CrossrefPubMedGoogle Scholar
• 18 Hochholzer W, Trenk D, Fromm MF. 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: 2427-2434.
  CrossrefPubMedGoogle Scholar
• 19 Mega JL, Close SL, Wiviott SD. et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
  CrossrefPubMedGoogle Scholar
• 20 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
  Article in Thieme ConnectPubMedGoogle Scholar
• 21 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: 53-59.
  CrossrefPubMedGoogle Scholar
• 22 Kazui M, Nishiya Y, Ishizuka T. et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 2010; 38: 92-99.
  CrossrefPubMedGoogle Scholar
• 23 Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. J Am Coll Cardiol 2011; 57: 1251-1263.
  CrossrefPubMedGoogle Scholar
• 24 Lau WC, Waskell LA, Watkins PB. et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: A new drug-drug interaction. Circulation 2003; 107: 32-37.
  CrossrefPubMedGoogle Scholar
• 25 Trenk D, Hochholzer W, Frundi D. et al. Impact of cytochrome P450 3A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement. Thromb Haemost 2008; 99: 174-181.
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Angiolillo DJ, Gibson CM, Cheng S. 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: 65-74.
  CrossrefPubMedGoogle Scholar
• 27 Bhatt DL, Cryer BL, Contant CF. et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363: 1909-1917.
  CrossrefPubMedGoogle Scholar
• 28 Hulot J-S, Collet J-P, Silvain J. et al. 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: 134-143.
  CrossrefPubMedGoogle Scholar
• 29 Siller-Matula JM, Lang I, Christ G. et al. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008; 52: 1557-1563.
  CrossrefPubMedGoogle Scholar
• 30 Harmsze AM, Robijns K, van Werkum JW. 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: 920-925.
  Article in Thieme ConnectPubMedGoogle Scholar
• 31 Kurihara A, Hagihara K, Kazui M. et al. In vitro metabolism of antiplatelet agent clopidogrel: Cytochrome P450 isoforms responsible for two oxidation steps involved in the active metabolite formation. Drug Metab Rev 2005; 37: 99.
  PubMedGoogle Scholar
• 32 Hulot JS, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-2247.
  CrossrefPubMedGoogle Scholar
• 33 Wedlund PJ. The CYP219 enzyme polymorphism. Pharmacology 2000; 61: 174-183.
  CrossrefPubMedGoogle Scholar
• 34 Desta Z, Zhao X, Shin JG. et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41: 913-958.
  CrossrefPubMedGoogle Scholar
• 35 Collet JP, Hulot JS, Pena A. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: A cohort study. Lancet 2009; 373: 309-317.
  CrossrefPubMedGoogle Scholar
• 36 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: 916-922.
  PubMedGoogle Scholar
• 37 Simon T, Verstuyft C, Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
  CrossrefPubMedGoogle Scholar
• 38 Mega JL, Simon T, Collet JP. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: A meta-analysis. J Am Med Assoc 2010; 304: 1821-1830.
  CrossrefPubMedGoogle Scholar
• 39 Sim SC, Risinger C, Dahl ML. et al. 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: 103-113.
  CrossrefPubMedGoogle Scholar
• 40 Frere C, Cuisset T, Gaborit B. et al. 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; 07: 1409-1411.
  CrossrefPubMedGoogle Scholar
• 41 Sibbing D, Gebhard D, Koch W. et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost 2010; 08: 1685-1693.
  CrossrefPubMedGoogle Scholar
• 42 Harmsze AM, van Werkum JW, Hackeng CM. et al. The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting. Pharmacogenet Genomics 2012; 22: 169-175.
  CrossrefPubMedGoogle Scholar
• 43 Li Y, Tang HL, Hu YF. et al. The gain-of-function variant allele CYP2C19*17: A double-edged sword between thrombosis and bleeding in clopidogrel-treated patients. Journal of Thrombosis and Haemostasis 2012; 10: 199-206.
  CrossrefPubMedGoogle Scholar
• 44 Zabalza M, Subirana I, Sala J. 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: 100-108.
  CrossrefPubMedGoogle Scholar
• 45 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. J Am Med Assoc 2009; 302: 849-857.
  CrossrefPubMedGoogle Scholar
• 46 Taubert D, von Beckerath N, Grimberg G. et al. Impact of p-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501.
  CrossrefPubMedGoogle Scholar
• 47 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. The Lancet 2010; 376: 1320-1328.
  CrossrefPubMedGoogle Scholar
• 48 Luo M, Li J, Xu X. et al. ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: A meta-analysis. Thromb Res 2012; 129: 754-759.
  CrossrefPubMedGoogle Scholar
• 49 Bouman HJ, Schömig E, van Werkum JW. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 2011; 17: 110-116.
  CrossrefPubMedGoogle Scholar
• 50 Sibbing D, Koch W, Massberg 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: 1605-1613.
  CrossrefPubMedGoogle Scholar
• 51 Trenk D, Hochholzer W, Fromm MF. et al. Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. Circ Cardiovasc Genet 2011; 04: 429-436.
  CrossrefPubMedGoogle Scholar
• 52 Reny JL, Combescure C, Daali Y. et al. Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: A systematic review and meta-analysis. J Thrombos Haemostas 2012; 10: 1242-1251.
  PubMedGoogle Scholar
• 53 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
  CrossrefPubMedGoogle Scholar
• 54 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
  CrossrefPubMedGoogle Scholar
• 55 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: 600-607.
  CrossrefPubMedGoogle Scholar
• 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; 05: 2429-2436.
  CrossrefPubMedGoogle Scholar
• 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: 2553-2560.
  CrossrefPubMedGoogle Scholar
• 58 Wiviott SD, Trenk D, Frelinger AL. et al. Prasugrel compared with high loading-and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation-thrombolysis in myocardial infarction 44 trial. Circulation 2007; 116: 2923-2932.
  CrossrefPubMedGoogle Scholar
• 59 Siller-Matula JM, Jilma B. Ticagrelor: From discovery to phase III clinical trial. Future Cardiol 2010; 06: 753-764.
  CrossrefPubMedGoogle Scholar
• 60 Teng R, Oliver S, Hayes MA. et al. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 2010; 38: 1514-1521.
  CrossrefPubMedGoogle Scholar
• 61 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: 2577-2585.
  CrossrefPubMedGoogle Scholar
• 62 Steinhubl SR, Talley JD, Braden GA. et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: Results of the GOLD (AU-assessing ULTEGRA) multicenter study. Circulation 2001; 103: 2572-2578.
  CrossrefPubMedGoogle Scholar
• 63 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: Response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
  CrossrefPubMedGoogle Scholar
• 64 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
  CrossrefPubMedGoogle Scholar
• 65 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
  CrossrefPubMedGoogle Scholar
• 66 Barragan P, Bouvier JL, Roquebert PO. et al. Resistance to thienopyridines: Clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003; 59: 295-302.
  CrossrefPubMedGoogle Scholar
• 67 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
  CrossrefPubMedGoogle Scholar
• 68 Aradi D, Komocsi A, Vorobcsuk A. et al. Prognostic significance of high onclopidogrel platelet reactivity after percutaneous coronary intervention: Systematic review and meta-analysis. Am Heart J 2010; 160: 543-551.
  CrossrefPubMedGoogle Scholar
• 69 Brar SS, ten Berg J, Marcucci R. et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: A collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011; 58: 1945-1954.
  CrossrefPubMedGoogle Scholar
• 70 Bonello L, Tantry US, Marcucci R. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
  CrossrefPubMedGoogle Scholar
• 71 Food and Drug Administration. FDA drug safety communication: Reduced effectiveness of plavix (clopidogrel) in patients who are poor metabolizers of the drug. Available at: http://wwwfdagov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888htm#AIHP 03-12-2010
  PubMedGoogle Scholar
• 72 Price MJ, Berger PB, Teirstein PS. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. J Am Med Assoc 2011; 305: 1097-1105.
  CrossrefPubMedGoogle Scholar
• 73 Leon MB, Baim DS, Popma JJ. et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998; 339: 1665-1671.
  CrossrefPubMedGoogle Scholar
• 74 Buonamici P, Marcucci R, Migliorini A. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
  CrossrefPubMedGoogle Scholar
• 75 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of postclopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
  CrossrefPubMedGoogle Scholar
• 76 Trenk D, Stone GW, Gawaz M. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: Results of the TRIGGER-PCI (Testing platelet Reactivity In patients underGoing elective stent placement on clopidogrel to Guide alternative thErapy with pRasugrel) study. J Am Coll Cardiol 2012; 59: 2159-2164.
  CrossrefPubMedGoogle Scholar
• 77 Stone GW. A large-scale, prospective, multicenter registry examining the relationship between platelet responsiveness and stent thrombosis after DES implantation. Results from the ADAPT-DES study. J Am Coll Cardiol. 2011 58. Suppl B xii Abstract LBCT
  PubMedGoogle Scholar
• 78 Aradi D, Komocsi A, Price MJ. et al. Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: Systematic review and meta-analysis. Int J Cardiol. 2012 epub ahead of print
  PubMedGoogle Scholar
• 79 Mehta SR, Bassand JP, Chrolavicius S. et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930-942.
  CrossrefPubMedGoogle Scholar
• 80 Mehta SR, Tanguay J-F, Eikelboom JW. et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): A randomised factorial trial. Lancet 2010; 376: 1233-1243.
  CrossrefPubMedGoogle Scholar
• 81 Raber L, Juni P, Nuesch E. et al. Long-term comparison of everolimus-eluting and sirolimus-eluting stents for coronary revascularisation. J Am Coll Cardiol 2011; 57: 2143-2151.
  CrossrefPubMedGoogle Scholar
• 82 Stone GW, Teirstein PS, Meredith IT. et al. A prospective, randomized evaluation of a novel everolimus-eluting coronary stent: The PLATINUM (A prospective, randomized, multicenter trial to assess an everolimus-eluting coronary stent system [PROMUS element] for the treatment of up to two de novo coronary artery lesions) trial. J Am Coll Cardiol 2011; 57: 1700-1708.
  CrossrefPubMedGoogle Scholar
• 83 Yeung AC, Leon MB, Jain A. et al. Clinical evaluation of the RESOLUTE zotarolimus-eluting coronary stent system in the treatment of de novo lesions in native coronary arteries: The RESOLUTE US clinical trial. J Am Coll Cardiol 2011; 57: 1778-1783.
  CrossrefPubMedGoogle Scholar
• 84 Bonello L, Pansieri M, Mancini J. et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 2011; 58: 467-473.
  CrossrefPubMedGoogle Scholar
• 85 Sibbing D, Koch W, Gebhard D. 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: 512-518.
  CrossrefPubMedGoogle Scholar
• 86 Bonello L, Mancini J, Pansieri M. et al. Relationship between post-treatment platelet reactivity and ischaemic and bleeding events at one year follow-up in patients receiving prasugrel. J Thromb Haemost 2012; 10: 1999-2005.
  CrossrefPubMedGoogle Scholar
• 87 Trenk D, Zolk O, Fromm MF. et al. Personalizing antiplatelet therapy with clopidogrel. Clin Pharmacol Ther 2012; 92: 476-485.
  PubMedGoogle Scholar
• 88 Bonello L, Camoin-Jau L, Arques S. et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: A multicenter randomized prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
  CrossrefPubMedGoogle Scholar
• 89 Bonello L, Camoin-Jau L, Armero S. et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009; 103: 5-10.
  CrossrefPubMedGoogle Scholar
• 90 Valgimigli M, Campo G, de Cesare N. et al. Tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel (3t/2r). Rationale for the study and protocol design. Cardiovasc Drugs Ther 2008; 22: 313-320.
  CrossrefPubMedGoogle Scholar
• 91 Cuisset T, Frere C, Quilici J. et al. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: A prospective, randomized study. JACC Cardiovasc Interv 2008; 01: 649-653.
  PubMedGoogle Scholar
• 92 Aradi D, Rideg O, Vorobcsuk A. et al. Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity. Eur J Clin Invest 2012; 42: 384-392.
  CrossrefPubMedGoogle Scholar
• 93 Ari H, Ozkan H, Karacinar A. et al. The effect of high-dose clopidogrel treatment in patients with clopidogrel resistance (The EFFICIENT trial). Int J Cardiol 2012; 157: 374-380.
  CrossrefPubMedGoogle Scholar
• 94 Hazarbasanov D, Velchev V, Finkov B. et al. Tailoring clopidogrel dose according to multiple electrode aggregometry decreases the rate of ischaemic complications after percutaneous coronary intervention. J Thromb Thrombolysis 2012; 34: 85-90.
  CrossrefPubMedGoogle Scholar
• 95 Wang XD, Zhang DF, Zhuang SW. et al. Modifying clopidogrel maintenance doses according to vasodilator-stimulated phosphoprotein phosphorylation index improves clinical outcome in patients with clopidogrel resistance. Clin Cardiol 2011; 34: 332-338.
  CrossrefPubMedGoogle Scholar
• 96 Collet J-P, Cuisset T, Rangé G. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367: 2100-2109.
  CrossrefPubMedGoogle Scholar