Download PDF
Thromb Haemost 2011; 106(02): 211-218
DOI: 10.1160/TH11-03-0137
Theme Issue Article
Schattauer GmbH

Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel

Thomas Gremmel
1   Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Simon Panzer
2   Clinical Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received: 01 March 2011

Accepted after major revision: 29 April 2011

Publication Date:
25 November 2017 (online)

    Permissions and Reprints

Summary

Platelet inhibition by clopidogrel varies from one individual to the next. Further, in vitro high on-treatment residual adenosine-diphosphate inducible platelet reactivity (HRPR) is associated with an increased risk for major adverse cardiovascular events after percutaneous coronary intervention (PCI) with stent implantation. Recent studies identified numerous influencing factors for the antiplatelet effect of clopidogrel. Besides genetic predispositions, diverse clinical conditions as well as pharmacological interactions were shown to significantly impair clopidogrel-mediated platelet inhibition. Consequently, these influencing factors may affect clinical outcome after PCI and it is therefore desirable to identify cofounders of HRPR by platelet reactivity testing. It is apparent, that not all assays are sensitive to the same variables, and only cofounders of HRPR that are repeatedly identified by more than one test system may be clinically meaningful. However, treatment adjustment based on platelet function testing has not been associated with improved patients’ outcome. This summary shall provide an overview over current knowledge on influencing factors for clopidogrel-mediated platelet inhibition and aid guidance for critical interpretation of in vitro obtained data on HRPR.

Keywords

Clopidogrel - platelet function testing - influencing factors
 

  • References

  • 1 Yusuf S, Zhao F, Mehta SR. et al. 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
  • 2 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348: 1329-1339.
    CrossrefPubMedGoogle Scholar
  • 3 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 5 (Suppl. 01) 230-237
    CrossrefPubMedGoogle Scholar
  • 4 Cotter G, Shemesh E, Zehavi M. et al. Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?. Am Heart J 2004; 147: 293-300.
    CrossrefPubMedGoogle Scholar
  • 5 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
  • 6 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
  • 7 Sofi F, Giusti B, Marcucci R. et al. Cytochrome P450 2C19(*)2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J 2011; 11: 199-206.
    CrossrefPubMedGoogle Scholar
  • 8 Snoep JD, Hovens MM, Eikenboom JC. et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221-231.
    CrossrefPubMedGoogle Scholar
  • 9 Breet NJ, van Werkum JW, Bouman HJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. J Am Med Assoc 2010; 303: 754-762.
    CrossrefPubMedGoogle Scholar
  • 10 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
    CrossrefPubMedGoogle Scholar
  • 11 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
    CrossrefPubMedGoogle Scholar
  • 12 Marcucci R, Gori AM, Paniccia R. et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009; 119: 237-242.
    CrossrefPubMedGoogle Scholar
  • 13 Gurbel PA, Bliden KP, Guyer K. et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46: 1820-1826.
    CrossrefPubMedGoogle Scholar
  • 14 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
  • 15 Bonello L, Paganelli F, Arpin-Bornet M. et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007; 5: 1630-1636.
    CrossrefPubMedGoogle Scholar
  • 16 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
    CrossrefPubMedGoogle Scholar
  • 17 Frere C, Cuisset T, Quilici J. et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost 2007; 98: 838-843.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 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
  • 19 Siller-Matula JM, Christ G, Lang IM. et al. Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay. J Thromb Haemost 2010; 8: 351-359.
    CrossrefPubMedGoogle Scholar
  • 20 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
    CrossrefPubMedGoogle Scholar
  • 21 Blindt R, Stellbrink K, de Taeye A. et al. The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis. Thromb Haemost 2007; 98: 1329-1334.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Rossini R, Capodanno D, Lettieri C. et al. Prevalence, predictors, and long-term prognosis of premature discontinuation of oral antiplatelet therapy after drug eluting stent implantation. Am J Cardiol 107: 186-194.
    PubMedGoogle Scholar
  • 24 Airoldi F, Colombo A, Morici N. et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007; 116: 745-754.
    CrossrefPubMedGoogle Scholar
  • 25 Iakovou I, Schmidt T, Bonizzoni E. et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. J Am Med Assoc 2005; 293: 2126-2130.
    CrossrefPubMedGoogle Scholar
  • 26 Gremmel T, Steiner S, Seidinger D. et al. Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101: 333-339.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Paniccia R, Antonucci E, Gori AM. et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 2007; 5: 1839-1847.
    CrossrefPubMedGoogle Scholar
  • 28 Lordkipanidze M, Pharand C, Nguyen TA. et al. Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients. Eur Heart J 2008; 29: 2877-2885.
    CrossrefPubMedGoogle Scholar
  • 29 von Beckerath N, Sibbing D, Jawansky S. et al. Assessment of platelet response to clopidogrel with multiple electrode aggregometry, the VerifyNow P2Y12 analyzer and platelet Vasodilator-Stimulated Phosphoprotein flow cytometry. Blood Coagul Fibrinolysis 2010; 21: 46-52.
    CrossrefPubMedGoogle Scholar
  • 30 Paniccia R, Antonucci E, Maggini N. et al. Comparison of methods for monitoring residual platelet reactivity after clopidogrel by point-of-care tests on whole blood in high-risk patients. Thromb Haemost 2010; 104: 287-292.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Judge HM, Buckland RJ, Sugidachi A. et al. Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function. Thromb Haemost 2010; 103: 1210-1217.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Cattaneo M. Resistance to anti-platelet agents. Throm Res 2011; 127 (Suppl. 03) S61-63
    CrossrefPubMedGoogle Scholar
  • 33 Siller-Matula JM, Haberl K, Prillinger K. et al. The effect of antiplatelet drugs clopidogrel and aspirin is less immediately after stent implantation. Thromb Res 2009; 123: 874-880.
    CrossrefPubMedGoogle Scholar
  • 34 Hochholzer W, Trenk D, Frundi D. et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.
    CrossrefPubMedGoogle Scholar
  • 35 Frelinger AL, Li Y, Linden MD. et al. Aspirin resistance: role of pre-existent platelet reactivity and correlation between tests. J Thromb Haemost 2008; 6: 2035-2044.
    CrossrefPubMedGoogle Scholar
  • 36 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
  • 37 Harrison P, Frelinger AL, 3rd Furman MI. et al. Measuring antiplatelet drug effects in the laboratory. Thromb Res 2007; 120: 323-336.
    CrossrefPubMedGoogle Scholar
  • 38 Toth O, Calatzis A, Penz S. et al. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96: 781-788.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Schwarz UR, Geiger J, Walter U. et al. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets–definition and detection of ticlopi-dine/clopidogrel effects. Thromb Haemost 1999; 82: 1145-1152.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 van Werkum JW, Bouman HJ, Breet NJ. et al. The Cone-and-Plate(let) analyzer is not suitable to monitor clopidogrel therapy: a comparison with the flowcytometric VASP assay and optical aggregometry. Thromb Res 2010; 126: 44-49.
    CrossrefPubMedGoogle Scholar
  • 41 Migliorini A, Valenti R, Marcucci R. et al. High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease. Circulation 2009; 120: 2214-2221.
    CrossrefPubMedGoogle Scholar
  • 42 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
  • 43 Neubauer H, Engelhardt A, Kruger JC. et al. Pantoprazole does not influence the antiplatelet effect of clopidogrel-a whole blood aggregometry study after coronary stenting. J Cardiovasc Pharmacol 2010; 56: 91-97.
    CrossrefPubMedGoogle Scholar
  • 44 Price MJ, Nayak KR, Barker CM. et al. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009; 103: 1339-1343.
    CrossrefPubMedGoogle Scholar
  • 45 Patti G, Nusca A, Mangiacapra F. et al. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 2008; 52: 1128-1133.
    CrossrefPubMedGoogle Scholar
  • 46 Gremmel T, Steiner S, Seidinger D. et al. Adenosine diphosphate-inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel. J Thromb Haemost 2010; 8: 37-42.
    CrossrefPubMedGoogle Scholar
  • 47 Marcucci R, Gori AM, Paniccia R. et al. Residual platelet reactivity is associated with clinical and laboratory characteristics in patients with ischemic heart disease undergoing PCI on dual antiplatelet therapy. Atherosclerosis 2007; 195: e217-223.
    CrossrefPubMedGoogle Scholar
  • 48 Cuisset T, Frere C, Quilici J. et al. Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response. Thromb Res 2009; 123: 597-603.
    CrossrefPubMedGoogle Scholar
  • 49 Trenk D, Hochholzer W, Fromm MF. et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-1934.
    CrossrefPubMedGoogle Scholar
  • 50 Zuern CS, Geisler T, Lutilsky N. et al. Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy. Thromb Res 2010; 125: e51-54.
    CrossrefPubMedGoogle Scholar
  • 51 Geisler T, Grass D, Bigalke B. et al. The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) score. J Thromb Haemost 2008; 6: 54-61.
    PubMedGoogle Scholar
  • 52 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
  • 53 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
  • 54 Geisler T, Zurn C, Paterok M. et al. Statins do not adversely affect post-interventional residual platelet aggregation and outcomes in patients undergoing coronary stenting treated by dual antiplatelet therapy. Eur Heart J 2008; 29: 1635-1643.
    CrossrefPubMedGoogle Scholar
  • 55 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; 9: 1251-1259.
    CrossrefPubMedGoogle Scholar
  • 56 Geisler T, Mueller K, Aichele S. et al. Impact of inflammatory state and metabolic control on responsiveness to dual antiplatelet therapy in type 2 diabetics after PCI: prognostic relevance of residual platelet aggregability in diabetics undergoing coronary interventions. Clin Res Cardiol 2010; 99: 743-752.
    CrossrefPubMedGoogle Scholar
  • 57 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
  • 58 Sibbing D, von Beckerath O, Schomig A. et al. Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention. Am J Cardiol 2007; 100: 203-205.
    CrossrefPubMedGoogle Scholar
  • 59 Sibbing D, Morath T, Braun S. et al. Clopidogrel response status assessed with Multiplate point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost 2010; 103: 151-159.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Sibbing D, Morath T, Stegherr J. et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101: 714-719.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Sibbing D, von Beckerath N, Morath T. et al. Oral anticoagulation with coumarin derivatives and antiplatelet effects of clopidogrel. Eur Heart J 2010; 31: 1205-1211.
    CrossrefPubMedGoogle Scholar
  • 62 Bernlochner I, Steinhubl S, Braun S. et al. Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment. Thromb Haemost 2010; 104: 1193-200.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Bonello-Palot N, Armero S, Paganelli F. et al. Relation of body mass index to high on-treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009; 104: 1511-1515.
    CrossrefPubMedGoogle Scholar
  • 64 Gori AM, Marcucci R, Migliorini A. et al. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug-eluting stents. J Am Coll Cardiol 2008; 52: 734-739.
    CrossrefPubMedGoogle Scholar
  • 65 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
  • 66 Geisler T, Anders N, Paterok M. et al. Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care 2007; 30: 372-374.
    CrossrefPubMedGoogle Scholar
  • 67 Angiolillo DJ, Bernardo E, Ramirez C. et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006; 48: 298-304.
    CrossrefPubMedGoogle Scholar
  • 68 Serebruany V, Pokov I, Kuliczkowski W. et al. Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thromb Haemost 2008; 100: 76-82.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Erlinge D, Varenhorst C, Braun OO. 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: 1968-1977.
    CrossrefPubMedGoogle Scholar
  • 70 Ferroni P, Basili S, Falco A. et al. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2: 1282-1291.
    CrossrefPubMedGoogle Scholar
  • 71 Ferreira IA, Mocking AI, Feijge MA. et al. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 2006; 26: 417-422.
    PubMedGoogle Scholar
  • 72 Angiolillo DJ, Bernardo E, Capodanno D. et al. Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual antiplatelet therapy. J Am Coll Cardiol 2010; 55: 1139-1146.
    CrossrefPubMedGoogle Scholar
  • 73 Gremmel T, Steiner S, Seidinger D. et al. Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition. Heart 2010; 96: 186-189.
    CrossrefPubMedGoogle Scholar
  • 74 Gremmel T, Steiner S, Seidinger D. et al. Smoking promotes clopidogrel-mediated platelet inhibition in patients receiving dual antiplatelet therapy. Thromb Res 2009; 124: 588-591.
    CrossrefPubMedGoogle Scholar
  • 75 Bliden KP, Dichiara J, Lawal L. et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 2008; 52: 531-533.
    CrossrefPubMedGoogle Scholar
  • 76 Hulot JS, Collet JP, 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
  • 77 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
  • 78 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
  • 79 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
  • 80 Harmsze AM, van Werkum JW, Ten Berg JM. et al. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J 2010; 31: 3046-3053.
    CrossrefPubMedGoogle Scholar
  • 81 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376: 1312-1319.
    CrossrefPubMedGoogle Scholar
  • 82 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
  • 83 Giusti B, Gori AM, Marcucci R. et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 2009; 103: 806-811.
    CrossrefPubMedGoogle Scholar
  • 84 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
  • 85 Brandt JT, Close SL, Iturria SJ. et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 2429-2436.
    CrossrefPubMedGoogle Scholar
  • 86 Frere C, Cuisset T, Morange PE. et al. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008; 101: 1088-1093.
    CrossrefPubMedGoogle Scholar
  • 87 Angiolillo DJ, Fernandez-Ortiz A, Bernardo 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: 1895-1900.
    CrossrefPubMedGoogle Scholar
  • 88 Gilard M, Arnaud B, Cornily JC. et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51: 256-260.
    CrossrefPubMedGoogle Scholar
  • 89 Cuisset T, Frere C, Quilici J. et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol 2009; 54: 1149-1153.
    CrossrefPubMedGoogle Scholar
  • 90 Siller-Matula JM, Spiel AO, Lang IM. et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009; 157: 148 e1-5.
    PubMedGoogle Scholar
  • 91 Gremmel T, Steiner S, Seidinger D. et al. The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by 5 different platelet function tests. J Cardiovasc Pharmacol 2010; 56: 532-539.
    CrossrefPubMedGoogle Scholar
  • 92 Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010; 31: 810-823.
    PubMedGoogle Scholar
  • 93 Rassen JA, Choudhry NK, Avorn J. et al. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009; 120: 2322-2329.
    CrossrefPubMedGoogle Scholar
  • 94 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
  • 95 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
  • 96 Mitsios JV, Papathanasiou AI, Rodis FI. et al. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation 2004; 109: 1335-1338.
    CrossrefPubMedGoogle Scholar
  • 97 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
  • 98 Price MJ, Berger PB, Teirstein PS. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc 2011; 305: 1097-1105.
    CrossrefPubMedGoogle Scholar