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Thromb Haemost 2015; 113(01): 37-52
DOI: 10.1160/TH14-13-0238
Review Article
Schattauer GmbH

How to improve the concept of individualised antiplatelet therapy with P2Y12 receptor inhibitors – is an algorithm the answer?

Jolanta M. Siller-Matula
1   Department of Cardiology, Medical University of Vienna, Austria
,
Dietmar Trenk
2   Clinics of Cardiology and Angiology II, Universitaets-Herzzentrum Freiburg · Bad Krozingen, Bad Krozingen, Germany
,
Karsten Schrör
3   Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany
,
Meinrad Gawaz
4   Medizinische Klinik III, Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany
,
Steen D. Kristensen
5   Department of Cardiology, Aarhus University Hospital, Denmark
,
Robert F. Storey
6   Department of Cardiovascular Science, University of Sheffield, UK
,
Kurt Huber
7   3rd Medical Department, Cardiology and Emergency Medicine, Wilhelminenhospital, Vienna, Austria
,
for the European Platelet Academy › Author Affiliations
Further Information

Publication History

Received: 16 March 2014

Accepted after major revision: 22 July 2014

Publication Date:
09 March 2018 (online)

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Summary

Within the past decade, high on-treatment platelet reactivity (HTPR) on clopidogrel and its clinical implications have been frequently discussed. Although it has been previously assumed that HTPR is a phenomenon occurring only in patients treated with clopidogrel, recent data show that HTPR might also occur during treatment with prasugrel or ticagrelor in the acute phase of ST-elevation myocardial infarction. Moreover, it has been postulated that there is a therapeutic window for P2Y12 receptor blockers, thus indicating that HTPR is associated with thrombotic events whereas low on-treatment platelet reactivity (LTPR) is associated with bleeding events. The current paper focuses on tools to identify risk factors for HTPR (pharmacogenomic testing, clinical scoring and drug-drug interactions) and on the use of platelet function testing in order to identify patients who might not respond adequately to clopidogrel. The majority of recent clinical randomised trials have not supported the hypothesis that platelet function testing and tailored antiplatelet therapy are providing a favourable clinical outcome. These trials, mainly performed in low-to-moderate risk patients, will be reviewed and discussed. Finally, an algorithm based on current knowledge is suggested, which might be of use for design of clinical trials.

Keywords

Platelet reactivity - clopidogrel - prasugrel - ticagrelor
 

  • References

  • 1 Tantry US. et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischaemia and bleeding. J Am Coll Cardiol 2013; 62: 2261-2273.
    CrossrefPubMedGoogle Scholar
  • 2 Siller-Matula JM. et al. Response Variability to P2Y12 Receptor Inhibitors: Expectations and Reality. JACC Cardiovasc Interv 2013; 06: 1111-1128.
    CrossrefPubMedGoogle Scholar
  • 3 Sibbing D. 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
  • 4 Geisler T. et al. Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions. Eur Heart J 2010; 31: 59-66.
    CrossrefPubMedGoogle Scholar
  • 5 Siller-Matula JM. et al. Multiple Electrode Aggregometry predicts stent thrombosis better than the VASP assay. J Thromb Haemost 2010; 08: 351-359.
    CrossrefPubMedGoogle Scholar
  • 6 Buonamici P. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
    CrossrefPubMedGoogle Scholar
  • 7 Migliorini A. 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
  • 8 Gori AM. 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
  • 9 Cuisset T. et al. Predictive values of post-treatment adenosine diphosphate-in-duced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients. Am J Cardiol 2009; 104: 1078-1082.
    CrossrefPubMedGoogle Scholar
  • 10 Matetzky S. 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
  • 11 Gurbel PA. 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
  • 12 Cuisset T. et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes. Thromb Haemost 2007; 97: 282-287.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Geisler T. et al. Genetic variation of platelet function and pharmacology: An update of current knowledge. Thromb Haemost 2013; 110: 876-887.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Gurbel PA. et al. Platelet reactivity to adenosine diphosphate and long-term is-chaemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target. Platelets 2008; 19: 595-604.
    CrossrefPubMedGoogle Scholar
  • 15 Siller-Matula JM. et al. Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. J Thromb Haemost 2012; 10: 529-542.
    CrossrefPubMedGoogle Scholar
  • 16 Geisler T. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
    CrossrefPubMedGoogle Scholar
  • 17 Hochholzer W. 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
  • 18 Bonello L. 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
  • 19 Michelson AD. et al. Pharmacodynamic assessment of platelet inhibition by pra-sugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J 2009; 30: 1753-1763.
    CrossrefPubMedGoogle Scholar
  • 20 Bonello L. et al. Relationship between post-treatment platelet reactivity and is-chaemic and bleeding events at one year follow-up in patients receiving prasu-grel. J Thromb Haemost 2012; 10: 1999-2005.
    CrossrefPubMedGoogle Scholar
  • 21 Alexopoulos D. et al. Prasugrel overcomes high on-clopidogrel platelet reactivity in chronic coronary artery disease patients more effectively than high dose (150 mg) clopidogrel. Am Heart J 2011; 162: 733-739.
    CrossrefPubMedGoogle Scholar
  • 22 Alexopoulos D. et al. Antiplatelet Effects of Prasugrel vs Double Clopidogrel in Patients on Hemodialysis and High On-Treatment Platelet Reactivity. J Thromb Haemost 2011; 09: 2379-2385.
    CrossrefPubMedGoogle Scholar
  • 23 Alexopoulos D. et al. randomised Assessment of Ticagrelor Versus Prasugrel Antiplatelet Effects in Patients with ST-Segment-Elevation Myocardial Infarction. Circ Cardiovasc Interv 2012; 05: 797-804.
    CrossrefPubMedGoogle Scholar
  • 24 Parodi G. et al. Comparison of prasugrel and ticagrelor loading doses in ST-seg-ment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013; 61: 1601-1606.
    CrossrefPubMedGoogle Scholar
  • 25 Sibbing D. et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010; 08: 250-256.
    CrossrefPubMedGoogle Scholar
  • 26 Sibbing D. et al. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol 2010; 56: 317-318.
    CrossrefPubMedGoogle Scholar
  • 27 Campo G. et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011; 57: 2474-2483.
    CrossrefPubMedGoogle Scholar
  • 28 Mokhtar OA. et al. Relationship between platelet reactivity inhibition and non-CABG related major bleeding in patients undergoing percutaneous coronary intervention. Thromb Res 2010; 126: e147-149.
    CrossrefPubMedGoogle Scholar
  • 29 Parodi G. et al. Residual Platelet Reactivity, Bleedings, and Adherence to Treatment in Patients Having Coronary Stent Implantation Treated With Prasugrel. Am J Cardiol 2012; 109: 214-218.
    CrossrefPubMedGoogle Scholar
  • 30 Cuisset T. et al. Clinical implications of very low on-treatment platelet reactivity in patients treated with thienopyridine: the POBA study (predictor of bleedings with antiplatelet drugs). JACC Cardiovasc Interv 2013; 06: 854-863.
    CrossrefPubMedGoogle Scholar
  • 31 Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care 2009; 32: 531-540.
    CrossrefPubMedGoogle Scholar
  • 32 Geisler T. et al. The Residual Platelet Aggregation after Deployment of Intracor-onary Stent (PREDICT) score. J Thromb Haemost 2008; 06: 54-61.
    PubMedGoogle Scholar
  • 33 Cayla G. et al. Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. J AmMed Assoc 2011; 306: 1765-1774.
    PubMedGoogle Scholar
  • 34 Neubauer H. et al. Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance--the BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy. BMC Med 2011; 09: 3.
    CrossrefPubMedGoogle Scholar
  • 35 Htun P. et al. Low responsiveness to clopidogrel increases risk among CKD patients undergoing coronary intervention. J Am Soc Nephrol 2011; 22: 627-633.
    CrossrefPubMedGoogle Scholar
  • 36 Muller K. et al. Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease. Atherosclerosis 2010; 213: 256-262.
    CrossrefPubMedGoogle Scholar
  • 37 Siller-Matula JM. et al. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008; 52: 1557-1563.
    CrossrefPubMedGoogle Scholar
  • 38 Harmsze AM. 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
  • 39 Hochholzer W. 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
  • 40 Harmsze AM. 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; 09: 1892-1901.
    CrossrefPubMedGoogle Scholar
  • 41 Gilard M. et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomised, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51: 256-260.
    CrossrefPubMedGoogle Scholar
  • 42 Cuisset T. 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 randomised study. J Am Coll Cardiol 2009; 54: 1149-1153.
    CrossrefPubMedGoogle Scholar
  • 43 Siller-Matula JM. et al. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemost 2010; 08: 2624-2641.
    CrossrefPubMedGoogle Scholar
  • 44 Siller-Matula JM. et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009; 157: 148.e1-.e5..
    CrossrefPubMedGoogle Scholar
  • 45 Teng R. Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor. Clin Pharmacokinet 2012; 51: 305-318.
    CrossrefPubMedGoogle Scholar
  • 46 Siller-Matula JM. et al. Clinical implications of drug-drug interactions with P2Y12 receptor inhibitors. J Thromb Haemost 2014; 12: 2-13.
    CrossrefPubMedGoogle Scholar
  • 47 Hobl EL. et al. Morphine decreases clopidogrel concentrations and effects: a randomised, double-blind, placebo-controlled trial. J Am Coll Cardiol 2014; 63: 630-635.
    CrossrefPubMedGoogle Scholar
  • 48 Hulot JS. et al. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv 2011; 04: 422-428.
    CrossrefPubMedGoogle Scholar
  • 49 Giusti B. 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
  • 50 Collet JP. 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
  • 51 Mega JL. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
    CrossrefPubMedGoogle Scholar
  • 52 Shuldiner AR. 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
  • 53 Bhatt DL. et al. The relationship between CYP2C19 polymorphisms and is-chaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study. Eur Heart J 2012; 33: 2143-2150.
    CrossrefPubMedGoogle Scholar
  • 54 Mega JL. et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. J Am Med Assoc 2011; 306: 2221-2228.
    PubMedGoogle Scholar
  • 55 Simon T. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
    CrossrefPubMedGoogle Scholar
  • 56 Harmsze AM. 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
  • 57 Jeong YH. et al. Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin. Circ Cardiovasc Interv 2011; 04: 585-594.
    CrossrefPubMedGoogle Scholar
  • 58 Wallentin L. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: 1320-1328.
    CrossrefPubMedGoogle Scholar
  • 59 Sibbing 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
  • 60 Frere C. 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
  • 61 Mega JL. 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
  • 62 Jaitner J. 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; 05: 82-88 S1-2.
    CrossrefPubMedGoogle Scholar
  • 63 Campo G. et al. Relationship between paraoxonase Q192R gene polymorphism and on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention. J Thromb Haemost 2011; 09: 2106-2108.
    CrossrefPubMedGoogle Scholar
  • 64 Fontana P. et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 2003; 108: 989-995.
    CrossrefPubMedGoogle Scholar
  • 65 Mega JL. 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
  • 66 von Beckerath N. et al. A double-blind, randomised study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007; 28: 1814-1819.
    CrossrefPubMedGoogle Scholar
  • 67 Angiolillo DJ. et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007; 50: 1541-1547.
    CrossrefPubMedGoogle Scholar
  • 68 Angiolillo DJ. et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions. Results of a randomised study. Thromb Haemost 2008; 99: 161-168.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Bonello L. 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
  • 70 Bonello L. 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 randomised prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
    CrossrefPubMedGoogle Scholar
  • 71 Siller-Matula JM. et al. Personalised antiplatelet treatment after percutaneous coronary intervention: the MADONNA study. Int J Cardiol 2013; 167: 2018-2023.
    CrossrefPubMedGoogle Scholar
  • 72 Trenk D. et al. Antiplatelet response to the 150-mg maintenance dose of clopi-dogrel in patients with insufficient platelet inhibition after clopidogrel loading for elective coronary stent placement. EuroIntervention 2008; 04: 214-221.
    CrossrefPubMedGoogle Scholar
  • 73 Aleil B. et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomised study. JACC Cardiovasc Interv 2008; 01: 631-638.
    CrossrefPubMedGoogle Scholar
  • 74 Jeong YH. et al. randomised comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomised study. J Am Coll Cardiol 2009; 53: 1101-1109.
    CrossrefPubMedGoogle Scholar
  • 75 Collet JP. et al. High doses of clopidogrel to overcome genetic resistance: the randomised crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2). JACC Cardiovasc Interv 2011; 04: 392-402.
    CrossrefPubMedGoogle Scholar
  • 76 Valgimigli M. et al. Intensifying platelet inhibition with tirofiban in poor re-sponders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomised Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel study. Circulation 2009; 119: 3215-3222.
    CrossrefPubMedGoogle Scholar
  • 77 Cuisset T. et al. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomised study. JACC Cardiovasc Interv 2008; 01: 649-653.
    CrossrefPubMedGoogle Scholar
  • 78 Price MJ. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomised trial. J Am Med Assoc 2011; 305: 1097-1105.
    CrossrefPubMedGoogle Scholar
  • 79 Trenk D. et al. A randomised 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 TRIGGERPCI (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
  • 80 Gurbel PA. et al. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularisation: the TRILOGY ACS platelet function substudy. J Am Med Assoc 2012; 308: 1785-1794.
    CrossrefPubMedGoogle Scholar
  • 81 Aradi D. 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 2013; 167: 2140-2148.
    CrossrefPubMedGoogle Scholar
  • 82 Collet JP. et al. Bedside Monitoring to Adjust Antiplatelet Therapy for Coronary Stenting. N Engl J Med 2012; 367: 2100-2109.
    CrossrefPubMedGoogle Scholar
  • 83 Stone G. 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 Supplement B Abstract LBCT.
    PubMedGoogle Scholar
  • 84 Collet JP. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367: 2100-2109.
    CrossrefPubMedGoogle Scholar
  • 85 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 05 (Suppl. 01) 230-237.
    CrossrefPubMedGoogle Scholar
  • 86 Sumaya W. et al. Hirudin anticoagulation allows more rapid determination of P2Y(1)(2) inhibition by the VerifyNow P2Y12 assay. Thromb Haemost 2013; 109: 550-555.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 87 Schror K. et al. Functional testing methods for the antiplatelet effects of aspirin. Biomarkers Med 2011; 05: 31-42.
    CrossrefPubMedGoogle Scholar
  • 88 Weber AA, Schror K. Differential inhibition of adenosine diphosphate- versus thrombin receptor-activating peptide-stimulated platelet fibrinogen binding by abciximab due to different glycoprotein IIb/IIIa activation kinetics. Blood 2001; 98: 1619-1621.
    CrossrefPubMedGoogle Scholar
  • 89 Clopidogrel Genotyping for Antiplatelet Guidance in MI Stenting: Maybe Reduced Ischaemic Risk. Medscape 2013;. Nov. 6, 2013.
    PubMedGoogle Scholar
  • 90 Gurbel PA. et al. The relation between CYP2C19 genotype and phenotype in stented patients on maintenance dual antiplatelet therapy. Am Heart J 2011; 161: 598-604.
    CrossrefPubMedGoogle Scholar
  • 91 Aradi D. et al. Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol 2014; 63: 1061-1070.
    CrossrefPubMedGoogle Scholar
  • 92 Siller-Matula JM, Jilma B. Why have studies of tailored anti-platelet therapy failed so far?. Thromb Haemost 2013; 110: 628-631.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 93 Gurbel PA. et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007; 50: 1822-1834.
    CrossrefPubMedGoogle Scholar
  • 94 Storey RF. et al. Lower Mortality Following Pulmonary Adverse Events and Sepsis with Ticagrelor Compared to Clopidogrel in the PLATO Study. Platelets. 2013 Epub ahead of print.
    PubMedGoogle Scholar
  • 95 Kozinski M. et al. Diurnal variation in platelet inhibition by clopidogrel. Platelets 2011; 22: 579-587.
    CrossrefPubMedGoogle Scholar
  • 96 Kozinski M. et al. Increased morning ADP-dependent platelet aggregation persists despite dual antiplatelet therapy in patients with first ST-segment elevation myocardial infarction: Preliminary report. Cardiol J 2008; 15: 530-536.
    PubMedGoogle Scholar
  • 97 Siller-Matula JM. et al. The effect of antiplatelet drugs clopidogrel and aspirin is less immediately after stent implantation. Thromb Res 2009; 123: 874-880.
    CrossrefPubMedGoogle Scholar
  • 98 De Caterina R. et al. Bedside monitoring of antiplatelet therapy for coronary stenting. N Engl J Med 2013; 368: 871.
    PubMedGoogle Scholar
  • 99 Jneid H. 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: 645-681.
    CrossrefPubMedGoogle Scholar
  • 100 Hamm CW. 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.
    CrossrefPubMedGoogle Scholar
  • 101 Levine GN. et al. 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.
    CrossrefPubMedGoogle Scholar
  • 102 Wallentin L. et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 361: 1045-1057.
    CrossrefPubMedGoogle Scholar
  • 103 Wiviott SD. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
    CrossrefPubMedGoogle Scholar
  • 104 Steg PG. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012; 33: 2569-2619.
    CrossrefPubMedGoogle Scholar
  • 105 O’Gara PT. et al. 2013 ACCF/AHA guideline for the management of ST-elev-ation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2013; 82: E1-27.
    CrossrefPubMedGoogle Scholar
  • 106 Huber K, Lip GY. Differences between ACC/AHA and ESC Guidelines on anti-platelet therapy in patients with acute coronary syndromes. Thromb Haemost 2013; 110: 11-13.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 107 Siller-Matula J. et al. Thienopyridines in cardiovascular disease: focus on clopi-dogrel resistance. Thromb Haemost 2007; 97: 385-393.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 108 Alexopoulos D. et al. Prevalence of contraindications and conditions for precaution for prasugrel administration in a real world acute coronary syndrome population. J Thromb Thrombolysis 2011; 32: 328-333.
    CrossrefPubMedGoogle Scholar
  • 109 Geisler T. et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 2008; 09: 1251-1259.
    CrossrefPubMedGoogle Scholar
  • 110 Breet NJ. 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
  • 111 Freynhofer MK. et al. Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events. Thromb Haemost 2011; 106: 230-239.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 112 Bonello L. et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postpro-cedural major adverse cardiovascular events. J Thromb Haemost 2007; 05: 1630-1636.
    CrossrefPubMedGoogle Scholar
  • 113 Bal Dit Sollier C. et al. Differential sensitivity and kinetics of response of different ex vivo tests monitoring functional variability of platelet response to clopi-dogrel. Thromb Haemost 2010; 104: 571-581.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 114 Johnston LR. et al. Methodological considerations for the assessment of ADP induced platelet aggregation using the Multiplate(R) analyser. Platelets 2013; 24: 303-307.
    CrossrefPubMedGoogle Scholar
  • 115 Capranzano P. et al. Platelet function profiles in the elderly: Results of a phar-macodynamic study in patients on clopidogrel therapy and effects of switching to prasugrel 5 mg in patients with high platelet reactivity. Thromb Haemost 2011; 106: 1149-1157.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 116 Ferreiro JL. et al. Impact of Adjunctive Cilostazol Therapy Versus High Maintenance Dose of Clopidogrel in Suboptimal Responders With Diabetes Melli-tus. Rev Esp Cardiol 2011; 65: 105-106.
    PubMedGoogle Scholar
  • 117 Kozinski M. et al. Prasugrel overcomes high on-clopidogrel platelet reactivity in the acute phase of acute coronary syndrome and maintains its antiplatelet potency at 30-day follow-up. Cardiol J. 2014 Epub ahead of print.
    PubMedGoogle Scholar
  • 118 Matetzky S. et al. Effectiveness of reloading to overcome clopidogrel nonre-sponsiveness in patients with acute myocardial infarction. Am J Cardiol 2008; 102: 524-529.
    CrossrefPubMedGoogle Scholar
  • 119 Gurbel PA. et al. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP2C19*2 genotype: first experience in patients. J Thromb Haemost 2010; 08: 43-53.
    CrossrefPubMedGoogle Scholar
  • 120 Gurbel PA. et al. Response to ticagrelor in clopidogrel nonresponders and re-sponders and effect of switching therapies: the RESPOND study. Circulation 2010; 121: 1188-1199.
    CrossrefPubMedGoogle Scholar
  • 121 Neubauer H. et al. How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification. Thromb Haemost 2008; 99: 357-362.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 122 Roberts JD. et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012; 379: 1705-1711.
    CrossrefPubMedGoogle Scholar
  • 123 Kim IS. et al. Platelet inhibition by adjunctive cilostazol versus high maintenance-dose clopidogrel in patients with acute myocardial infarction according to cytochrome P450 2C19 genotype. JACC Cardiovasc Interv 2011; 04: 381-391.
    CrossrefPubMedGoogle Scholar
  • 124 Hwang SJ. et al. Cytochrome 2C19 polymorphism and response to adjunctive cilostazol versus high maintenance-dose clopidogrel in patients undergoing percutaneous coronary intervention. Circ Cardiovasc Interv 2010; 03: 450-459.
    CrossrefPubMedGoogle Scholar
  • 125 Gurbel PA. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
    CrossrefPubMedGoogle Scholar
  • 126 Bouman HJ. et al. Which platelet function test is suitable to monitor clopido-grel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel. J Thromb Haemost 2010; 08: 482-488.
    CrossrefPubMedGoogle Scholar
  • 127 Breet NJ. et al. High on-treatment platelet reactivity to both aspirin and clopi-dogrel is associated with the highest risk of adverse events following percutaneous coronary intervention. Heart 2011; 97: 983-990.
    CrossrefPubMedGoogle Scholar
  • 128 Elsenberg EH. et al. The influence of clinical characteristics, laboratory and inflammatory markers on ‘high on-treatment platelet reactivity’ as measured with different platelet function tests. Thromb Haemost 2009; 102: 719-727.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 129 Gurbel PA. et al. Assessment of clopidogrel responsiveness: measurements of maximum platelet aggregation, final platelet aggregation and their correlation with vasodilator-stimulated phosphoprotein in resistant patients. Thromb Res 2007; 121: 107-115.
    CrossrefPubMedGoogle Scholar
  • 130 Jakubowski JA. et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry. Thromb Haemost 2008; 99: 215-222.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 131 Linnemann B. et al. Assessment of clopidogrel non-response by the PFA-100 system using the new test cartridge INNOVANCE PFA P2Y. Ann Hematol 2010; 89: 597-605.
    CrossrefPubMedGoogle Scholar
  • 132 Paniccia R. 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.
    PubMedGoogle Scholar
  • 133 Sibbing D. et al. Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost 2008; 99: 121-126.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 134 Li YG. et al. Inhibition of platelet aggregation with prasugrel and clopidogrel: an integrated analysis in 846 subjects. Platelets 2009; 20: 316-327.
    CrossrefPubMedGoogle Scholar
  • 135 Komosa A. et al. Comparison of the antiplatelet effect of two clopidogrel bisulfate formulations: Plavix and generic-Egitromb. Platelets. 2014 Epub ahead of print.
    PubMedGoogle Scholar
  • 136 Siller-Matula JM. et al. Dual non-responsiveness to antiplatelet treatment is a stronger predictor of cardiac adverse events than isolated non-responsiveness to clopidogrel or aspirin. Int J Cardiol 2013; 167: 430-435.
    CrossrefPubMedGoogle Scholar
  • 137 Christ G. et al. Platelet Inhibition by Abciximab Bolus-Only Administration and Oral ADP Receptor Antagonist Loading in Acute Coronary Syndrome Patients: The Blocking and Bridging Strategy. Thromb Res 2013; 132: e36-e41.
    CrossrefPubMedGoogle Scholar
  • 138 Spiel AO. et al. Effects of prasugrel on platelet inhibition during systemic en-dotoxaemia: a randomised controlled trial. Clin Sci 2012; 123: 591-600.
    CrossrefPubMedGoogle Scholar
  • 139 Siller-Matula JM. et al. ARC15105 is a potent antagonist of von Willebrand factor mediated platelet activation and adhesion. Arterioscler Thromb Vasc Biol 2012; 32: 902-909.
    CrossrefPubMedGoogle Scholar
  • 140 Kasprzak M. et al. Pantoprazole may enhance antiplatelet effect of enteric-coated aspirin in patients with acute coronary syndrome. Cardiol J 2009; 16: 535-544.
    PubMedGoogle Scholar
  • 141 Sibbing D. 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
  • 142 Blindt R. 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
  • 143 Lev EI. et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47: 27-33.
    CrossrefPubMedGoogle Scholar
  • 144 Cuisset T. 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: 893-899.
    CrossrefPubMedGoogle Scholar
  • 145 Frelinger 3rd, AL. et al. Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by pra-sugrel or high-dose clopidogrel. Results from PRINCIPLE-TIMI 44. Thromb Haemost 2011; 106: 219-226.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 146 Cuisset T. et al. Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris. Am J Cardiol 2008; 101: 1700-1703.
    CrossrefPubMedGoogle Scholar
  • 147 Jakubowski JA. et al. The use of the VerifyNow P2Y12 point-of-care device to monitor platelet function across a range of P2Y(12) inhibition levels following prasugrel and clopidogrel administration. Thromb Haemost 2008; 99: 409-415.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 148 Price MJ. 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
  • 149 Mayr FB. et al. The aptamer ARC1779 blocks von Willebrand factor-dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo. Transfusion 2010; 50: 1079-1087.
    CrossrefPubMedGoogle Scholar
  • 150 Siller-Matula JM. et al. Cross validation of the Multiple Electrode Aggrego-metry. A prospective trial in healthy volunteers. Thromb Haemost 2009; 102: 397-403.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 151 Panzer S. et al. Monitoring survival and function of transfused platelets in Bernard-Soulier syndrome by flow cytometry and a cone and plate(let) analyzer (Impact-R). Transfusion 2007; 47: 103-106.
    CrossrefPubMedGoogle Scholar
  • 152 Spiel AO. et al. Single dose granulocyte colony-stimulating factor markedly enhances shear-dependent platelet function in humans. Platelets 2010; 21: 464-469.
    CrossrefPubMedGoogle Scholar
  • 153 Lordkipanidze M. et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702-1708.
    CrossrefPubMedGoogle Scholar
  • 154 Grove EL. et al. A comparison of platelet function tests and thromboxane metabolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. Thromb Haemost 2010; 103: 1245-1253.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 155 Frelinger 3rd, AL. et al. Association of cyclooxygenase-1-dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterisation. Circulation 2009; 120: 2586-2596.
    CrossrefPubMedGoogle Scholar
  • 156 Gurbel PA. et al. Platelet reactivity in patients and recurrent events post-stent-ing: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46: 1820-1826.
    CrossrefPubMedGoogle Scholar
  • 157 Bliden KP. et al. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?. J Am Coll Cardiol 2007; 49: 657-666.
    CrossrefPubMedGoogle Scholar
  • 158 Craft RM. et al. A novel modification of the Thrombelastograph assay, isolating platelet function, correlates with optical platelet aggregation. J Lab Clin Med 2004; 143: 301-309.
    CrossrefPubMedGoogle Scholar
  • 159 Scharbert G. et al. Evaluation of the Platelet Mapping Assay on rotational thromboelastometry ROTEM. Platelets 2009; 20: 125-130.
    CrossrefPubMedGoogle Scholar
  • 160 Mahla E. et al. Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study. Circ Cardiovasc Interv 2012; 05: 261-269.
    CrossrefPubMedGoogle Scholar