Download PDF
Thromb Haemost 2015; 114(04): 708-716
DOI: 10.1160/TH15-02-0130
Cellular Haemostasis and Platelets
Schattauer GmbH

The effect of acenocoumarol on the antiplatelet effect of clopidogrel

Willem J.M. Dewilde   *
1   Department of Cardiology, Amphia Hospital, Breda, the Netherlands
,
Paul W.A. Janssen   *
2   Department of Cardiology, St Antonius Hospital, Nieuwegein, the Netherlands
4   St Antonius Center for Platelet Function Research, St Antonius Hospital, Nieuwegein, the Netherlands
,
Thomas O. Bergmeijer
2   Department of Cardiology, St Antonius Hospital, Nieuwegein, the Netherlands
4   St Antonius Center for Platelet Function Research, St Antonius Hospital, Nieuwegein, the Netherlands
,
Johannes C. Kelder
2   Department of Cardiology, St Antonius Hospital, Nieuwegein, the Netherlands
4   St Antonius Center for Platelet Function Research, St Antonius Hospital, Nieuwegein, the Netherlands
,
Christian M. Hackeng
3   Department of Clinical Chemistry, St Antonius Hospital, Nieuwegein, the Netherlands
4   St Antonius Center for Platelet Function Research, St Antonius Hospital, Nieuwegein, the Netherlands
,
Jurriën M. ten Berg
2   Department of Cardiology, St Antonius Hospital, Nieuwegein, the Netherlands
4   St Antonius Center for Platelet Function Research, St Antonius Hospital, Nieuwegein, the Netherlands
› Author Affiliations
Further Information

Publication History

Received: 10 February 2015

Accepted after major revision: 19 May 2015

Publication Date:
29 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Patients exhibiting high on-clopidogrel platelet reactivity (HPR) are at an increased risk of atherothrombotic events following percutaneous coronary interventions (PCI). The use of concomitant medication which is metabolised by the hepatic cytochrome P450 system, such as phenprocoumon, is associated with HPR. We assessed the level of platelet reactivity on clopidogrel in patients who received concomitant treatment with acenocoumarol (another coumarin derivative). Patients scheduled for PCI were included in a prospective, single centre, observational registry. Patients who were adequately pre-treated with clopidogrel were eligible for this analysis, which included 1,582 patients, of whom 104 patients (6.6 %) received concomitant acenocoumarol treatment. Platelet reactivity, as measured with the VerifyNow P2Y12 assay and expressed in P2Y12 Reaction Units (PRU), was significantly higher in patients on concomitant acenocoumarol treatment (mean PRU 229 ± 88 vs 187 ± 95; p< 0.001). In patients with concomitant acenocoumarol use, the proportion of patients with HPR was higher, defined as PRU > 208 (57.7 % vs 41.1 %; p=0.001) and PRU236 (49.0 % vs 31.4 %; p< 0.001). In multivariable analysis, concomitant acenocoumarol use was independently associated with a higher PRU and the occurrence of HPR defined as PRU236 (OR 2.00, [1.07–3.79]), but not with HPR defined as PRU > 208 (OR 1.37, [0.74–2.54]). PRU also was significantly increased after 1:1 propensity matching (+28.2; p< 0.001). As this was an observational study, confounding by indication cannot be excluded, although multivariable analyses and propensity matching were performed. The impact of the findings from this hypothesis-generating study on clinical outcome requires further investigation.

Keywords

Platelet aggregation - clopidogrel - acenocoumarol - oral anticoagulation - high on-treatment platelet reactivity - VerifyNow

* These two authors contributed equally to this research and this manuscript.


 

  • References

  • 1 Hamm CW, Bassand JP, Agewall S. 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.
    CrossrefPubMedSearch in Google Scholar
  • 2 Levine GN, Bates ER, Blankenship JC. 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.
    CrossrefPubMedSearch in Google Scholar
  • 3 Aradi D, Storey RF, Komócsi A. et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 2014; 35: 209-215.
    CrossrefPubMedSearch in Google Scholar
  • 4 Stone GW, Witzenbichler B, Weisz G. et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013; 382: 614-623.
    CrossrefPubMedSearch in Google Scholar
  • 5 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
    CrossrefPubMedSearch in Google Scholar
  • 6 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.
    CrossrefPubMedSearch in Google Scholar
  • 7 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.
    CrossrefPubMedSearch in Google Scholar
  • 8 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.
    CrossrefPubMedSearch in Google Scholar
  • 9 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.
    CrossrefPubMedSearch in Google Scholar
  • 10 Bliden KP, DiChiara J, Tantry US. et al. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoingpercutaneous coronary intervention: is the current antiplatelet therapy adequate?. J Am Coll Cardiol 2007; 49: 657-666.
    CrossrefPubMedSearch in Google Scholar
  • 11 Price MJ, Angiolillo DJ, Teirstein PS. et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011; 124: 1132-1137.
    CrossrefPubMedSearch in Google Scholar
  • 12 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.
    CrossrefPubMedSearch in Google Scholar
  • 13 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 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.
    CrossrefPubMedSearch in Google Scholar
  • 15 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.
    CrossrefPubMedSearch in Google Scholar
  • 16 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 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.
    PubMedSearch in Google Scholar
  • 18 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.
    CrossrefPubMedSearch in Google Scholar
  • 19 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.
    CrossrefPubMedSearch in Google Scholar
  • 20 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 (OmeprazoleCLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51: 256-260.
    CrossrefPubMedSearch in Google Scholar
  • 21 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.
    CrossrefPubMedSearch in Google Scholar
  • 22 Tirkkonen T, Heikkilä P, Vahlberg T. et al. Epidemiology of CYP3A4-Mediated Clopidogrel Drug-Drug Interactions and Their Clinical Consequences. Cardiovasc Ther 2013; 31: 344-351.
    CrossrefPubMedSearch in Google Scholar
  • 23 Saw J, Steinhubl SR, Berger PB. et al. Clopidogrel for the Reduction of Events During Observation Investigators. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 2003; 108: 921-924.
    CrossrefPubMedSearch in Google Scholar
  • 24 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.
    CrossrefPubMedSearch in Google Scholar
  • 25 Ojeifo O, Wiviott SD, Antman EM. et al. Concomitant Administration of Clopidogrel With Statins or Calcium Channel Blockers: Insights From the TRITONTIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38) Trial. ACC Cardiovasc Interv 2013; 6: 1275-1281.
    PubMedSearch in Google Scholar
  • 26 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.
    CrossrefPubMedSearch in Google Scholar
  • 27 Beinema M, Brouwers JR, Schalekamp T. et al. Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost 2008; 100: 1052-1057.
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol.lin. Pharmacokinet 2005; 44: 1227-1246.
    CrossrefPubMedSearch in Google Scholar
  • 29 Dewilde W, Verheugt FW, Breet N. et al. ’Ins’ and ’outs’ of triple therapy: Optimal antiplatelet therapy in patients on chronic oral anticoagulation who need coronary stenting. Netherl Heart J 2010; 18: 444-450.
    PubMedSearch in Google Scholar
  • 30 Dewilde WJ, Oirbans T, Verheugt FW. et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Ancet 2013; 381: 1107-1115.
    PubMedSearch in Google Scholar
  • 31 Chugh SS, Havmoeller R, Narayanan K. et al. Worldwide Epidemiology of Atrial Fibrillation: A Global Burden of Disease 2010 Study. Circulation 2014; 129: 837-847.
    CrossrefPubMedSearch in Google Scholar
  • 32 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.
    CrossrefPubMedSearch in Google Scholar
  • 33 Tantry US, Bonello L, Aradi D. et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013; 62: 2261-2273.
    CrossrefPubMedSearch in Google Scholar
  • 34 Ridgeway G, McCaffrey D, Morral A. et al. TWANG: Toolkit for Weighting and Analysis of Nonequivalent Groups. R package version 1.4–0. 18–3–2014. Available at: CRAN.R-project.org/web/packages/twang Last accessed 10–10–2014.
    PubMed
  • 35 Breet NJ, Sluman MA, van Berkel MA. et al. Effect of gender difference on platelet reactivity. Neth Heart J 2011; 19: 451-457.
    CrossrefPubMedSearch in Google Scholar
  • 36 Elsenberg EH, van Werkum JW, van de Wal RM. 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 37 Bouman HJ, Harmsze AM, van Werkum JW. et al. Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting. Heart 2011; 97: 1239-1244.
    CrossrefPubMedSearch in Google Scholar
  • 38 Heestermans AA, van Werkum JW, Taubert D. et al. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thromb Res 2008; 122: 776-781.
    CrossrefPubMedSearch in Google Scholar
  • 39 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.
    CrossrefPubMedSearch in Google Scholar
  • 40 Mangiacapra F, Bartunek J, Bijnens N. et al. Periprocedural variations of platelet reactivity during elective percutaneous coronary intervention. J. Thromb. Hae-most 2012; 10: 2452-2461.
    CrossrefPubMedSearch in Google Scholar
  • 41 Ufer M, Svensson JO, Krausz KW. et al. Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro. Eur J Clin Pharmacol 2004; 60: 173-182.
    CrossrefPubMedSearch in Google Scholar
  • 42 Dewilde WJ, Janssen PW, Verheugt FW. et al. Triple Therapy for Atrial Fibrillation and Percutaneous Coronary Intervention: A Contemporary Review. J Am Coll Cardiol 2014; 64: 1270-1280.
    CrossrefPubMedSearch in Google Scholar
  • 43 Leadbeater PDM, Kirkby NS, Thomas S. et al. Aspirin has little additional anti-platelet effect in healthy volunteers receiving prasugrel. J Thromb Haemost 2011; 9: 2050-2056.
    CrossrefPubMedSearch in Google Scholar
  • 44 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.
    CrossrefPubMedSearch in Google Scholar
  • 45 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.
    CrossrefPubMedSearch in Google Scholar
  • 46 Ferri N, Corsini A, Bellosta S. Pharmacology of the New P2Y12 Receptor Inhibitors: Insights on Pharmacokinetic and Pharmacodynamic Properties. Drugs 2013; 73: 1681-1709.
    CrossrefPubMedSearch in Google Scholar
  • 47 Sarafoff N, Martischnig A, Wealer J. et al. Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol 2013; 21 (61) 2060-2066.
    PubMedSearch in Google Scholar
  • 48 Lip GY, Windecker S, Huber K. et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J. 2014 Epub ahead of print.
    PubMedSearch in Google Scholar
  • 49 Windecker S, Kolh P, Alfonso F. et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35: 2541-2619.
    CrossrefPubMedSearch in Google Scholar
  • 50 Janssen PW, Ten Berg JM. Platelet function testing and tailored antiplatelet therapy. J Cardiovasc Transl Res 2013; 6: 316-328.
    CrossrefPubMedSearch in Google Scholar