Abstract
Dabigatran and rivaroxaban are novel, vitamin K-independent oral anticoagulants (NOACs) and act via antagonism of the coagulation factor (F) IIa (dabigatran) or FXa (rivaroxaban), respectively. Compared to vitamin-K-antagonists, NOACs have shown non-inferiority of risk and benefit in patients with non valvular atrial fibrillation (AF). In clinical practice there is increasing use of NOACs combined with platelet inhibitors in patients with AF and coronary artery disease. However, whether NOACs affect the function of platelet inhibitors remains incompletely known. This observational study aimed to assess the platelet function in patients receiving dabigatran or rivaroxaban and concomitant platelet inhibitors. A single centre observational study was performed analysing the platelet aggregation of patients treated with dabigatran or rivaroxaban with or without concomitant platelet inhibitors. Measurements before the initiation of NOAC therapy served as the respective control group. Platelet aggregation was measured by multiple electrode aggregometry and was induced with adenosine diphosphate (ADP, 6.5 µM) and arachidonic acid (AA, 0.5 mM), respectively. In order to evaluate whether NOACs interact with platelet inhibition by ASA or the P2Y12-antagonist clopidogrel, 87 patients were grouped according to their concomitant antiplatelet medication. Comparing the ADP- and AA-induced platelet aggregation in patients without concomitant platelet inhibitors (n = 45) no significant differences under therapy with dabigatran (d) or rivaroxaban (r) compared to the control group (c) were observed. In patients taking clopidogrel as a concomitant platelet inhibitor (n = 21), neither dabigatran nor rivaroxaban affected the ADP-induced platelet aggregation (c 20 ± 11, d 21 ± 14, r 18 ± 8 AU*min, p = 0.200). Patients receiving dabigatran or rivaroxaban in combination with ASA (n = 42; 21 ASA only, 21 ASA + clopidogrel) showed no significant differences of the AA-induced aggregation compared to the control group (c 10 ± 8, d 9 ± 7, r 10 ± 8 AU*min, p = 0.810). The antiplatelet effects of ASA and clopidogrel monitored by AA- or ADP-induced platelet aggregation were not affected by NOAC therapy.
Similar content being viewed by others
References
Ajjan R, Grant PJ (2006) Coagulation and atherothrombotic disease. Atherosclerosis 186:240–259
Walsh PN (2004) Platelet coagulation-protein interactions. Semin Thromb Hemost 30:461–471
Hoffman M (2003) Remodeling the blood coagulation cascade. J Thromb Thrombolysis 16:17–20
Borissoff JI, Spronk HM, ten Cate H (2011) The hemostatic system as a modulator of atherosclerosis. N Engl J Med 364:1746–1760
Crawley JT, Zanardelli S, Chion CK, Lane DA (2007) The central role of thrombin in hemostasis. J Thromb Haemost 5(Suppl 1):95–101
Olivier C, Diehl P, Bode C, Moser M (2013) Thrombin receptor antagonism in antiplatelet therapy. Cardiol Ther 2:57–68
Coughlin SR (2005) Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 3:1800–1814
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891
Moser M, Olivier CB, Bode C (2014) Triple antithrombotic therapy in cardiac patients: more questions than answers. Eur Heart J 35:216–223
Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL et al (2012) Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366:9–19
Alexander JH, Lopes RD, James S, Kilaru R, He Y et al (2011) Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 365:699–708
Olivier CB, Weik P, Meyer M, Weber S, Anto-Michel N et al (2015) TRAP-induced platelet aggregation is enhanced in cardiovascular patients receiving dabigatran. Thromb Res 138:63–68
Olivier CB, Schnabel K, Weber S, Zhou Q, Bode C et al (2016) Platelet reactivity after administration of third generation P2Y-antagonists does not depend on body weight in contrast to clopidogrel. J Thromb Thrombolysis. doi:10.1007/s11239-016-1340-9
Gornbein JA, Lazaro CG, Little RJ (1992) Incomplete data in repeated measures analysis. Stat Methods Med Res 1:275–295
Perzborn E, Heitmeier S, Buetehorn U, Laux V (2014) Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor-induced hypercoagulability in vitro and in vivo. J Thromb Haemost 12:1054–1065
Martischnig AM, Mehilli J, Pollak J, Petzold T, Fiedler AK et al (2015) Impact of dabigatran versus phenprocoumon on ADP induced platelet aggregation in patients with atrial fibrillation with or without concomitant clopidogrel therapy (the Dabi-ADP-1 and Dabi-ADP-2 Trials). Biomed Res Int 2015:798486
Kuliczkowski W, Witkowski A, Polonski L, Watala C, Filipiak K et al (2009) Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 30:426–435
Zemer-Wassercug N, Haim M, Leshem-Lev D, Orvin KL, Vaduganathan M et al (2015) The effect of dabigatran and rivaroxaban on platelet reactivity and inflammatory markers. J Thromb Thrombolysis 40:340–346
Eller T, Busse J, Dittrich M, Flieder T, Alban S et al (2014) Dabigatran, rivaroxaban, apixaban, argatroban and fondaparinux and their effects on coagulation POC and platelet function tests. Clin Chem Lab Med 52:835–844
Weisshaar S, Litschauer B, Gouya G, Mayer P, Smerda L et al (2014) Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects. J Thromb Haemost 12:1850–1860
Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J et al (2011) Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 32:2781–2789
Gibson CM, Mehran R, Bode C, Halperin J, Verheugt F et al (2015) An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J 169(472–478):e475
Yamamoto J, Inoue N, Otsui K, Ishii H, Gorog DA (2014) Global Thrombosis Test (GTT) can detect major determinants of haemostasis including platelet reactivity, endogenous fibrinolytic and thrombin generating potential. Thromb Res 133:919–926
Acknowledgments
This work was supported by a grant from the Deutsche Forschungsgemeinschaft (OL 371/1–1 to Christoph B. Olivier).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
C Olivier, P. Diehl, Q. Zhou and M. Moser are investigators in PIONEER AF-PCI. P. Diehl received speaker’s fees from Lilly Deutschland GmbH. C. Bode received speaker’s fees from Merck, AstraZeneca, Sanofi und Bayer. M. Moser received speaker’s fees from Bayer Vital GmbH, AstraZeneca GmbH, Daiichi Sankyo Deutschland GmbH, Pfizer/Bristol-Myers Squibb, Berlin Chemie AG, Lilly Deutschland GmbH, Boehringer Ingelheim Pharma GmbH & Co. and KG Sanofi-Aventis Deutschland GmbH.
Additional information
Martin Moser and Qian Zhou have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Olivier, C.B., Weik, P., Meyer, M. et al. Dabigatran and rivaroxaban do not affect AA- and ADP-induced platelet aggregation in patients receiving concomitant platelet inhibitors. J Thromb Thrombolysis 42, 161–166 (2016). https://doi.org/10.1007/s11239-016-1350-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-016-1350-7