Download PDF
Thromb Haemost 2012; 108(02): 217-224
DOI: 10.1160/TH12-03-0179
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban

A randomised crossover ex vivo study in healthy volunteers
Raphael Marlu
1   Haemostasis Unit, University Hospital Grenoble, France
,
Enkelejda Hodaj
2   Clinical Research Centre, INSERM CIC03, University Hospital Grenoble, France
,
Adeline Paris
2   Clinical Research Centre, INSERM CIC03, University Hospital Grenoble, France
,
Pierre Albaladejo
3   Department of Anaesthesiology, University Hospital Grenoble, France
5   Joseph Fourier Grenoble 1 University / CNRS TIMC-IMAG UMR 5525 / THemas, Grenoble, France
,
Jean Luc Crackowski
2   Clinical Research Centre, INSERM CIC03, University Hospital Grenoble, France
,
Gilles Pernod
4   Vascular Medical Unit, University Hospital Grenoble, France
5   Joseph Fourier Grenoble 1 University / CNRS TIMC-IMAG UMR 5525 / THemas, Grenoble, France
› Author Affiliations
Further Information

Publication History

Received: 21 March 2012

Accepted after major revision: 18 April 2012

Publication Date:
25 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

The new anticoagulants dabigatran and rivaroxaban can be responsible for haemorrhagic complications. As for any anticoagulant, bleeding management is challenging. We aimed to test the effect of all putative haemostatic agents on the anticoagulant activity of these new drugs using thrombin generation tests. In an ex vivo study, 10 healthy white male subjects were randomised to receive rivaroxaban (20 mg) or dabigatran (150 mg) in one oral administration. After a two weeks washout period, they received the other anticoagulant. Venous blood samples were collected just before drug administration (H0) and 2 hours thereafter. Reversal of anticoagulation was tested in vitro using prothrombin complex concentrate (PCC), rFVIIa or FEIBA® at various concentrations. Rivaroxaban affects quantitative and kinetic parameters, including the endogenous thrombin potential (ETP-AUC and more pronouncedly the thrombin peak), the lag-time and time to peak. PCC strongly corrected ETP-AUC, whereas rFVIIa only modified the kinetic parameters. FEIBA corrected all parameters. Dabigatran specially affects the kinetics of thrombin generation with prolonged lag-time and time to peak. Although PCC increased ETP-AUC, only rFVIIa and FEIBA corrected the altered lag-time. For both anticoagulants, lower doses of FEIBA, corresponding to a quarter to half the dose usually used, have potential reversal profile of interest. In conclusion, some non-specific reversal agents appear to be able to reverse the anticoagulant activity of rivaroxaban or dabigatran. However, clinical evaluation is needed regarding haemorrhagic situations, and a meticulous risk-benefit evaluation regarding their use in this context is required.

Keywords

Anticoagulants - dabigatran - rivaroxaban - reversal - thrombin generation test
 

  • References

  • 1 Connolly SJ, Ezekowitz MD, Yusuf S. et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedSearch in Google Scholar
  • 2 Patel MR, Mahaffey KW, Garg J. et al. ROCKET AF Investigators Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
    CrossrefPubMedSearch in Google Scholar
  • 3 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Pengo V, Crippa L, Falanga A. et al. Questions and answers on the use of dabigatran and perpectives on the use of other new oral anticoagulants in patients with atrial fibrillation. A consensus document of the Italian Federation of Thrombosis Centers (FCSA). Thromb Haemost 2011; 106: 868-876.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost 2011; 09: 1705-1712.
    CrossrefPubMedSearch in Google Scholar
  • 6 Gatt A, van Veen JJ, Woolley AM. et al. Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro. Thromb Haemost 2008; 100: 350-355.
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Kubitza D, Becka M, Wensing G. et al. Safety, pharmacodynamics, and phar-macokinetics of BAY 59–7939--an oral, direct Factor Xa inhibitor--after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: 873-880.
    CrossrefPubMedSearch in Google Scholar
  • 8 Stangier J, Rathgen K, Stähle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
    CrossrefPubMedSearch in Google Scholar
  • 9 Hemker HC, Al Dieri R, De Smedt E. et al. Thrombin generation, a function test of the haemostatic thrombotic system. Thromb Haemost 2006; 96: 553-561.
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Freyburger G, Macouillard G, Labrouche S. et al. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: Tw o observational studies in patients undergoing total hip or total knee replacement. Thromb Res 2011; 127: 457-465.
    CrossrefPubMedSearch in Google Scholar
  • 11 Hillarp A, Baghaei F, Fagerberg Blixter I. et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 09: 133-139.
    CrossrefPubMedSearch in Google Scholar
  • 12 Graff J, von Henting N, Misselwitz F. et al. Effects of the oral, direct factor Xa Rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007; 47: 1398-1407.
    CrossrefPubMedSearch in Google Scholar
  • 13 Legrand M, Mateo J, Aribaud A. et al. The Use of Dabigatran in Elderly Patients. Arch Int Med 2011; 171: 1285-1288.
    CrossrefPubMedSearch in Google Scholar
  • 14 Levi MM, Eerenberg E, Löwenberg E. et al. Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management. Neth J Med 2010; 68: 68-76.
    PubMedSearch in Google Scholar
  • 15 Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med 2009; 02: 217-225.
    CrossrefPubMedSearch in Google Scholar
  • 16 Eerenberg ES, Kamphuisen PW, Sijpkens MK. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573-1579.
    CrossrefPubMedSearch in Google Scholar
  • 17 Godier A, Miclot A, Le Bonniec B. et al. Evaluation of Prothrombin Complex Concentrate and Recombinant Activated Factor VII to Reverse Rivaroxaban in a Rabbit Model. Anesthesiology 2012; 116: 1-9.
    CrossrefPubMedSearch in Google Scholar
  • 18 Gerotziafas GT, Elalamy I, Depasse F. et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007; 05: 886-888.
    CrossrefPubMedSearch in Google Scholar
  • 19 Bijsterveld NR, Moons AH, Boekholdt SM. et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-2554.
    CrossrefPubMedSearch in Google Scholar
  • 20 Bijsterveld NR, Vink R, van Aken BE. et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 2004; 124: 653-658.
    CrossrefPubMedSearch in Google Scholar
  • 21 Al Dieri R, Peyvandi F, Santagostino E. et al. The Thrombogram in Rare Inherited Coagulation Disorders: Its Relation to Clinical Bleeding. Thromb Haemost 2002; 88: 576-582.
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Perzborn E, Tinel H. FEIBA reverses the effects of a high dose of rivaroxaban in rats. Pathophysiol Haemost Thromb 2007; 36 (Suppl. 01) A40.
    CrossrefPubMedSearch in Google Scholar
  • 23 Gruber A, Marzec UM, Buetehorn U. et al. Potential of activated complex concentrate and activated factor VII to reverse the anticoagulant effects of Rivaroxaban in primates. Haematologica. 2009 92. Suppl 2 181 (Abstract 0449).
    PubMedSearch in Google Scholar
  • 24 Wienen W, Stassen JM, Priepke H. et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007; 98: 155-162.
    Thieme ConnectPubMedSearch in Google Scholar
  • 25 Van Ryn J, Dörr B, Kaspereit F. et al. Beriplex P/N reverses bleeding in an acute renal injury model after dabigatran overdose in rabbits. Pathophysiol Haemost Thromb. 2010 37. A94-P486. (Abstract).
    PubMedSearch in Google Scholar
  • 26 Zhou W, Schwarting S, Illanes S. et al. Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran. Stroke 2011; 42: 3594-3599.
    CrossrefPubMedSearch in Google Scholar
  • 27 Wolzt M, Levi M, Sarich TC. et al. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 2004; 91: 1090-1096.
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Sørensen B, Ingerslev J. A direct thrombin inhibitor studied by dynamic whole blood clot formation. Haemostatic response to ex-vivo addition of recombinant factor VIIa or activated prothrombin complex concentrate. Thromb Haemost 2006; 96: 446-453.
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 van Ryn J, Ruehl D, Priepke H. et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor Dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate. Haematologica. 2008 93. Suppl 1 148 (Abstract).
    PubMedSearch in Google Scholar
  • 30 Luu H, Ewenstein B. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia 2004; 10 (Suppl. 02) 10-16.
    CrossrefPubMedSearch in Google Scholar
  • 31 Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 2002; 08: 83-90.
    CrossrefPubMedSearch in Google Scholar
  • 32 Hron G, Kollars M, Binder BR. et al. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. J Am Med Assoc 2006; 296: 397-402.
    CrossrefPubMedSearch in Google Scholar
  • 33 Ay C, Dunkler D, Simanek R. et al. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2011; 29: 2099-2103.
    CrossrefPubMedSearch in Google Scholar
  • 34 Warkentin TE, Margetts P, Connolly SJ. et al. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012; 119: 2172-2174.
    CrossrefPubMedSearch in Google Scholar
  • 35 Samama MM, Martinoli JL, LeFlem L. et al. Assessment of laboratory assays to measure Rivaroxaban – an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103: 815-825.
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Hillarp A, Baghaei F, Fagerberg Blixter I. et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 09: 133-139.
    CrossrefPubMedSearch in Google Scholar
  • 37 Barrett YC, Wang Z, Frost C. et al. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104: 1263-1271.
    Thieme ConnectPubMedSearch in Google Scholar