Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates

Summary

Rivaroxaban is an oral, direct factor Xa inhibitor for the management of thromboembolic disorders. Despite its short half-life, the ability to reverse rivaroxaban anticoagulation could be beneficial in life-threatening emergencies. The potential of prothrombin complex concentrate (PCC; Beriplex®), activated PCC (aPCC; FEIBA®) or recombinant activated factor VII (rFVIIa; NovoSeven®) to reverse rivaroxaban in rats and baboons was investigated. Anaesthetised rats pre-treated with intravenous rivaroxaban (2 mg/kg) received intravenous rFVIIa (100/400 μg/kg), PCC (25/50 U/kg) or aPCC (50/100 U/kg) after initiation of bleeding. Clotting times and bleeding times (BTs) were recorded. Rivaroxaban was administered as an intravenous 0.6 mg/kg bolus followed by continuous 0.6 mg/kg/hour infusion in baboons. Animals received intravenous aPCC 50 U/kg (2 U/kg/minute) or rFVIIa 210 μg/kg. BT and clotting parameters were measured. In rats pre-treated with high-dose rivaroxaban, PCC 50 U/kg, aPCC 100 U/kg and rFVIIa 400 μg/kg significantly reduced BT vs rivaroxaban alone (5.4 ± 1.4-fold to 1.5 ± 0.4-fold [p<0.05]; 3.0 ± 0.4-fold to 1.4 ± 0.1-fold [p<0.001]; and 3.5 ± 0.7-fold to 1.7 ± 0.2-fold [p<0.01] vs baseline, respectively). In baboons pre-infused with rivaroxaban and then given aPCC, BT increased by 2.0 ± 0.2-fold and aPCC returned BT to baseline for the duration of its infusion. rFVIIa reduced BT from 2.5 ± 0.3-fold over baseline to 1.7 ± 0.3-fold over baseline. Prolongation of prothrombin time was reduced by PCC, aPCC and rFVIIa in both species. Rivaroxaban reduced thrombin-antithrombin levels; application of PCC and aPCC, but not rFVIIa, increased these levels. In conclusion, PCC, aPCC or rFVIIa have the potential to reverse the anticoagulant and anti-haemostatic effects of rivaroxaban.

Keywords

Baboons - prothrombin complex concentrate - rats - recombinant factor VIIa - rivaroxaban

• References

• 1 Bayer AGPharma. Xarelto^® (rivaroxaban) Summary of Product Characteristics. 2013 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/000944/WC500057108.pdf Accessed March 18, 2013.
• 2 Janssen Pharmaceuticals Inc. Xarelto^® (rivaroxaban) Prescribing Information. 2013 Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022406s004lbl.pdf Accessed March 18, 2013.
• 3 Biemond BJ, Friederich PW, Levi M. et al. Successful inhibition of venous thrombus growth after oral administration of BAY 59-7939, a direct Factor Xa inhibitor in rabbits. Pathophysiol Haemost Thromb. 2004 33. Suppl 2: 24. Abstract OC014.
• 4 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 – an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 03: 514-521.
• 5 Turpie AGG, Lassen MR, Eriksson BI. et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105: 444-453.
• 6 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
• 7 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 8 The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
• 9 Levine MN, Raskob G, Beyth RJ. et al. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 287S-310S.
• 10 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines. (8th Edition). Chest 2008; 133: 160S-198S.
• 11 Hirsh J, Bauer KA, Donati MB. et al. Parenteral anticoagulants: American College of Chest Physicians evidence-based clinical practice guidelines. (8th Edition). Chest 2008; 133: 141S-159S.
• 12 Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 2008; 111: 4871-4879.
• 13 Bristol-Myers Squibb. Coumadin^® (warfarin sodium) Prescribing Information. 2011 Available at: http://packageinserts.bms.com/pi/pi_coumadin.pdf Accessed March 28, 2013.
• 14 sanofi-aventis US LLC. Lovenox^® (enoxaparin sodium) Prescribing Information. 2011 Available at: http://products.sanofiaventis.us/lovenox/lovenox.pdf Accessed March 28, 2013.
• 15 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
• 16 GlaxoSmithKline. Arixtra (fondaparinux sodium) Prescribing Information. 2011 Available at: http://us.gsk.com/products/assets/us_arixtra.pdf Accessed March 28, 2013.
• 17 Kubitza D, Becka M, Wensing G. et al. Safety, pharmacodynamics, and pharmacokinetics 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.
• 18 Pabinger-Fasching I. Warfarin-reversal: results of a phase III study with pasteurised, nanofiltrated prothrombin complex concentrate. Thromb Res 2008; 1221 Suppl: (Suppl. 02) S19-S22.
• 19 Scharrer I. Recombinant Factor VIIa for patients with inhibitors to Factor VIII or IX or Factor VII deficiency. Haemophilia 1999; 05: 253-259.
• 20 Shapiro AD, Gilchrist GS, Hoots WK. et al. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 1998; 80: 773-778.
• 21 Lusher JM, Shapiro SS, Palascak JE. et al. Efficacy of prothrombin-complex concentrates in hemophiliacs with antibodies to factor VIII: a multicenter therapeutic trial. N Engl J Med 1980; 303: 421-425.
• 22 Sjamsoedin LJ, Heijnen L, Mauser-Bunschoten EP. et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double-blind clinical trial. N Engl J Med 1981; 305: 717-721.
• 23 Negrier C, Goudemand J, Sultan Y. et al. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor Eight Bypassing Activity. Thromb Haemost 1997; 77: 1113-1119.
• 24 Hoffman M, Monroe III DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85: 958-965.
• 25 Turecek PL, Varadi K, Gritsch H. et al. FEIBA: mode of action. Haemophilia 2004; 10 Suppl: (Suppl. 02) 3-9.
• 26 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.
• 27 Fukuda T, Honda Y, Kamisato C. et al. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost 2012; 107: 253-259.
• 28 Marlu R, Hodaj E, Paris A. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108: 217-224.
• 29 Pragst I, Zeitler SH, Doerr B. et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012; 10: 1841-1848.
• 30 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: 94-102.
• 31 Elg M, Carlsson S, Gustafsson D. Effects of agents, used to treat bleeding disorders, on bleeding time prolonged by a very high dose of a direct thrombin inhibitor in anesthesized rats and rabbits. Thromb Res 2001; 101: 159-170.
• 32 Elg M, Carlsson S, Gustafsson D. Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res 2001; 101: 145-157.
• 33 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.
• 34 Chan S, Kong M, Minning DM. et al. Assessment of recombinant factor VIIa as an antidote for bleeding induced in the rabbit by low molecular weight heparin. J Thromb Haemost 2003; 01: 760-765.
• 35 Gruber A, Carlsson S, Kotze HF. et al. Hemostatic effect of activated factor VII without promotion of thrombus growth in melagatran-anticoagulated primates. Thromb Res 2007; 119: 121-127.
• 36 Todd ME, McDevitt E, Goldsmith EI. Blood-clotting mechanisms of nonhuman primates. Choice of the baboon model to simulate man. J Med Primatol 1972; 01: 132-141.
• 37 Gikakis N, Rao AK, Miyamoto S. et al. Enoxaparin suppresses thrombin formation and activity during cardiopulmonary bypass in baboons. J Thorac Cardiovasc Surg 1998; 116: 1043-1051.
• 38 van Wyk V, Neethling WM, Badenhorst PN. et al. r-Hirudin inhibits platelet-dependent thrombosis during cardiopulmonary bypass in baboons. J Cardiovasc Surg 1998; 39: 633-639.
• 39 Mueck W, Lensing AW, Agnelli G. et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50: 675-686.
• 40 Perzborn E, Roehrig S, Straub A. et al. Rivaroxaban: a new oral Factor Xa inhibitor. Arterioscler Thromb Vasc Biol 2010; 30: 376-381.
• 41 Kubitza D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
• 42 CSL Behring GmbH. Beriplex P/N^® Summary of Product Characteristics. 2011 Available at: http://www.medicines.org.uk/emc/medicine/21147/SPC/Beriplex+P+N+250+&+500+IU Accessed March 28, 2013.
• 43 Immuno Ltd. FEIBA^® (human plasma proteins with Factor VIII inhibitor bypassing activity) Summary of Product Characteristics. 2007 Available at: http://www.mhra.gov.uk/home/groups/l-unit1/documents/websiteresources/ con014534.pdf Accessed March 28, 2013.
• 44 Novo Nordisk A/S. NovoSeven^® (eptacog alfa [activated]) Summary of Product Characteristics. 2012 Available at: http://www.medicines.org.uk/emc/document.aspx?documentid=21171&docType=SPC#PRODUCTINFO Accessed March 28, 2013.
• 45 Petersen LC, Norby PL, Branner S. et al. Characterization of recombinant murine factor VIIa and recombinant murine tissue factor: a human-murine species compatibility study. Thromb Res 2005; 116: 75-85.
• 46 Lauritzen B, Hedner U, Johansen PB. et al. Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats. J Thromb Haemost 2008; 06: 804-811.
• 47 Dickneite G. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation. Thromb Res 2007; 119: 643-651.
• 48 Turpie AGG. Oral, direct Factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol 2007; 27: 1238-1247.
• 49 Dejana E, Callioni A, Quintana A. et al. Bleeding time in laboratory animals. II -A comparison of different assay conditions in rats. Thromb Res 1979; 15: 191-197.
• 50 Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16: 1-20.