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Frequently Asked Questions

What methods are available for reversal of dabigatran and rivaroxaban?

Introduction

Recently, 2 new anticoagulant agents-dabigatran and rivaroxaban-have been approved for use in the United States for reduction of the risk of stroke in association with atrial fibrillation (dabigatran) and for prophylaxis of deep vein thromboembolism in patients undergoing knee or hip replacement surgery (rivaroxaban).1,2 In addition to differing in labeled indications, the 2 agents differ in their mechanism of action. Dabigatran is a direct thrombin inhibitor, preventing the conversion of fibrinogen to fibrin and subsequent thrombus formation.1 Rivaroxaban is a factor Xa inhibitor, blocking an essential step in the coagulation cascade for thrombus formation.2 However, both agents are given in a fixed-dose regimen and do not require routine monitoring.3,4 In addition, unlike well-established anticoagulants such as warfarin and unfractionated heparin, there are no clear antidotes for reversal of the anticoagulant effects of either of these newer agents. Although both have relatively short half-lives (12 to 17 hours for dabigatran and 5 to 9 hours for rivaroxaban) there may be situations where urgent reversal of anticoagulant effects is needed (e.g., emergency surgery, overdose, or life-threatening bleeding).

Agents for reversal

Several publications are available with suggested approaches to reversal of the anticoagulant effects of dabigatran and rivaroxaban. Both recombinant factor VIIa (rFVIIa) and prothrombin complex concentrates (PCCs) have been suggested as agents for reversal for both dabigatran and rivaroxaban. van Ryn and colleagues conducted an in vitro study using rFVIIa and a PCC (FEIBA[a] to reverse the effects of high dose dabigatran in an animal model. 5 Following administration of dabigatran, rFVIIa (0.5 or 1 mg/kg) and FEIBA (50 or 100 U/kg) were both found to reduce bleeding time from 1455 seconds to less than 186 seconds. Use of rFVIIa also reduced activated prothrombin time (aPTT) from 58.8 seconds to ~ 30 seconds; however, FEIBA had no effect on aPTT.

Eerenberg conducted a double-blind crossover trial to assess the effects of PCCs[b] versus placebo in reversal of the effects of both dabigatran and rivaroxaban in healthy volunteers.6 Twelve healthy volunteers were randomized to either dabigatran (150 mg twice daily) or rivaroxaban (20 mg twice daily) for 2.5 days. On the third day, patients were given either a PCC or placebo (50 U/kg). The PCC used in this trial was Cofact, a nonactivated PCC containing factors II, VII, IX, and X. After 11 days, patients were crossed-over to the alternate anticoagulant treatment and the study procedures repeated. The results are given in the Table. Overall, PCC had a significant effect on normalizing elevated coagulation parameters following rivaroxaban but had no effects on abnormal coagulation parameters following dabigatran.

[a] FEIBA is an activated prothrombin complex concentrate, containing nonactivated factors I, IX, X, and activated factor VII.

[b] Prothrombin complex concentrates are generally classified as 4-factor and 3-factor concentrates. In the United States, only two PCCs are available (Profilnine and Bebulin), both of which are 3-factor concentrates and contain lower concentrations of factor VII as compared to 4-factor concentrates. Cofact, a 4-factor concentrate, is not available in the United States.

Table. Effects of PCC on anticoagulation with dabigatran and rivaroxaban.6

Anti-coagulant Reversal agent (change from posttreatment)
Baseline (after anticoagulant treatment) Post-PCC treatment value
PT aPTT ETPa TT ECT PT aPTT ETPa TT ECT
Dabigatran NA 59.4 s 7.5 m >120 s 69 s NA 70.3 s 8.7 m Immeasurable prolongation 86 s
Rivaroxaban 15.8 s NA 51% NA NA 12.8 sb NA 114%b NA

a Thrombin generation tests assess the change in the thrombin generation by treatment. In this study, the effects of treatment on thrombin generation (as endogenous thrombin potential [ETP]) were measured as lag time to thrombin generation for dabigatran and the potential (as percentage) for thrombin generation for rivaroxaban. Effective reversal of dabigatran would be indicated by a shorter lag time to thrombin generation and an increase in percentage of potential for rivaroxaban.

b Significant change from baseline.

aPTT, activated prothrombin time; ECT, ecarin clotting time; ETP, endogenous thrombin potential; NA, not applicable; PT, prothrombin time; TT, thrombin time.

Other interventions have been suggested for overdoses of dabigatran and rivaroxaban. van Ryn and colleagues have developed an algorithm for treatment of bleeding with dabigatran.3 For mild bleeding, a delay in dosing or discontinuation of the drug has been suggested. For patients with moderate to severe bleeding, treatment recommendations include mechanical compression, surgical intervention, fluid replacement, transfusion, oral charcoal (for ingestions < 2 h before), and hemodialysis. Use of either PCC, FVIIa, and fresh frozen plasma have been suggested by van Ryn and other authors for life-threatening bleeding, as well as charcoal filtration and hemodialysis.3,7 The PCCs have also been suggested for reversal of rivaroxaban, by providing more factor X and Xa.4 However, there is little clinical evidence for these interventions.

Summary

Currently, there are no definitive treatments for reversal of the effects of dabigatran or rivaroxaban. One available clinical trial supports the use of PCCs for rivaroxaban-associated bleeding. However, data are limited. Treatment of excess bleeding due to either of these agents needs to be individualized, with close monitoring of patient response.

References

1. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc: 2011.

2. Xarelto [package insert]. Titusville, NJ; Janssen Pharmaceuticals; 2011.

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(6):1116-1127.

4. DeLoughery T. Practical aspects of the oral new anticoagulants. Am J Hematol. 2011;86(7):586-590.

5. van Ryn J, Ruehl HD, Preipke H, Hauel N, Wienen W. 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.

6. Eerenberg E, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrates. Circulation. 2011. Doi. 10.1161/CirculationAHA.111.029017.

7. Watanabe M, Siddiqui F, Qureshi AI. Incidence and management of ischemic stroke and intracerebral hemorrhage in patients on dabigatran etexilate treatment. Neurocrit Care. 2011. Doi. 10.1007/s12028-011-9591-y.