A New Direction in Reversal

Target-specific oral anticoagulants (TSOACs) dabigatran, rivaroxaban, apixaban, and edoxaban are now being used in a larger and more diverse patient population. Despite the fact that bleeding with TSOACs is not expected to be higher compared with the use of other anticoagulant agents, life-threatening bleeding is still a concern. For most situations, a specific antidote may not be needed due to the short half-life of TSOACs. However, the availability of an antidote is essential for the management of any emergency situation. At this time, there are no clinically available reversal agents and there is a lack of guidance on how to restore hemostasis in the presence of significant bleeding from TSOACs.

Current reversal strategies focus on drug removal and managing bleeding. Immediate discontinuation of all anticoagulant and antiplatelet therapy is standard. Activated charcoal is a possible option if treatment is begun within 2 hours of the drug ingestion. Hemodialysis may facilitate removal of dabigatran if clinically feasible (approximately 60% removed in 2-3 hours). Hemostatic agents used as options for management of bleeding include antifibrinolytics (aminocaproic acid and tranexamic acid) and desmopressin. Other hemostatic agents, including activated prothrombin complex concentrate (aPCC), 3- and 4-factor prothrombin complex concentrate (PCC), and recombinant factor VIIa (rVIIa) have all been investigated, but their roles remain inconclusive.

In various healthy volunteer trials, 3-factor PCC and 4-factor PCC have had variable effects on correcting surrogate lab markers.^1,2 A recent study with 3- and 4-factor PCC showed a decrease in prothrombin time in rivaroxaban-treated patients but no effect on abnormal activated partial thromboplastin time or anti-Xa activity.³ aPCC has shown promise in in vitro analyses and was shown to correct abnormal thrombin generation indices in healthy volunteers treated with dabigatran and rivaroxaban.⁴ Recombinant factor VIIa has also shown variable results in in vitro and ex vivo studies but comes with an increased risk of arterial thrombosis in patients without hemophilia.⁵

An aPCC, such as Feiba, dosed at 50 units/kg is suggested for patients exposed to dabigatran. For rivaroxaban, apixaban, and edoxaban, a 4-factor PCC, such as KCentra, is suggested at a dose of 50 units/ kg. It is important to remember that factor concentrates are not antidotes; a thrombotic risk is present by creating hypercoagulability, not reversal. One meta-analysis demonstrated a 1.8% risk of thromboembolic events after 4-factor PCC usage,⁶ and Sarode et al found a 7.8% rate of thromboembolism with use of 4-factor PCC (3.9% deemed related to therapy).⁷

Idarucizumab and Andexanet Alfa

Idarucizumab and andexanet alfa are 2 agents that have been granted breakthrough therapy status by the FDA. Idarucizumab is a fragmented monoclonal antibody with a high affinity for dabigatran. Theoretically, this agent does not elicit procoagulant effects; however, it did successfully reverse bleeding in animal models.^8-10 In a phase 1 study, idarucizumab reversed prolonged clotting times in men and women of various ages and with a range of kidney function.¹¹

Andexanet alfa is a recombinant factor Xa derivative that lacks specific binding activity and is currently undergoing development for the reversal of anti-Xa agents.¹² In a phase 2 trial, the andexanet dose dependently decreased anti-Xa activity and reduced plasma concentrations of free apixaban compared with placebo.¹³ Preliminary results of a phase 3 trial displayed reversal of coagulation test abnormalities and restoration of thrombin generation in an older patient population treated with apixaban.¹⁴

Aripazine

Aripazine is a small synthetic molecule that binds to all TSOACs, as well as heparins, low molecular— weight heparins, fondaparinux, and argatroban. Aripazine has multiple binding sites present on the molecule for each anticoagulant. This reversal agent is currently undergoing phase 2 trials as a nonspecific reversal agent. It has shown promise in animal models¹⁵ and has decreased clotting times in edoxaban-treated healthy volunteers.¹⁶

Many factors affect the multimodal strategy to control or reverse clinical bleeding. Understanding what agents are in our armamentarium to combat bleeding in the setting of a TSOAC is vital, especially in an acute situation. The development of specific antidotes is promising and will increase the safety profile of TSOACs, but does not diminish the caution that needs to be practiced with high-risk patients.

Dr. Adams is a clinical pharmacist for Robert Wood Johnson University Hospital in Somerset, New Jersey, and an adjunct clinical assistant professor at Rutgers University in Piscataway, New Jersey. Dr. Resseguie is an advanced practice anticoagulation pharmacist for the Brigham & Women’s Hospital Anticoagulation Management Service in Boston, Massachusetts.

References

• Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107(2):253-259. doi: 10.1160/TH11-09-0668.
• Dinkelaar J, Molenaar PJ, Ninivaggi M, de Laat B, Brinkman HJ, Leyte A. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost. 2013;11(6):1111-1118. doi: 10.1111/jth.12236.
• Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428-1436. doi: 10.1111/jth.12599.
• Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost. 2014;111(5):989-995. doi: 10.1160/TH13-07-0607.
• Perzborn E, Heitmeier S, Laux V, Buchmuller A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res. 2014;133(4):671-681. doi: 10.1016/j.thromres.2014.01.017.
• Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulaion reversal of vitamin k antagonists. A meta-analysis. Thromb Haemost. 2011;106(3):429-38. doi: 10.1160/TH11-01-0052.
• Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin k antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-1243. doi: 10.1161/CIRCULATIONAHA.113.002283.
• van Ryn J, Schurer J, Kink-Eiband M, Clemens A. Reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation. Anesthesiology. 2014;120(6):1429-1440. doi: 10.1097/ALN.0000000000000255.
• van Ryn J, Litzenburger T, Gan G, Coble K, Schurer J. In vitro characterization, pharmacokinetics and reversal of supratherapeutic doses of dabigatran-induced bleeding in rats by a Managing target-specific oral anticoagulant specific antibody fragment antidote to dabigatran [abstract]. Blood. 2012;120(21):Abstract 3418.
• Toth J, Gan G, van Ryn J, et al. Reversal of dabigatran’s anticoagulant activity in the monkey by a specific antidote and pharmacokinetic and pharmacodynamic modeling. Blood. 2012;120(21):Abstract 22.
• Glund S, Stangier J, Schmohl M, et al. Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Blood. 2014;124(21):344.
• Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446-451. doi: 10.1038/nm.3102.
• Crowther M, Levy GG, Lu G, et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Blood. 2014;124(21):4269.
• Crowther M, Levy GG, Lu G, et al. ANNEXA-A: A phase 3 randomized, double-blind, placebo-controlled trial demonstrating reversal of apixaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Circulation. 2014;130(23):2105-2126.
• Hollenbach S, Lu G, DeGuzman F, et al. Abstract 14657: andexanet-alfa and PER977 (Arapazine) correct blood loss in a rabbit liver laceration model-only andexanet reverses markers of fXa-mediated anticoagulation. Circulation. 2014;130(suppl 2):A14657.
• Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141-2142. doi: 10.1056/NEJMc1411800.