A New Direction in Reversal

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Target-specific oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban are now being used in a larger and more diverse patient population.

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

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