Reversal of Anticoagulation: Therapeutic Advances and Clinical Guidelines

Abstract

Background: Anticoagulants are life-saving medications that prevent and treat thromboembolic disease and are of particular importance in the elderly population for prevention of stroke in atrial fibrillation. The advent of direct oral anticoagulants and reversal agents has yielded more options for patients, although complicating clinical decision-making. Areas of Uncertainty: The decision to anticoagulate in atrial fibrillation depends on the risks of stroke versus bleeding. The accompanying HAS-BLED score for predicting bleeding allows an estimation of net clinical benefit. Despite these tools, uncertainty remains. Notably, anticoagulation has traditionally been avoided in patients with recurrent falls. Yet, decision analytic modeling has shown that patients on warfarin would need hundreds of falls annually to warrant discontinuation. At the same time, direct oral anticoagulants, while theoretically simpler to dose than warfarin, should be dose-reduced or avoided in cases of renal impairment, extreme age or weight, or concomitant use of strong P-glycoprotein and/or CYP3A4 inducers/inhibitors. Therapeutic Advances: Prothrombin complex concentrates consist of endogenous coagulation factors and anticoagulants. One 4-factor prothrombin complex concentrates (factors II, VII, IX, X, proteins C, and S), when administered with intravenous vitamin K, effectively reversed warfarin in cases of life-threatening bleeding or need for urgent surgery/procedure in 2 phase IIIb trials, although it may be associated with thrombogenesis. Idarucizumab, a humanized monoclonal antibody, reversed dabigatran-associated bleeding in 11.4 hours in a late-stage trial and had no effect on thrombin in pharmacodynamic studies. Andexanet alfa, a recombinant molecule derived from factor X, is a class-specific reversal agent for factor Xa inhibitors. In trials of healthy individuals (ANNEXA-A, ANNEXA-R), andexanet alfa reversed apixaban and rivaroxaban, although increased levels of d-Dimer and prothrombin fragments 1 and 2, suggesting potential thrombogenesis; the later stage ANNEXA-4 trial is ongoing. Finally, ciraparantag, a small water-soluble molecule, reversed edoxaban and enoxaparin in phase 1/2 trials (by whole blood clotting time), and holds promise as a potential universal reversal agent.