Reversal agents for use with direct and indirect anticoagulants

Abstract

Purpose. The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market.Summary. Idarucizumab, which received Food and Drug administration approval in october 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance.Conclusion. as agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.Am J Health-Syst Pharm. 2016; 73(suppl 2):s27-48

Current knowledge on assessing the effects of and managing bleeding and urgent procedures with direct oral anticoagulants

“…Given the desire to have a specific reversal agent to manage bleeding in the presence of anticoagulation therapy or reverse its effects before an invasive procedure, several products are being developed and are described by Smythe et al 102 in this supplement. Idarucizumab, a specific reversal agent for dabigatran, was approved by FDA in October 2015.…”

Overview of direct oral anticoagulant therapy reversal

“…33,34,37,38 However, there is a lack of data on the role of this agent in managing serious bleeding in patients receiving oral anticoagulants. 25,39 Further, idarucizumab can be considered for dabigatran-related bleeding as discussed in the article by Smythe et al 40 in this supplement. Prolonged dialysis for patients taking dabigatran should be considered to avoid redistribution of the medication from the tissue compartment.…”

“…43 Currently, there are two additional reversal agents in late-stage development for emergency reversal in patients taking DOACs. These agents are discussed in more detail by Smythe et al 40 in this supplement and are summarized in Table 4. [44][45][46][47][48][49][50] The development of DOAC reversal agents that do not interact with native coagulation has generated much excitement.…”

Evaluating the benefits of home-based management of atrial fibrillation: current perspectives

“…Ciraparantag exerts its anticoagulation reversal effects by binding to heparins and NOACs through noncovalent hydrogen bonding, thus preventing them from binding to their endogenous targets 131. Ciraparantag is currently being investigated in Phase II trials 132,133. Ciraparantag has been investigated in healthy human volunteers.…”

“…Ciraparantag did not have procoagulant effects. The only adverse events reported were headache, taste distortion, and mild perioral and facial flushing 133. Similar to ANNEXA-A and ANNEXA-R trials, these trials did not assess the efficacy and safety of ciraparantag in patients who were actively bleeding or requiring emergent surgery.…”