Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants

Abstract

Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.

Extracorporeal Hemoperfusion as a Potential Therapeutic Option for Critical Accumulation of Rivaroxaban

“…With its high degree of protein binding of 92–95% [3], rivaroxaban is regarded as non-dialyzable, as also suggested by results from a clinical study conducted by Dias et al [5]. Since protein binding is regarded as not a limiting factor in hemoperfusion [6], the removal of rivaroxaban, as for example by commonly available coated charcoal cartridges, has been deemed possible, but experimental evidence is still lacking [7]. While Andexanet alfa may offer a promising approach to reverse the FXa inhibitor-mediated anticoagulation of rivaroxaban, it has not yet been approved [8].…”

“…b Inlet/outlet rivaroxaban plasma concentrations, ( c ) extraction ratios R e = (c in – c out )/c in and plasma clearances CL = Q B  × (1 – Hct) × R e [7] during 120 min blood recirculation through the miniaturized CytoSorb columns (mean ± SD, n = 2). CL values were calculated considering the mean hematocrit calculated from the values measured at the start and the end of each experiment (0.349 ± 0.018, n = 4).…”

Hemostasis in Intracranial Hemorrhage

“…It has been studied with rivaroxaban, apixaban, and low-molecular-weight heparin (81). Infusion of andexanet alfa was able to quickly normalize several laboratory assays in randomized controlled trials of healthy elderly volunteers (82).…”

“…Andexanet has no known hemostatic effects. It did reduce tissue factor pathway inhibitor levels, which may imply a prothrombotic effect (81). The ANNEXA-4 trial demonstrated that an initial bolus and subsequent 2-h infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with FXa-I, with effective hemostasis occurring in 79% (83).…”

“…The synthetic compound ciraparantag may prove to be an effective universal reversal agent. It was able to reduce bleeding in animal models and normalize coagulation assays in healthy volunteers given edoxaban and dabigatran with a single IV dose (81, 84). Results of further studies and review by the FDA are pending.…”