August 5, 2016Open Access
Management of bleeding in patients treated with direct oral anticoagulants
Key Result
Specific reversal agents, including idarucizumab for dabigatran and andexanet alfa for factor Xa inhibitors, are emerging as effective strategies for managing bleeding in patients treated with DOACs.
Structured PICO
P
Population
Patients treated with direct oral anticoagulants (DOACs) who present with bleeding complications or require an urgent invasive procedure
I
Intervention
Reversal strategies including nonspecific agents (prothrombin complex concentrates, recombinant factor VIIa) and specific antidotes (idarucizumab, andexanet-alfa, ciraparantag)
The development and availability of specific reversal agents and strategies for DOACs provide critical therapeutic options for managing severe bleeding or urgent procedural needs in anticoagulated patients.
Limitations
- Most interventions need further evaluation in clinical trials.
- There is very limited real-world evidence with regards to the incidence and severity of DOAC-related bleeding events.
Abstract
Recently, a new generation of direct-acting oral anticoagulants (DOACs) with a greater specificity towards activated coagulation factors was introduced based on encouraging results for efficacy and safety in clinical studies. An initial limitation of these new drugs was the absence of an adequate strategy to reverse the effect if a bleeding event occurs or an urgent invasive procedure has to be carried out. Specific reversing agents for DOACs have become available, however, and are now evaluated in clinical studies. For the anti-factor Xa agents (rivaroxaban, apixaban, and edoxaban) a number of studies have shown that the administration of prothrombin complex concentrate resulted in a correction of the prolonged prothrombin time and restored depressed thrombin generation after rivaroxaban treatment in a controlled trial in healthy human subjects. In view of the relatively wide availability of prothrombin complex concentrates, this would be an interesting option if the results can be confirmed in patients on oral factor Xa inhibitors who present with bleeding complications. More specific reversal can be achieved with andexanet, a new agent currently in development that competitively binds to the anti-factor Xa agents. For the direct thrombin inhibitor dabigatran, the administration of prothrombin complex concentrates showed variable results in various volunteer trials and efficacy at relatively high doses in animal studies. Recently, a Fab fragment of a monoclonal antibody (idarucizumab) was shown to be an effective reversal agent for dabigatran in human studies. For the new generation of DOACs, several reversal strategies and specific antidotes are under evaluation, although most interventions need further evaluation in clinical trials.