In the last decade, several direct oral anticoagulants (DOAC; dabigatran, 
rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or 
treatment of thromboembolism without having specific antidotes available for 
their reversal. Current management of bleeding associated to DOAC includes the 
removal of all antithrombotic medications and supportive care. Non-specific 
procoagulant agents (prothrombin complex concentrates and activated factor VIIa) 
have been used in case of serious bleeding. Currently, some specific antidotes 
for the DOAC are under development. Idarucizumab (BI 655075; Boehringer 
Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to 
the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, 
PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically 
inactive factor Xa, which binds and reverses the anticoagulant action of the 
factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine 
(PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) 
that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous 
fondaparinux and LMWH in vivo. These antidotes could provide an alternative for 
management of life-threatening bleeding events occurring with the 
above-mentioned anticoagulants. In addition, the specific antidote anivamersen 
(RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to 
reverse the anticoagulant effect of the parenteral factor IXa inhibitor 
pegnivacogin, which is also in development. This anticoagulant-antidote pair may 
provide an alternative in situations in which a fast onset and offset of 
anticoagulation is needed, like in patients undergoing cardiac surgery with 
extracorporeal circulation, as an alternative to the heparin/protamine pair. 
This patent review includes a description of the pharmacological characteristics 
of the novel specific antidotes, the available results from completed 
non-clinical and clinical studies and the description of ongoing clinical trials 
with the new compounds.