The Vitamin K antagonist warfarin was the only oral anticoagulant available for 
decades for the treatment of thrombosis and prevention of thromboembolism until 
Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got 
approved in the last few years. Direct thrombin inhibitor: dabigatran and factor 
Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the 
coagulation cascade. DOACs have many advantages over warfarin. However, the 
biggest drawback of DOACs has been the lack of specific antidotes to reverse the 
anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, 
and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific 
agents used in a DOAC associated bleeding but with limited success. 
Idarucizumab, the first novel antidote against direct thrombin inhibitor 
dabigatran was approved by US FDA in October 2015. It comprehensively reversed 
dabigatran-induced anticoagulation in a phase I study. A phase III trial on 
Idarucizumab also complete reversal of anticoagulant effect of dabigatran. 
Andexanet alfa (PRT064445), a specific reversal agent against factor Xa 
inhibitors, showed a complete reversal of anticoagulant activity of apixaban and 
rivaroxaban within minutes after administration without adverse effects in two 
recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. 
It is currently being studied in ANNEXA-4, a phase IV study. Aripazine 
(PER-977), the third reversal agent, has shown promising activity against 
dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and 
LMWH. This review article summarizes pharmacological characteristics of these 
novel antidotes, coagulation's tests affected, available clinical and 
preclinical data, and the need for phase III and IV studies.