Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data.

Abstract

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.

• Authors: Ramyashree Tummala, Ana Kavtaradze, Anjan Gupta, Raktim Kumar Ghosh
• Journal: International journal of cardiology (Int J Cardiol) Vol. 214 Pg. 292-8 (Jul 01 2016) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 27082776 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Anticoagulants
• Antidotes
• PRT064445
• Recombinant Proteins
• idarucizumab
• Factor Xa
• Dabigatran

Topics

• Administration, Oral
• Antibodies, Monoclonal, Humanized (administration & dosage, therapeutic use)
• Anticoagulants (administration & dosage, adverse effects)
• Antidotes (administration & dosage)
• Clinical Trials as Topic
• Dabigatran (administration & dosage, adverse effects)
• Factor Xa (administration & dosage, adverse effects)
• Hemorrhage (chemically induced, drug therapy)
• Humans
• Recombinant Proteins (administration & dosage, adverse effects)