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Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data.
Int J Cardiol. 2016 Jul 01; 214:292-8.IJ

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+Show Affiliations

Department of Internal Medicine, St. Vincent Charity Medical Center, A Teaching Affiliate of Case Western Reserve University, Cleveland, OH, USA.Department of Internal Medicine, St. Vincent Charity Medical Center, A Teaching Affiliate of Case Western Reserve University, Cleveland, OH, USA.Department of Cardiovascular Medicine, St. Vincent Charity Medical Center, A Teaching Affiliate of Case Western Reserve University, Cleveland, OH, USA.Department of Internal Medicine, St. Vincent Charity Medical Center, A Teaching Affiliate of Case Western Reserve University, Cleveland, OH, USA. Electronic address: raktimghoshmd@gmail.com.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

27082776

Citation

Tummala, Ramyashree, et al. "Specific Antidotes Against Direct Oral Anticoagulants: a Comprehensive Review of Clinical Trials Data." International Journal of Cardiology, vol. 214, 2016, pp. 292-8.
Tummala R, Kavtaradze A, Gupta A, et al. Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. Int J Cardiol. 2016;214:292-8.
Tummala, R., Kavtaradze, A., Gupta, A., & Ghosh, R. K. (2016). Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. International Journal of Cardiology, 214, 292-8. https://doi.org/10.1016/j.ijcard.2016.03.056
Tummala R, et al. Specific Antidotes Against Direct Oral Anticoagulants: a Comprehensive Review of Clinical Trials Data. Int J Cardiol. 2016 Jul 1;214:292-8. PubMed PMID: 27082776.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. AU - Tummala,Ramyashree, AU - Kavtaradze,Ana, AU - Gupta,Anjan, AU - Ghosh,Raktim Kumar, Y1 - 2016/03/28/ PY - 2016/01/08/received PY - 2016/03/13/revised PY - 2016/03/15/accepted PY - 2016/4/16/entrez PY - 2016/4/16/pubmed PY - 2017/7/19/medline KW - ANNEXA-A KW - ANNEXA-R KW - Andexanet alfa KW - Antidote KW - Apixaban KW - DOAC KW - Dabigatran KW - Edoxaban KW - Idarucizumab KW - NOAC KW - Praxbind KW - Rivaroxaban SP - 292 EP - 8 JF - International journal of cardiology JO - Int. J. Cardiol. VL - 214 N2 - 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. SN - 1874-1754 UR - https://www.unboundmedicine.com/medline/citation/27082776/Specific_antidotes_against_direct_oral_anticoagulants:_A_comprehensive_review_of_clinical_trials_data_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0167-5273(16)30468-5 DB - PRIME DP - Unbound Medicine ER -