Authors

  1. Rosini, Jamie M. PharmD, BCPS, BCCCP
  2. Tully, Andrea PharmD, BCPS, BCCCP

Article Content

Are any specific reversal agents available for direct oral anticoagulants (DOACs)?-T.S., MASS.

 

Jamie M. Rosini, PharmD, BCPS, BCCCP, and Andrea Tully, PharmD, BCPS, BCCCP, respond: The DOACs include dabigatran, a direct thrombin inhibitor, and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. DOACs are also sometimes referred to as target-specific oral anticoagulants. DOACs are similar in efficacy to warfarin for the prevention and treatment of thrombosis but with fewer food and drug interactions and without the requirement for regular international normalized ratio monitoring.1

 

Unlike warfarin, DOACs aren't reversed by vitamin K, and strategies for controlling bleeding for patients on these medications are limited.1 Although some guidelines recommend off-label use of prothrombin complex concentrates (PCCs) to reverse DOACs, no clinical trials support this practice, and in vitro studies have demonstrated inconsistent effects on coagulation parameters.2

 

The most serious adverse reaction related to PCC administration is thrombosis, including venous thromboembolism, disseminated intravascular coagulation, myocardial infarction, and stroke. Always carefully weigh the risk of thrombosis with the need for anticoagulant reversal. Dosing of PCCs is weight-based and may depend on the agent being reversed and type of PCC used; refer to clinical practice guidelines for dosing information.

 

Idarucizumab is a humanized monoclonal antibody fragment that's FDA-approved for reversal of dabigatran for emergency surgery or urgent procedures and for life-threatening or uncontrolled bleeding.3 It binds to dabigatran, neutralizing its anticoagulant effect within minutes.4 Adverse reactions related to idarucizumab administration include hypersensitivity reactions and thrombotic events related to reversal of anticoagulation.

 

Several medications specifically intended for reversal of DOACs are in the pipeline. Andexanet alfa is a recombinant modified human factor Xa decoy protein. Anticoagulants that typically bind with factor Xa have a higher affinity for binding with andexanet, which makes them unavailable to inhibit the coagulation cascade.5 It's currently being studied for reversal of the oral factor Xa inhibitors as well as some parenteral anticoagulants.

 

In a clinical trial assessing the safety and efficacy of andexanet in patients on Xa inhibitors with acute major bleeding, antifactor Xa activity was significantly decreased and hemostasis was achieved in most patients at 12 hours. Thrombotic events occurred in 18% of patients within 30 days, mostly due to discontinuation of anticoagulation. The FDA determined that additional information related to manufacturing and use for reversal of edoxaban and enoxaparin are needed prior to approval.6

 

Ciraparantag is a small molecule currently in development that directly binds factor Xa inhibitors, dabigatran, heparin, low-molecular-weight heparin, and fondaparinux to neutralize their anticoagulant effects.7,8 Animal studies have demonstrated that ciraparantag decreases blood loss in rat-tail bleeding models. Studies in healthy volunteers are ongoing.9,10

 

FXa (I16L) is a mutant form of factor Xa that's also being studied as a universal DOAC antidote. Mouse models have demonstrated that FXa (I16L) rapidly restores hemostasis in the presence of inhibitors of thrombin and factor Xa.11

 

Availability of new reversal agents may alleviate concerns about bleeding with DOACs, which may result in more prescribing of these agents and less warfarin use in the community.

 

REFERENCES

 

1. Battinelli EM. Reversal of new oral anticoagulants. Circulation. 2011;124(14):1508-1510. [Context Link]

 

2. Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost. 2015;13(suppl 1):S187-S194. [Context Link]

 

3. Praxbind (idarucizumab) injection, for intravenous use. Prescribing information. http://www.praxbind.com.[Context Link]

 

4. Pollack CV Jr, Reilly PA, Eikelboom J, et al Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511-520. [Context Link]

 

5. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141. [Context Link]

 

6. Portola Pharmaceuticals receives complete response letter from FDA for biologics license application for AndexXa. Portola Pharmaceuticals, Inc. News release. August 17, 2017. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsroomArticle&ID=2196085. [Context Link]

 

7. Ciraparantag (PER977): broad-spectrum anticoagulant reversal agent. Perosphere, Danbury, CT; 2017. http://perosphere.com/content/research/per977.htm. [Context Link]

 

8. Mo Y, Yam FK. Recent advances in the development of specific antidotes for target-specific oral anticoagulants. Pharmacotherapy. 2015;35(2):198-207. [Context Link]

 

9. ClinicalTrials.gov. Study of PER977 administered to subjects with steady state edoxaban dosing and re-anticoagulation with edoxaban. 2015. https://clinicaltrials.gov/ct2/show/NCT02207257. [Context Link]

 

10. ClinicalTrials.gov. Evaluation of the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of PER977 following heparin. 2015. https://clinicaltrials.gov/ct2/show/NCT02206087. [Context Link]

 

11. Thalji NK, Ivanciu L, Davidson R, Gimotty PA, Krishnaswamy S, Camire RM. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med. 2016;22(8):924-932. [Context Link]