Antidote for Factor Xa Inhibitors: Approved

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Whenever I have a conversation with a patient about starting anticoagulation for nonvalvular atrial fibrillation (AF) with a CHA₂DS₂-Vasc score ≥2, I always go into the advantages and disadvantages of warfarin vs the direct oral anticoagulants (DOACs). Until now, one of the main limitations to clinical use of three of the DOACs-the factor Xa (FXa) inhibitors apixaban, rivaroxaban, and edoxaban, was the lack of a reversal agent. Fresh frozen plasma is typically used to reverse warfarin in acute, life-threatening situations; similarly, idarucizumab (Praxbind) was approved by the FDA in 2015 to reverse the action of the direct thrombin inhibitor dabigatran (Pradaxa). The lack of a reversal agent for the FXa inhibitors often leads patients to question the safety of these medications.

The scenario changed in early May 2018 with the FDA approval of andexanet alfa (Andexxa, Portola Pharmaceuticals), for the reversal of apixaban and rivaroxaban in situations of life-threatening or uncontrolled bleeding. The approval came via FDA’s accelerated approval pathway and is based on reversal of rivaroxaban in the ANNEXA-R trial and of apixaban in the ANNEXA-A trial in healthy volunteers. A bolus of this agent results in a rapid and sustained decrease in levels of anti-FXa (>90% for rivaroxaban; >93% for apixaban in ~50% of patients). There have been no studies yet of edoxaban and andexanet.

There are several warnings associated with andexanet use, including arterial and venous thromboembolic events, ischemic events such as MI and stroke, or cardiac arrest/sudden death (occurred in ~18% of patients in the ANNEXA-4 safety study with a median time to event of 6 days). To reduce the incidence of such events, it is suggested that anticoagulation be resumed as soon as possible. Andexanet has not been studied in patients with disseminated intravascular coagulation within the previous 2 weeks or in those who receive prothrombin complex concentrate, recombinant factor VIIa, or blood products within 7 days of bleeding event. 

The ANNEXA-4 is the ongoing safety study. Thus far, there have been no significant adverse reactions:  ≥5% of patients had UTIs and pneumonia and ≥3% had infusion-related reactions. Furthermore, there were low titers of anti-andexanet antibodies in 17% of subjects with 14% of all subjects having titers present after 1 month. None of these antibodies were neutralizing or cross-reacting with FX or FXa. The FDA considered these data when approving this agent.

Although cost data are not yet available, andexanet is likely to be expensive. 

The approval of andexanet provides another discussion point when the topic of oral anticoagulation comes up with a patient diagnosed with nonvalvular AF.

References:

1. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexxa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413-2424.

2. Andexxa [package insert]. South San Francisco, CA: Portola Pharmaceuticals Inc; 2018.