Andexanet alfa, a recombinant inactive form of human factor Xa, was developed for reversal of factor Xa (FXa) inhibitors. This publication is the final report of the ANNEXA-4 study, which enrolled 352 patients with major acute bleeding within 18 hours after taking a FXa inhibitor (mostly apixaban and rivaroxaban).

As previously reported, andexanet alfa was given as an IV bolus, followed by a 2-hour infusion. The co-primary outcomes included percent change in anticoagulant (anti-factor Xa activity) after treatment and percentage of patients with excellent or good haemostatic efficacy at 12 hours at the end of the infusion. Most patients presented with either intracranial haemorrhage (ICH) (227 patients; 64%) or gastrointestinal (GI) bleeding (90 patients; 26%).

Excellent or good haemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event was reported in 34 (10%). The authors observed that anti-factor Xa activity reduction was not predictive of haemostatic efficacy overall but was modestly predictive with ICH. The investigators concluded that andexanet alfa reduced anti-factor Xa activity and 82% of patients had excellent or good haemostatic efficacy at 12 hours.

This data is consistent with earlier reports regarding the efficacy of andexanet alfa. Of note, however, is that most patients had ICH (64%) or GI bleeding (26%). When you examine the anti-factor Xa activity, the andexanet load and infusion reduce levels for ~3 hours, and the anticoagulation activity levels return to placebo patients and matches renal and hepatic elimination. More critically ill patients with an ICH who had a GCS <7 or intracerebral haematoma >60 cc were excluded from the study. Surgical patients have not been studied. Andexanet also reverses heparin and low-molecular-weight heparin.

The European Commission recently granted conditional marketing authorisation for andexanet alfa. However, costs and availability have been limiting factors for its use in the United States, with most hospitals focusing on its use for ICH.

Andexanet alfa is now the second specific antidote available for the non-vitamin K oral anticoagulants after prior approval and availability of idarucizumab for dabigatran reversal. However, FXa inhibitors including apixaban and rivaroxaban are the most widely used agents of this drug class, supporting the importance of having specific reversal strategies. Additionally, there are increasing reports of the off-label use of prothrombin complex concentrates for reversal of FXa inhibitors, and potential recommendations for their use in different guidance and guideline documents.

– Jerrold H. Levy