Andexanet alfa for the management of severe bleeding: what should critical care physicians know about it?

Oral anticoagulants are used for the prevention and treatment of arterial and venous thromboembolism.Over the past 20 years, there has been a shift from the use of vitamin K antagonists (VKAs) to the use of direct oral anticoagulants (DOACs).(1) Among DOACs, oral direct FXa inhibitors are increasingly being used for oral anticoagulation.(2) The in-hospital mortality rate is nearly 30% in patients with spontaneous intracranial hemorrhage (ICH) receiving FXa inhibitors, and the risk of mortality is higher in patients on FXa inhibitors than in those not on anticoagulants.(3) The reversal of DOACs is indicated in patients with severe or life-threatening bleeding.Because DOAC use is likely to increase with the introduction of generics, the availability of reversal agents for DOACs is an important medical need.(4) Andexanet alfa is a specific antidote that reverses the anticoagulant effect of FXa inhibitors.Andexanet is a recombinant human FXa protein that binds with high affinity to circulating FXa inhibitors, thereby sequestering them.(5) The dosing regimen for andexanet varies according to the type, dose, and time of the last dose of the FXa inhibitor.Additionally, guideline recommendations vary with regard to the dose.(4,(6)(7)(8) The low dose of andexanet is a 400mg IV bolus administered at 30mg/minute followed by an infusion of 4mg/minute for up to 120 minutes.Conversely, the high dose of andexanet is an 800mg IV bolus administered at 30mg/minute followed by an infusion of 8mg/minute for up to 120 minutes.(9) The ANNEXA-A and ANNEXA-R trials (10) were designed to assess the efficacy and safety of andexanet for the reversal of anticoagulation with apixaban or rivaroxaban in healthy volunteers.The primary endpoint was anti-FXa activity.The safety outcomes were thrombotic events and antibodies against FXa or andexanet.Among the apixaban-treated participants, anti-FXa activity was reduced by 94% among those who received an andexanet bolus compared with 21% among those who received a placebo.Among the rivaroxaban-treated participants, anti-FXa activity was reduced by 92% among those who received an andexanet bolus compared with 18% among those who received a placebo.No serious adverse or thrombotic events were reported.ANNEXA-4 was a multicenter, prospective, single-group cohort study (11) that enrolled patients with acute major bleeding within 18 hours of FXa inhibitor administration.The primary endpoints were anti-FXa activity during andexanet treatment and excellent or good hemostatic efficacy.The safety outcomes included major bleeding criteria, hemostatic efficacy, thrombotic events and death.There were 479 patients enrolled.Bleeding was predominantly intracranial in 69% of the patients and gastrointestinal in 23%.Excellent or good hemostasis occurred in 274 of the 342 evaluable patients.In the population in whom safety was evaluated, thrombotic events occurred in 10% of the patients.In 16 patients, these events occurred during treatment with prophylactic anticoagulation that began after the bleeding event.No thrombotic episodes occurred after oral anticoagulation was restarted.In that study, the authors concluded that in patients with major bleeding associated with FXa inhibitors, treatment with andexanet reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of the patients.