Andexanet Alfa for Anti-Xa Reversal and Acute Bleeding
How effective is andexanet alpha in reversing the effect of factor Xa inhibitors among patients presenting with acute major bleeding?
In ANNEXA-4, a multicenter, prospective, open-label, single-group study, 67 patients who presented with acute major bleeding and recent (within 18 hours) use of a factor Xa inhibitor drug were followed. Patients received a bolus followed by 2-hour infusion of andexanet alpha. Outcomes measured included anti-factor Xa activity levels and clinical hemostatic efficacy assessment. All patients were followed for 30 days to assess for subsequent major bleeding or thrombotic events.
Of the 67 initial patients, 47 were deemed to have adequate factor Xa drug levels at the time of presentation and a clinically major bleeding event. These patients were taking rivaroxaban (n = 26), apixaban (n = 20), and enoxaparin (n = 1), with a mean age of 77 years. Bleeding events were primarily gastrointestinal (25/47, 53%) or intracranial (20/47, 43%). Following andexanet alpha bolus administration, the anti-Xa activity level decreased by 89% (95% confidence interval [CI], 87%-84%) in rivaroxaban-treated patients, and by 93% (95% CI, 87-94%) in apixaban-treated patients. These levels remained similar during the 2-hour andexanet alpha infusion, then began to rise slightly over the next 10 hours. Twelve hours after andexanet apha infusion, clinical hemostasis was adjudicated as excellent or good in 37/47 patients (75%, 95% CI, 64%-89%). Thrombotic events occurred in 12/67 (18%) during the 30-day follow-up period.
The authors concluded that an initial bolus and 2-hour infusion of andexanet alpha substantially reduced anti-factor Xa activity in patients with acute major bleeding with effective hemostasis in the vast majority of patients.
This is an important interim report of the ongoing phase 4 clinical study of andexanet alpha for reversal of anti-Xa medications (e.g., rivaroxaban and apixaban). While the healthy volunteers study was presented in 2015 (N Engl J Med 2015;373:2413-24), the Food and Drug Administration (FDA) recently declined to approve the drug based on the available data at that time (8/17/2016). Given the rising use of all direct oral anticoagulants, there is great need for an effective reversal agent in patients with active bleeding. This report provides compelling data in ‘real world’ bleeding patients. However, unlike the RE-VERSE AD study of idarucixumab in dabigatran-treated patients, this study did not include patients who required reversal for an emergent surgery or procedure. Reassuringly, the adjudication of clinical hemostasis was highly effective. Clinicians and patients eagerly await the availability of an anti-Xa reversal agent, and this report may be adequate to compel the FDA to approve andexanet alpha.
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