The use of direct oral anticoagulants (DOACs) for stroke prevention in patients with atrial fibrillation has become routine clinical practice, and use of DOACs for the prevention and treatment of venous thromboembolism has been steadily increasing. Consequently, the demand for safe and effective reversal agents to manage bleeding complications in these patients, particularly after acute traumatic hemorrhage, is high.1
The US Food and Drug Administration (FDA) approval of andexanet alfa in patients with life-threatening or uncontrolled bleeding who are taking a direct or indirect factor Xa inhibitor represented the first global approval of a universal anticoagulant reversal agent.2 In a recent review article in Blood, Beverley Jane Hunt, MD, of the department of thrombosis and hemostasis at King’s College London in the United Kingdom, and colleagues reviewed the clinical use, mechanism of action, and safety implications of andexanet alfa and addressed several key questions about its current role in managing bleeding complications in patients taking DOACs.
“With the arrival of andexanet alfa for reversal of major bleeding in patients receiving DOACs with factor Xa inhibitor activity, acute and emergency care providers together with hemostasis experts will need to learn for whom and when andexanet alfa is indicated,” the reviewers wrote.
Over 10 Years of Clinical History
Early studies of natural inhibitors of factor Xa, an activated serine protease, demonstrated that these agents could be safe and effective oral anticoagulants in humans. Before the widespread clinical use of DOACs, vitamin K antagonists, including warfarin and other coumarin derivatives, were commonly administered to patients with atrial fibrillation to reduce the risk of stroke, and to prevent thromboembolism in patients with mechanical heart valves.3
Direct inhibitors targeting factor Xa have been used clinically since 2008, beginning with the FDA approval of rivaroxaban.4 In the past decade, several additional direct and indirect anticoagulants have been approved, including apixaban, edoxaban, low molecular weight heparin (LMWH), and fondaparinux. DOACs make up an increasing proportion of oral anticoagulants prescribed to aging populations.
Andexanet Alfa Reverses Direct and Indirect Anticoagulants
Andexanet alfa is a recombinant intravenous biologic that targets and inhibits direct and indirect factor Xa anticoagulants and reverses their activity. Evidence for the use of andexanet alfa is largely drawn from non-randomized data collected from patients with intracranial hemorrhage or gastrointestinal bleeding in clinical settings. The reversal effect of andexanet alfa was demonstrated when patients who had taken apixaban and rivaroxaban, both direct factor Xa inhibitors, were given andexanet alfa. For these two inhibitors, more than 90% of anticoagulant effects were reversed, and control of hemostasis was found to be good or excellent in almost 80% of patients given the reversal agent.
Further studies revealed that higher dosing of andexanet alfa was necessary if the oral anticoagulant had been recently ingested. Moreover, no data exists to effectively guide treatment in patients with renal or hepatic dysfunction. From a safety perspective, one study showed a 15% death rate within 30 days of DOAC reversal in a group of bleeding patients; however, the study lacked a control group, making the findings difficult to apply to a clinical setting.