Anticoagulation Stewardship Program in the DOAC Era

Background: Direct oral anticoagulants (DOACs) have transformed antithrombotic therapy but carry significant bleeding risks requiring prompt reversal. Recent regulatory changes have altered the reversal landscape, notably with the withdrawal of andexanet alfa from the U.S. market. Anticoagulation stewardship programs (ASPs) are essential for navigating this evolving environment and optimizing safe use of anticoagulants. Methods: This narrative review synthesizes evidence from landmark clinical trials (RE-VERSE AD, ANNEXA-4, ANNEXA-I), contemporary guidelines, emerging literature on reversal agents, and critical regulatory updates including the 2025 U.S Food and Drug Administration (FDA) withdrawal of andexanet alfa. Results: Idarucizumab remains the only FDA-approved specific antidote for dabigatran. Following the withdrawal of andexanet alfa, prothrombin complex concentrates (PCCs), both 4-factor and activated are now the primary reversal options for Factor Xa inhibitors, with recent evidence demonstrating comparable hemostatic efficacy. Ciraparantag, a universal reversal agent, is currently in Phase III development. Effective ASPs must now adapt protocols to the post-andexanet era while ensuring timely access to alternative reversal strategies. Conclusions: The reversal landscape has undergone a fundamental transformation with the loss of andexanet alfa. Success in DOAC-associated bleeding management now depends on optimizing PCC-based strategies, integrating systematic stewardship approaches, and preparing for emerging universal antidotes. Institutions must urgently update algorithms, ensure PCC availability, and monitor outcomes in this new therapeutic environment.