BACKGROUND: Review of clinical data on andexanet alfa for the reversal of factor Xa (FXa) inhibitor associated anticoagulation. DATA SOURCES: In the present review, we identified articles PubMed using the combined keywords andexanet alfa, apixaban, enoxaparin, edoxaban, and rivaroxaban. Additional online searches PubMed, Google Scholar, and Lexicomp were conducted for both prescribing and cost information. Portola Pharmaceuticals was contacted for information used for United States Food and Drug Administration approval of andexanet alfa. STUDY SELECTION AND DATA EXTRACTION: English-language clinical trials and reviews published between January 2008 and April 2019 were included for review. Bibliographies of selected articles were reviewed manually for relevant publications, focusing on reversal strategies for apixaban, enoxaparin, edoxaban, or rivaroxaban associated anticoagulation using andexanet alfa. Review articles were excluded. DATA SYNTHESIS: The safety and tolerability of andexanet alfa were evaluated in one phase I, two phase II, and one phase III clinical trials. The use of andexanet alfa for reversing FXa inhibitor-associated anticoagulation were evaluated in the phase III ANNEXA-4 study. CONCLUSIONS: Studies evaluating laboratory parameters for coagulation show that andexanet alfa rapidly neutralizes the anticoagulant effects of apixaban, enoxaparin, edoxaban, and rivaroxaban. Clinical studies show that andexanet alfa improves markers related to coagulation, and reverses major bleeding in healthy volunteers and patients with life-threatening bleeding. Interruption of anticoagulation may result in thromboembolic and ischemic events. The use of andexanet alfa requires close monitoring for signs and symptoms of thromboembolic events, ischemic events, and cardiac arrest. Furthermore, anticoagulation should be resumed following the administration of andexanet alfa as soon as medically appropriate.