Variation in Anticoagulant Hemorrhage Management Guidelines for Factor-Xa Inhibitors: A Survey and Analysis of U.S. Academic Institutions
Authors: Singh Rishabh , Tatake Ishan J , Sibley Joseph , Gangaraju Radhika , Martin Karlyn A. , Rosovsky Rachel P. , Byrnes Diana Marie , Lim Ming Y , Gaddh Manila , Cogan Jacob , Youkhana Kimberley , Baumann Kreuziger Lisa , Peseski Andrew M. 
Published: December 2024

Background
Andexanet alfa (AA) is a decoy protein that acts by binding and sequestering factor-Xa inhibitors. Approved by the United States (US) Food and Drug Administration in 2018, it is indicated for reversing the anticoagulation effects during life-threatening or uncontrolled bleeding of apixaban and rivaroxaban. Prior to its approval, inactivated three- and four-factor prothrombin complex concentrates (3F-PCC and 4F-PCC) were the primary off-label agents used for management of factor-Xa inhibitor-associated hemorrhage. While AA has efficacy in reversing factor-Xa inhibitors and achieving hemostasis in major bleeding events, safety concerns emerged due to thrombotic complications. In addition, AA carries a significant financial burden for most institutions. Currently, the Anticoagulation Forum and American College of Cardiology guidelines for managing hemorrhage associated with apixaban and rivaroxaban recommend AA as the first-line agent for life-threatening, critical site bleeding or major bleeding not responding to maximal supportive measures. However, AA and PCC have not been compared head-to-head. Our objective was to compare institutional guidelines for factor-Xa inhibitor hemorrhage management and explore the incorporation of ANEXXA-4 and ANEXXA-I data into organizational guidelines.
Methods
A seven-question survey of various clinical scenarios was distributed via email to members of the Systems-Based Hematology Committee of Venous ThromboEmbolism Network US (VENUS). The survey asked respondents whether institutional guidelines exist for management of hemorrhage related to factor Xa inhibitors, specifically for intracranial and/or intraspinal hemorrhage, emergent gastrointestinal (GI) bleeds, emergency surgery, or other life-threatening bleeds. More than one survey response was permitted in each clinical scenario. Additionally, the survey inquired whether a hematology consultation was recommended in these clinical scenarios. Respondents were asked to share existing institutional guidelines with the study team.
Results
Of surveys sent to 188 VENUS members, there were 29 (15%) responses from unique institutions across the US. Of the respondents, 71% (21/29) have factor-Xa inhibitor hemorrhage management guidelines at their institution. Twenty-one percent (6/29) of institutions always involve hematology in clinical scenarios of factor-Xa inhibitor hemorrhage management, while 71% (21/29) involve hematology some of the time. For intracranial and/or intraspinal hemorrhage, 44% (16/36) of institutions utilize AA as the preferred agent for hemorrhage management, 44% (16/36) utilize 4F-PCC, while 12% (4/36) use other agents. 4F-PCC is the preferred agent for hemorrhage management for emergent GI bleeds in 73% (24/33), emergent surgery in 67% (23/24), and other life-threatening bleeds in 73% (24/33) of responses.
Of the 29 survey respondents, six shared their institutional practice guidelines. Two institutions do not have AA on formulary. Of the remaining four institutions, three recommend AA as the hemostatic agent for intracranial and/or intraspinal hemorrhage management if specific criteria are met. For emergent GI bleeds, emergency surgery, and other life-threatening bleeds, all four institutions recommend 4F-PCC. However, if AA is requested, all four institutions require a hematology consult and specific criteria for approval. The specific criteria for using AA differs across institutions based on time of last dose of factor-Xa inhibitor, location of critical organ bleeding, patient comorbidities, upcoming surgeries and type of surgery, and other medical treatments previously administered.
Conclusion
US academic institutions differ in the management of factor Xa-inhibitor-associated hemorrhage in various clinical scenarios and in the criteria for using AA versus 4F-PCC. Although we were only able to review six institutional guidelines, provider survey results were generally consistent with the institutional guidelines that were shared. This study highlights the variability in clinical practice and importance of standardization in organizational guidelines.