{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:55:38Z","timestamp":1791273338508,"version":"4.1.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Direct oral anticoagulants (DOACs) include the factor Xa inhibitors (FXaI) apixaban and rivaroxaban and were approved in the United States and European Union in approximately 2010. Three- and four-factor prothrombin complex concentrates (3F-PCC and 4F-PCC) have been available in the US and EU since 1986 and 2005 for repletion of factors in patients anticoagulated with vitamin K antagonists. Despite their long-standing availability, no large, well-designed prospective clinical trials have been conducted to assess efficacy and safety of PCCs in bleeding patients anticoagulated with DOACs. Although off-label use of PCCs for bleed management of DOAC patients began before the availability of the specific reversal agents idarucizumab and andexanet, utilization increased substantially after antidote approval despite a paucity of evidence. The ANNEXA-I trial compared andexanet with usual care and was terminated early due to superior hemostatic efficacy of andexanet. Heterogeneous interpretation of results underscores significant methodological challenges to performing definitive anticoagulant reversal studies in complex populations at high-risk for mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Authors identified publications through prior guidance statements, guidelines, review articles, PubMed, and ClinicalTrials.gov. We provide a narrative review of the history of PCCs, other clotting factor concentrates, and the target-specific reversal agent, andexanet for FXaI-related bleeding, in the context of warnings issued by the 2021 Congressional Research Service Report on Off-Label Use. We discuss limitations in regulatory and post-marketing mechanisms for evaluating widespread off-label use. We present a framework to interpret limitations of available real-world evidence on off-label use of 4F-PCC for FXaI-related bleeding, along with clinical practice guideline recommendations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>While target-specific reversal strategies are supported by generally higher quality evidence than non-specific agents, concerns remain about thrombotic complications, functional outcomes, cost-effectiveness, and implementation. Future well-designed, adequately powered, randomized studies should address these concerns to aid decision-making across varied patient bleeding profiles.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1895868","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:44:45Z","timestamp":1791272685000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Overcoming inertia in anticoagulant reversal: the current evidence gap and need for critical assessment of factor replacement strategies"],"prefix":"10.3389","volume":"13","author":[{"given":"Charles E.","family":"Mahan","sequence":"first","affiliation":[{"name":"College of Pharmacy, University of New Mexico Health Sciences Center","place":["Albuquerque, NM, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Grandoni","sequence":"additional","affiliation":[{"name":"Anticoagulation Clinic, Dana-Farber Cancer Institute","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Tsaftaridis","sequence":"additional","affiliation":[{"name":"Feinstein Institutes for Medical Research, Northwell Health","place":["Manhasset, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Riello","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel V.","family":"Fontaine","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Intermountain Health","place":["Salt Lake City, UT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle A.","family":"Hultz","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Memorial Hospital West","place":["Pembroke Pines, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Cave","sequence":"additional","affiliation":[{"name":"Department of Veteran Affairs","place":["West Palm Beach VA Health Care System, West Palm Beach, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Singer","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Center for Excellence in Research and Clinical Trials, Renaissance School of Medicine at Stony Brook University","place":["Stony Brook, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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