Persistent andexanet thromboembolic signals among reversal agents in FAERS

Background Idarucizumab, andexanet alfa, and four-factor prothrombin complex concentrate (4F-PCC) are the principal strategies for anticoagulant reversal. In December 2025, andexanet alfa was withdrawn from the U.S. market because of post-marketing thrombosis concerns. This withdrawal renewed scrutiny of the post-marketing safety profiles of reversal agents. Objective To systematically characterize and compare adverse-event (AE) signal profiles for these three agents in the U.S. FDA Adverse Event Reporting System (FAERS). Methods FAERS quarterly ASCII files were standardized and de-duplicated according to FDA rules. Reports from 2013Q2 to 2026Q1 that listed idarucizumab, andexanet alfa, or 4F-PCC as primary or secondary suspect drugs were analyzed. Disproportionality at the system-organ-class (SOC) and preferred-term (PT) levels was assessed with four algorithms. Additional analyses included target-event clustering, andexanet alfa versus 4F-PCC head-to-head (H2H) comparison, Weibull time-to-onset modeling, temporal trends, mortality regression, and sensitivity analyses. Results A total of 3950 AE reports were identified: 1558 for idarucizumab, 1050 for andexanet alfa, and 1342 for 4F-PCC. Strong PT signals numbered 39, 29, and 32, respectively. Andexanet alfa showed the most prominent thromboembolic profile, with thromboembolic events in 37.8% of reports (ROR 23.54) and cerebral infarction as the leading signal (ROR 146.24). It was also the only agent with a strong nervous-system SOC signal and showed early-onset thrombosis in the Weibull analysis (median 1 day, β 0.66). The andexanet thrombotic ROR increased across the pre-advisory, post-advisory, and post-withdrawal periods, paralleling the andexanet alfa versus 4F-PCC H2H ROR. After full adjustment, mortality remained highest for idarucizumab, with lower odds for andexanet alfa and 4F-PCC overall (OR 0.52 and 0.18) and in the intracranial hemorrhage (ICH) subgroup (0.30 and 0.25). Conclusion The three reversal agents showed distinct AE profiles. Andexanet alfa showed persistent, early-onset thromboembolic signals through the advisory and withdrawal periods. Idarucizumab showed hemorrhagic and critical-illness signals, with residual differences that may reflect unmeasured ICH severity. These findings support individualized risk management and proactive post-marketing surveillance.