Disseminated Intravascular Coagulation Following Idarucizumab and Andexanet Alfa: Assessment of a Signal of Disproportionate Reporting From the Food and Drugs Administration Adverse Event Reporting System (FAERS) Database

BACKGROUND: Idarucizumab and andexanet alfa are licensed for the emergency reversal of the antithrombotic effect of direct oral anticoagulants (DOAC). Given their recent commercialization and rare use in clinical practice, current evidence on rare thromboembolic adverse events following idarucizumab or andexanet alfa administration is insufficient to draw definitive conclusions. OBJECTIVE: The aim of this study was to perform a signal detection analysis based on data from a large spontaneous reporting database to identify possible safety signals concerning rare, serious and unexpected thromboembolic events reported following the administration of idarucizumab and andexanet alfa, respectively. METHODS: queries. Signals of disproportionate reporting (SDR) were drug-event pairs reported in three or more ICSRs, with the lower 95% CI of RORs > 1. SDRs corresponding to unexpected and biologically plausible drug-event pairs were selected for further evaluation through a case-by-case assessment. Original ICSRs, including case narratives, were obtained from the FDA. The WHO-UMC system for standardized case causality assessment was used to guide and classify the expert-based judgement of individual cases. RESULTS: A total of 11,561,146 ICSRs submitted to FAERS between 2004 and 2022 were analysed. Idarucizumab and andexanet alfa were listed as suspected drugs in 1463 and 399 reports, respectively. A total of 21 SDRs for idarucizumab and 19 for andexanet alfa were obtained. Eleven ICSRs containing the drug-event pair idarucizumab-disseminated intravascular coagulation (DIC) (ROR 14.5; 95% CI 8.0-26.3) and four containing andexanet-alfa-DIC (ROR 19.4; 95% CI 7.2-51.9) were selected for case-by-case assessment. Two additional andexanet-alfa-DIC ICSRs submitted in 2023 were identified using the FAERS Public Dashboard, although one was a duplicate. Nine of the 11 for idarucizumab and four of the five for andexanet alfa were original ICSRs with a case narrative available. Age was reported in ten idarucizumab cases (mean 79 years) and four andexanet alfa cases (mean 71 years). Nine idarucizumab cases and four andexanet alfa cases were fatal. Causality was judged 'possible' for five idarucizumab cases and three andexanet alfa cases which occurred within 1 day from administration. The remaining ICSRs were classified as 'unlikely' or 'conditional/unclassifiable'. CONCLUSIONS: The disproportionality analysis of the FAERS allowed us to highlight the associations between idarucizumab-DIC and andexanet-alfa-DIC, which might otherwise have remained unobserved due to the rarity of DIC and the low utilization of idarucizumab and andexanet alfa. Although the case-by-case evaluation was limited by the intrinsic indication bias, a causal link remained possible in those cases that occurred soon after administration. Since DIC is a life-threatening and often fatal condition, further investigation is warranted while close follow-up of high-risk patients may be considered to promptly detect any sign of coagulopathy following the administration of DOAC reversal agents. Any such observed adverse events should be reported to the relevant pharmacovigilance system in a timely manner.