Safety of direct oral anticoagulants reversal agents in older patients: an analysis of individual case safety reports of adverse drug reaction from VigiBase®

Background: Real-world data on adverse drug reactions (ADRs) associated with idarucizumab and andexanet alfa are limited. Aim: This study aimed to assess the frequency, the characteristics and clinical and demographic factors associated with ADRs related to their use. Methods: This is a retrospective analysis of ADR reports collected in Vigibase® until May 31, 2023. Multivariable logistic regression estimated reporting odds ratios (RORs) for serious ADRs, death, and thromboembolic events according to demographical and clinical covariates. Results: A total of 1095 Individual Case Safety Reports (ICSRs) reporting idarucizumab (72%) or andexanet alfa (28%) as suspected/interacting agents were collected. Most of the subjects were males (44.5%), with a median age of 78 years, and exposed to only one suspected/interacting medication (73.6%). ADRs were defined as serious in 88.6% of cases, with a total of 614 (56.1%) fatal cases. Compared to patients without concomitant medications, probability of serious ADRs and death were both higher in those receiving ≥ 5 concomitant medications in the idarucizumab subgroup (ROR 4.04 and 1.66, respectively) and in those receiving 1-4 concomitant medications in the andexanet alfa subgroup (ROR 5.66 and 4.80, respectively). Moreover, the probability of thromboembolic events was significantly lower for subjects aged > 75 years (ROR for 75-84 years 0.55; ROR for ≥ 85 years 0.50). Discussion: In real-world, ADRs associated with idarucizumab and andexanet alfa use are generally serious, resulting in death in a high percentage of subjects. Conclusion: Clinicians should pay particular attention when managing individuals needing these drugs, especially if vulnerable and requiring polytherapy.