Intracranial Hemorrhage Following Anticoagulant Treatment in Denmark: Spontaneous Adverse Drug Reaction Reports Versus Real-World Data

Introduction: In Denmark, physicians are legally obliged to report serious adverse drug reactions (ADRs), such as intracranial hemorrhage (ICH) following anticoagulant (AC) treatment, to the Danish Medicines Agency. We were therefore puzzled to discover a high number of reports concerning ICHs following treatment with the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin. This was surprising, as all DOACs have been found to be associated with a lower risk of ICH compared with warfarin in phase III randomized controlled trials. Objectives: The primary aim of the study was to estimate the level of underreporting of ICH as an ADR following treatment with warfarin, dabigatran, rivaroxaban, and apixaban. Methods: This observational study covered a 5-year period (2014–2018). Using nationwide registries held by the Danish Health Data Authority, the number of users, exposure time in person-years, and related ICH events for each of the study drugs were estimated. Data on ADR-ICH reports were extracted from the interactive ADR overviews held by the Danish Medicines Agency. Results: From 2014 to 2018, 97.0% of the identified warfarin-related ICH events were not reported as ADRs. For the DOACs, the level of underreporting ranged from 88.8 to 90.8%. Conclusion: We found a heavy and differentiated level of underreporting of ICH as an ADR following treatment with the four study drugs.