Andexanet alfa: trials just leave us with more questions

ANNEXA-I, the first ever randomised controlled trial of a reversal agent for direct oral anticoagulants, was published in 2024. The trial, which randomised patients with intracranial haemorrhage to andexanet alfa or usual care was mandated by the Federal Drugs Administration as part of its conditional approval in 2018, an approval that was originally based on the single-arm trial, ANNEXA-4. ANNEXA-I was stopped early for benefit and showed a reduction in the number of patients with significant haematoma expansion. However, the study was not powered for clinical endpoints such as disability or death and showed no difference in these outcomes. It did, however, show an increased risk of thrombosis, predominantly stroke with andexanet alfa. In this perspective, I reflect on some of the key criticisms of the trial and the implications for its interpretation.