(B-251) Andexanet Alfa and Potential Risk of Thrombotic Events

Background: Andexanet alfa (AA), a recombinant factor Xa inhibitor, is approved by the Saudi Food & Drug Authority (SFDA) for the management of adult patients with life-threatening or uncontrolled bleeding while on apixaban or rivaroxaban. Thrombotic events (TEs) are labeled in the product information as uncommon adverse effects.

Objectives: To evaluate the potential association and frequency of TEs with AA. The signal was evaluated following to the completion of the post-marketing requirement trial; ANNEXA-I trial in the United States.

Methods: We conducted a systematic literature search in November 2024, using several search engines, including PubMed, Embase, Cochrane library, and Google Scholar, for English language articles on human investigating the association between AA and the risk of TEs. The search terms included ‘Andexanet alfa’ OR ‘Andexxa’ OR ‘Ondexxya’ AND ‘Atrial thrombosis’ OR ‘Myocardial infarction’ OR ‘cerebrovascular accident’ OR ‘ischaemic stroke’ OR ‘pulmonary embolism’ OR ‘deep vein thrombosis’ OR ‘thromboembolism’ OR ‘thrombotic event’ OR ‘thrombosis’. Moreover, we conducted a search in the World Health Organization (WHO) database “VigiBase” and in the local database of the National Pharmacovigilance Center (NPC) to retrieve case reports up to November 2024. Finally, the causality assessment of the cases was performed using the WHO-Uppsala Monitoring Center (UMC) causality system.

Results: Six studies were identified. Two meta-analysis studies demonstrated a significantly higher risk of TEs with AA compared to usual care (UC), with risk ratio of 1.47 (95% CI 1.01–2.15) and 1.74 (95%CI 1.09-2.77), respectively. One single-arm clinical trial reported a TE incidence of approximately 10% with AA. One post-marketing clinical trial reported significantly higher incidence of TE with AA compared to UC (P=0.048). Two retrospective observational studies with multiple limitations did not show a significant increase in the TE risk. In VigiBase, 153 global cases were reported and 17 cases with completeness score >0.7 were assessed; 11 cases were probably related, 5 cases were possibly related, and 1 was un-assessable. No local cases were reported to the SFDA.

Conclusions: The available evidence suggests a potential association between AA and TEs with an estimated frequency of ≈10%. Therefore, the frequency of TEs in the product information was updated. Given the emergent and serious nature of this adverse event, a direct healthcare professional communication was requested from the marketing authorization holder.