Hemorrhagic and thrombotic adverse events associated with emicizumab and extended half-life factor VIII replacement drugs: EudraVigilance data of 2021

Background: Safety concerns for an increased risk of thrombotic complications in pa-tients with hemophilia A have been pointed out, particularly during nonreplacement treatment with emicizumab and concomitant bypassing agents. Surveillance with the Roche Global Database reporting adverse events for emicizumab has been dis-continued on May 2021. Objectives: The objective of this study was to evaluate the reporting rate of hemor-rhagic and thrombotic adverse drug reactions (ADRs) associated with nonreplacement (emicizumab) and replacement extended half-life (EHL) factor VIII (FVIII) products as retrieved from the EudraVigilance database. Methods: Total ADR reported during treatment with emicizumab or EHL FVIII prod-ucts from January 1 to December 31, 2021, were collected. The proportional reporting ratio and the reporting odds ratio (ROR) with their 95% CIs were calculated to express the hemorrhagic and thrombotic ADR reporting frequency ratio between emicizumab and EHL FVIII products. Results: Overall, 406 and 376 ADRs were reported for emicizumab and for EHL FVIII products, respectively. Hemorrhagic and thrombotic ADRs were 232 and 24 for emi-cizumab and 275 and 9 for the EHL FVIII products. Approximately 25% of thrombotic ADRs were reported concomitantly with eptacog alfa. ROR of 0.49 (95% CI, 0.36-0.66) for hemorrhagic and of 2.56 (95% CI, 1.18-5.59) for thrombotic ADRs were obtained for emicizumab compared with EHL FVIII products. Conclusion: The analysis of 2021 EudraVigilance reports shows a lower reporting rate of hemorrhagic ADR vs a higher reporting rate of thrombotic ADR for emicizumab than for EHL FVIII products. These signals stress the importance of monitoring novel drugs in hemophilia, particularly when administered in association with bypassing agents.