Comparative safety of drug therapies used in hemophilia A and B in Canada: a multi-center, retrospective study

Background: Comparative safety data on hemophilia therapies are scarce. Objectives: To compare the risk of adverse drug reactions (ADRs) associated with extended-half-life (EHL) and standard-half-life (SHL) clotting factor therapies, bypassing agents, and emicizumab. Methods and Analysis: We analyzed Canadian Bleeding Disorders Registry data from 2018 to 2022. ADRs were defined as adverse events (AEs) if definitely, possibly, or probably treatment-related. We compared incidence rates of ADRs between therapies to estimate incidence rate ratios and 95% CIs. Results: We found a total of 183 AEs and 67 ADRs. Reported AEs varied from 6.1 to 14.8 events per 1000 patients per year. Allergic reactions were the most prevalent ADRs. A higher incidence of allergic reactions was associated with emicizumab compared with EHL (IRR 3.59; 95% CI, 1.43-9.00) and SHL (IRR 11.86; 95% CI, 4.73-29.72) clotting factor concentrates. Events reflecting inadequate hemostatic control and other unintended events occurred more often with emicizumab compared with SHL (IRR 6.39, 95% CI, 1.29-31.63) and EHL concentrates (IRR 2.77, 95% CI, 0.56-13.72). No inhibitor development was reported with emicizumab or bypassing agents. Cases of neurological events and thrombosis were reported when emicizumab was used in combination with other hemostatic therapies. Conclusion: This study highlights the relative safety of therapies approved for the management of hemophilia A and B. While more ADRs were reported with emicizumab, no inhibitor development was observed. However, novelty bias cannot be ruled out. Our estimates are limited by the use of routinely collected data with no adjustment for confounding due to low event rates and missing data.