Abstract
Introduction Safety evaluation of novel drugs for treatment of hemophilia A is challenging due to the small number of patients involved in clinical trials. Concerns of increased risk of thrombotic complications against bleeding in patients with hemophilia A have been discussed, particularly with non-replacement treatment and concomitant bypassing agents. Surveillance with Roche Global Database reporting adverse events in emicizumab has been discontinued on May 2021 and reporting was transferred directly to regulators.
Aim To evaluate the reporting rate for hemorrhagic and thrombotic adverse drug reactions (ADR) with non-replacement (emicizumab) and replacement extended half-life (EHL) FVIII products as retrieved from the EudraVigilance database during the post-marketing surveillance phase.
Methods Total ADR reported during treatment with emicizumab or with EHL FVIII products (rurioctocog alfa pegol, efmoroctocog alfaturoctocog alfa pegol and danoctocog alfa pegol) retrieved from January 1st to December 31st, 2021 from EudraVigilance database were collected. The proportional reporting ratios (PRR), i.e., the ratio of the proportion of all reported cases of event of interest among people exposed to a particular drug compared with the corresponding proportion among people exposed to other drugs was calculated. Moreover, the reporting odds ratio (ROR), i.e,. a derived as a case-control measure where cases of interest such as hemorrhagic or thrombotic ADR represent the case series and the remaining ADR represent the control series, with their relative 95% confidence intervals (CI) was also calculated to express the hemorrhagic and thrombotic ADR reporting frequency ratio between emicizumab and EHL-FVIII products.
Results We retrieved from the EudraVigilance surveillance database 406 ADR for emicizumab and 376 for EHL FVIII products. Overall, 232 and 275 hemorrhagic ADR were reported for emicizumab and for EHL FVIII products, respectively. Thrombotic ADR were 24 for emicizumab (i.e. 1 disseminated intravascular coagulation, 1 microangiopathy, 8 venous and 14 arterial thrombosis) and 9 for EHL FVIII products (i.e. 1 disseminated intravascular coagulation for danoctocog alfa pegol, 3 venous and 4 arterial thrombosis for efmoroctocog alfa and 1 arterial thrombosis for turoctocog alfa pegol).On the whole, about 25% of thrombotic ADR were reported in concomitance with eptacog alfa (activated). The reporting rates of hemorrhagic and thrombotic ADR are shown in the Table. The reporting odds of hemorrhagic ADR was smaller for emicizumab than for EHL FVIII products, with a ROR of 0.49 (95% CI 0.36-0.66). On the other hand, excluding 1 thrombotic microangiopathy and 2 disseminated intravascular coagulation events and including only thrombosis in large vessels, the reporting odds of thrombotic ADR was higher in emicizumab than in EHL products, with a ROR of 2,56 (95%CI 1,18-5,59).
Conclusion In conclusion, the analysis of pharmacovigilance reports of 2021 detects a signal of increased reporting rate of thrombotic ADR in emicizumab (25% in association with eptacog alfa (activated) and 8% with FVIII) despite a lower reporting rate of hemorrhagic ADR when compared to what observed in EHL FVIII products. We maintain pharmacovigilance is pivotal in monitoring novel drugs in hemophilia. However, this signal requires further validation by mean of cohort studies to estimate the magnitude of the adverse effect minimizing possible. Moreover, the treatment benefit-risk balance should be personalized according to the different hemostatic power of replacement and non-replacement drugs alongside with the individual bleeding and thrombotic risk factors.
Disclosures
Ciavarella:Bayer: Consultancy, Other: Bayer Hemophilia Awards Fellowship. Peyvandi:Takeda: Honoraria; Roche: Honoraria; Sobi: Honoraria; Sanofi: Honoraria; BioMarin: Honoraria; Grifols: Honoraria.
