Experience with minor surgeries in people with hemophilia A or B with and without inhibitors receiving fitusiran

Abstract

Abstract Introduction While the number of approved non-factor hemophilia therapies is increasing, data regarding the perioperative management utilizing these therapeutics is limited. Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia (PwH) A/B, with or without inhibitors. For the management of perioperative hemostasis, bleed management guidelines (BMG) in which reduced doses and/or frequency of clotting factor concentrates (CFC) or bypassing agents (BPA) were implemented. In a previous analysis of 60 major surgeries in PwHA/B, hemostatic control on the day of the surgery was rated excellent/good in 39/41 (95%) cases with fitusiran prophylaxis. In this abstract, we describe the hemostatic outcomes of minor surgeries conducted while on fitusiran prophylaxis in PwHA/B aged ≥12 years, with or without inhibitors. Methods All minor surgeries in the fitusiran clinical development program until June 2023 (Phase 2 OLE [NCT02554773], Phase 3 ATLAS-INH [NCT03417102], ATLAS-A/B [NCT03417245], ATLAS-PPX [NCT03549871] and ATLAS-OLE [NCT03754790]) were evaluated, including participants on the original dose regimen (ODR; 80 mg fixed once monthly) and the antithrombin-based dose regimen (AT-DR; adjustable dose regimen with a starting dose of 50 mg once every two months, targeting AT activity levels of 15–35%). Informed consent and ethics committee approval were obtained for all studies. Procedures conducted during fitusiran prophylaxis and when AT activity was <60% were included. Minor surgeries were defined as any invasive operative procedure in which only skin, mucous membranes, or superficial connective tissue were manipulated and did not meet the criteria for major surgery. Perioperative hemostatic control was assessed by the investigators or surgeon based on the ISTH 4-point response scale (excellent/good/moderate/poor) on the day of the surgery. Perioperative use of antifibrinolytics was reported from the day of the surgery until Day 7 post surgery. Results In addition to the 60 major surgeries, a total of 71 minor surgeries were performed in 44 participants (HA with inhibitors, n=8; HB with inhibitors, n=12; HA without inhibitors, n=20; HB without inhibitors, n=4). Minor surgeries (n=71) included dental (n=21), soft tissue (n=12), abdominal (n=12), central or peripheral access-related (n=10), orthopedic (n=7), plastic/reconstructive (n=4), airway management and emergency (n=3), and ophthalmic (n=2) procedures. In total, 26 surgeries were performed in PwH with the ODR and 45 surgeries were performed in PwH with the AT-DR. Of the 22 surgeries with a hemostatic control assessment on the day of the surgery, 21 (95%) cases were rated as excellent/good and 1 (5%) case was rated as moderate. ATIII concentrate was not used to reverse the pharmacodynamic effect of fitusiran in 99% (n=70/71) of minor surgeries. A total of 67% (n=14/21) of dental surgeries and 87% (n=62/71) of all minor surgeries did not require the use of antifibrinolytics. In 18% (n=13/71) of minor surgeries, neither antifibrinolytics nor CFC/BPA were required. Median (range) duration of antifibrinolytic use was 4 (1–8) days. No major treatment-related safety concerns were identified perioperatively. Conclusions Minor surgeries can be safely and effectively conducted in patients receiving fitusiran prophylaxis, irrespective of inhibitor status. Excellent/good perioperative hemostatic control on the day of the surgery was achieved in 95% of minor surgeries in PwH, with or without inhibitors, receiving fitusiran prophylaxis. Reversal of the AT-lowering effect of fitusiran with ATIII concentrate was rarely performed in the reported minor surgeries and is not necessary. In total, 67% of dental surgeries and 87% of all minor surgeries were performed without the use of antifibrinolytics. Overall, these data contribute to the growing evidence base for the perioperative management of PwH receiving fitusiran prophylaxis.