Surgical Experience with Recombinant FVIIa (rFVIIa) in Patients with Hemophilia and Inhibitors to Factors VIII or IX.

Patients with congenital hemophilia with inhibitors (CHwI) are at particularly high risk of intra- and post-operative bleeding complications since replacement of the missing protein is ineffective, presenting a therapeutic challenge in elective or emergency surgical procedures. The management of peri-operative bleeding in CHwI patients therefore requires the use of bypassing agents such as recombinant activated FVII (rFVIIa, NovoSeven®).

Surgical procedures in CHwI patients managed with rFVIIa from two randomized clinical trials, the Hemophilia Research Society/Hemophilia and Thrombosis Research Society (HRS/HTRS) registry databases and published medical literature were analyzed to identify surgical (non-dental), dental and other medical procedures. Demographics, rFVIIa dosing and exposure, efficacy and safety results from the five different data sources were also collected, eliminating publications with any overt potential for overlap.

There were 400 rFVIIa-treated procedures reported for 267 CHwI patients (51 patients [51 procedures] from two clinical trials, 15 patients [28 procedures] from the HRS/HTRS registry [1999-2004], 66 patients [143 procedures] from the current phase of the HTRS registry [2004 – 2008] and 135 patients [209 procedures] from published literature). Overall, there were 264 surgical, 91 dental and 45 other medical procedures. In trials, initial rFVIIa dosing was 35 or 90 mcg/kg bolus injection or 50 mcg/kg/hr continuous infusion. Dosing in HRS, HTRS, and in the literature was more variable. In the HRS and HTRS, the dosing was 37-300 mcg/kg bolus injection and in published literature dosing was 35-300 mcg/kg bolus injection or 2.5-50 mcg/kg/hr continuous infusion. Recombinant FVIIa effectiveness was comparable across the different data sources with an overall rate of 85% (339/400). In the clinical trials, bleeding was controlled in 80% (41/51) of procedures. In the HRS/HTRS registry, bleeding was reported as “stopped” after treatment with rFVIIa in 86% of procedures (24/28). Bleeding slowed, but did not stop, in three procedures, and not reported for one procedure. In the HTRS registry, bleeding was reported as stopped in 93% (50/54) of dental, 89% (39/44) of surgical and 87% (39/45) of other medical procedures. Bleeding was reported to have slowed but not stopped in 6% of dental, 11% of surgical and 11% of other medical procedures. In only 1 procedure in HTRS, an additional hemostatic product (aPCC) was administered to stop bleeding. In HTRS, rFVIIa was used as second-line rescue therapy in 12 instances (surgery:3, dental:5, other medical procedures:4). In these instances aPCC was administered first in 5 cases, aminocaproic in 5, aminocaproic/rFVIII in 1 and rFVIII in 1). For the published case reports, treatment with rFVIIa was evaluated to be effective in 83% (147/178) of the surgical cases, partially effective in 6%, and ineffective in 8% of the procedures. Effectiveness was not reported in 4% of procedures. Within this analysis of 400 rFVIIa-treated surgical interventions, one thrombotic event was reported for a 4-year-old with CHwI who developed a partially occlusive right internal jugular thrombosis two days after port-a-cath placement. Additionally, there were a total of 5 events of localized thrombophlebitis (1 from clinical trials, 4 from published literature).

Recombinant FVIIa has consistently demonstrated effectiveness in treatment of bleeding episodes in CHwI patients undergoing surgery and other procedures. The extent of the risk of thrombotic adverse events after treatment with rFVIIa in patients with hemophilia and inhibitors is not known, but is considered to be low. Within this analysis, the possibility of thrombotic events does not appear to present an overriding clinical risk (0.25%

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