Use of Higher Doses of rFVIIa in Individuals with Congenital Hemophilia Complicated by Alloantibody Inhibitors: Analysis of Data Capture from the Hemophilia and Thrombosis Research Society (HTRS) Registry (2004–2008)
Authors: Kessler Craig M. , Gill Joan Cox , Wilke Caitlyn T. , Cooper David L. ,   HRS HTRS Investigators
Published: April 2020

In 1999, recombinant factor VIIa (rFVIIa, NovoSeven®) received FDA approval with recommended dosing of 90 mcg/kg every 2 hours. Individual case reports and small series have described the use of rFVIIa at doses ≥ 270 mcg/kg and 3 randomized trials have suggested that one bolus dose of rFVIIa at 270 mcg/kg provides equivalent efficacy and safety when compared to the conventional regimen of three doses of 90 mcg/kg over 6 hrs. The extent to which higher doses of rFVIIa have been used in clinical practice in the US is unknown.

The HTRS registry records data regarding the treatment of acute bleeding episodes in those with hemophilia A or B and related hemorrhagic disorders with special emphasis on outcomes in individuals with congenital hemophilia complicated by alloantibody inhibitors; From over 5,000 evaluable bleeding episodes reported between January 2004 and March 2008, all episodes treated with at least one dose of ≥ 250 mcg/kg rFVIIa were examined for their initial and total dose, number of doses, and number of days on rFVIIa therapy. The efficacy of two treatment regimens was assessed:

an initial high dose ≥250 mcg/kg followed by “as needed” lower doses; some of these only required a single high dose; and initial smaller doses of rFVIIa or aPCC followed by a≥250 mcg/kg dose for salvage.

Of 2,532 bleeds treated with rFVIIa, 153 bleeds treated with at least one dose ≥ 250 mcg/kg were reported in 21 individuals with either congenital hemophilia A (n=17) or B (n=4) with alloantibody inhibitors. These 153 bleeding episodes required 1642 doses of rFVIIa of which 358 doses were ≥ 250 mcg/kg. The mean patient age was 12.6 years (0.9– 41.7 years). Mean titers of anti-FVIII and anti-FIX alloantibodies were 104.6 BU (0–683) and 0.9 BU (0–5.6), respectively. Bleed sites were in joints (102 bleeds, 67%), muscles (31 bleeds, 20%), mucosal surfaces (7 bleeds, 5%), and subcutaneous areas (6 bleeds, 4%). Bleeds were treated mainly in the home (78%).

Of 153 bleeding episodes treated with at least one dose ≥ 250 mcg/kg rFVIIa, 80 had at least one dose ≥ 270 mcg/kg, and 49 had at least one dose ≥ 300 mcg/kg. For the whole group, mean (median, range) total dose was 1835 (867, 250–27323) mcg/kg with 10.4 (4, 1–201) doses over 3.8 (2.0, 1–79) days. Half of the doses received for these bleeds were ≥ 250 mcg/kg, and 79.1% had an initial dose of ≥ 250 mcg/kg. For those receiving a dose of ≥250 mcg/kg, there were 14.5 (4, 1–157) doses prior to the dose of ≥ 250 mcg/kg. Efficacy was 90% in 147 bleeds where rFVIIa was used as primary treatment and 100% in 6 bleeds where rFVIIa was used after a mean 154 U/kg (2.0 doses) of aPCC. Efficacy was 90% for joint bleeds and 94% for muscle bleeds. There were 15 episodes of presumed efficacy where documentation did not indicate bleeding stopped, but no other medications were recorded, resulting in adjusted overall efficacy of 100%.

There were 9 patients with 23 bleeding episodes treated with a single dose of ≥ 250 mcg/kg, including mostly joint bleeds (10 spontaneous, 7 traumatic), and mostly home treatment (21). Dosing was 307 ± 62.1 (300, 250–500) mcg/kg and in 91% physicians reported “bleeding stopped” (remaining 2 had no other doses or medications). Cumulative exposure in this group was 157 doses of 250–269 mcg/kg, 70 doses of 270–299 mcg/kg, and 131 of 300–500 mcg/kg. There were no serious adverse drug related events or thrombotic complications reported after treatment of these bleeding episodes.

The 2004–2008 data from HTRS provides the largest single source of data on the safety and efficacy of higher doses of rFVIIa administered to reverse moderate to severe bleeds in a broad cohort of inhibitor patients with hemophilia. Efficacy was consistent for both intra-articular or muscle bleeds in a home setting and rFVIIa was an effective single hemostatic agent in this context so the administration of additional replacement products was unnecessary. Importantly, rFVIIa ≥250 mcg/kg was not associated with any serious adverse drug reactions or thrombogenicity. These data support the feasibility of an initial high dose of rFVIIa for treatment of bleeds in inhibitor patients and justifies the conduct of a prospective, randomized clinical trial to confirm these observations.