Use of Single Dose of rFVIIa in Congenital Hemophilia: Analysis of Data Capture from the Hemophilia and Thrombosis Research Society Registry (2004–2008)

The recommended dose of recombinant factor VIIa (rFVIIa, NovoSeven®) is 90 mcg/kg every 2–3 hours. The Home Treatment Study demonstrated an average of 2.2 doses of 90 mcg/kg were required to treat mild to moderate bleeds. Since it is recognized that a single dose administered shortly after a bleed, if equally effective, would be more convenient and possibly could reduce bleeding morbidity, this study examined the experience registered with the use of single rFVIIa doses in the United States.

The HTRS database contains patient data relating to hemophilia treatment and related disorders, and in particular the treatment of acute bleeding episodes in individuals with hemophilia complicated by anti-factor VIII (FVIII) or IX (FIX) alloantibody inhibitors. Between January 2004 and March 2008, the database contained information on over 5,000 bleeding episodes. The data for patients receiving only a single bolus intravenous dose of rFVIIa and no additional treatment were evaluated. The parameters assessed included patient demographics, bleed location, bleed type (specifically joint and muscle bleeds), and dose.

Of 2,532 patients who received rFVIIa, 70 with congenital hemophilia A (n=63) or B (n=7) and inhibitors experienced 508 bleeding episodes that were treated solely with a single dose of rFVIIa. The mean (median, range) age at the time of bleed was 12.7 years (8.2, 0.6–60.4). Mean titers for anti-FVIII and anti-FIX were 62.2 BU (15.0, 0–1408) and 6.8 BU (1.3, 0–31.7), respectively. The bleed sites recorded were joints (271 bleeds [53%], including 55 in target joints [20.2% of joint bleeds]), muscle (78, 15%), mucosal (45, 9%), intracranial (25, 5%), and subcutaneous (21, 4%). Joint bleeds occurred primarily in the ankles (124 bleeds), elbows (61 bleeds) and knees (53 bleeds).

For 508 bleeds treated with a single dose of rFVIIa, the mean (median, range) dose was 119.5 mcg/kg (100, 25–500) with 20 of those doses ≥270 mcg/kg. Patients with joint bleeds were treated with 123.1 mcg/kg (100, 25–500), target joint bleeds with 155.3 (140, 50–393), and those with the muscle bleeds received 120.1 mcg/kg (100, 50–500). The most common single dose regimen overall and for the joint and muscle bleeds was 90 mcg/kg rFVIIa.

The majority of bleeds (424, 82.7%) were treated at home, but bleeds were also treated at Hemophilia Treatment Centers (61, 12.0%) and in the emergency room (15, 3.0%). Overall, physician reported “bleeding stopped” in 97% of the 494 bleeds, 97% of hemarthroses, 96% of target joint hemarthroses and 96% of muscle bleeds. For the remaining 14 episodes, although documentation did not indicate “bleeding stopped”, no other medications were recorded.

There were no serious adverse drug reactions.

Registry data can only demonstrate the treatment reported in selected bleeds captured, and the analysis here specifically examined bleeds treated with only a single dose either because of bleed resolution or by physician/patient choice. The data analyzed here demonstrate single doses of rFVIIa of up to 500 mcg/kg (mean 119 mcg/kg) for mild to moderate bleeds effectively resolved bleeds in 97%, including hemarthrosis, target joints hemarthrosis, and muscle bleeds. These data support the possibility that rFVIIa can be administered in a single bolus dose with equivalent or superior efficacy as multiple lower doses for bleeding episodes treated as part of a home therapy regimen. While 3 randomized trials have examined the equivalence of a single dose of 270 mcg/kg with 3 doses of 90 mcg/kg, these data suggest that single doses of rFVIIa therapy in the real world often were empirically titrated on a patient specific basis, according to the severity and site of the bleeding episode. These registry data provide justification for prospective, randomized, single dose titration trials of rFVIIa or future analogues.