Abstract
Patients with severe hemophilia are at risk for developing neutralizing antibodies (inhibitors) in response to treatment with factor concentrates. Inhibitors develop in >30% of patients with factor VIII (FVIII) deficiency, in 3–6% of patients (pts) with factor IX (FIX) deficiency, and significantly increase the disease-related morbidity. Cranial hemorrhage is a serious bleeding complication in the presence of high titer inhibitors. Treatment strategies include bypassing agents such as activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa). For rFVIIa, 90–120μg/kg every 2–3hr represents the standard initial dosing regimen, although higher doses have been studied. Despite its licensure in 1999 for treatment of hemophilia patients with inhibitors, little has been published on rFVIIa dosing and efficacy in such pts with cranial bleeding. To examine the US experience with this therapeutic challenge, we conducted a retrospective review of the HTRS 2004–2008 database that includes >5000 bleeding episodes in hemophilia inhibitor pts collected retrospectively from 2000 onwards. This analysis included congenital hemophilia inhibitor (CHI) pts treated at least partially with rFVIIa for “head” bleeds designated as either spontaneous or traumatic and either intra- (ICH) or extracranial (ECH). Each cranial hemorrhage was analyzed with respect to initial, initial 24 hour and total infused dose of FVIIa, total number of doses and days of therapy and investigator-assigned outcome.
In all, 29 CHI pts with 56 cranial bleeding episodes met study criteria; 27 had FVIII and 2 had FIX deficiency. Mean ages (years) at spontaneous and traumatic bleeding were 12.2 and 3.7 respectively for FVIII pts; 16 and 1.5 respectively in FIX pts. Most cranial bleeds were traumatic (75%) and extracranial (80%). Importantly, 8/11 ICHs developed spontaneously while 39/45 ECHs were traumatic. In all, 51/56 cranial hemorrhages were treated exclusively with rFVIIa. In 4, therapy included a single aPCC dose. In 1 case, rFVIIa followed a 2 week course of FVIII, on which the pt developed an inhibitor.
ICHs were treated with a mean of 58 infusions over 8.9 days (median: 23 infusions, 7 days); ECHs were treated with a mean of 6 infusions over 1.3 days (median: 1 infusion, 1 day) (p=.011). The mean/median initial infusion dose for all cranial bleeds were with 137/106μg/kg and varied little by location and nature of the hemorrhage. All ICHs were initially treated in hospital settings, while ⅔ of ECHs were initially treated at home. However, initial treatment setting did not impact initial dose. Interestingly, higher initial doses of rFVIIa were used to treat cranial hemorrhage through 2005 (mean 150 μg/kg; range 60–400 μg/kg) than were used from 2006–08 (103 μg/kg; range 80–170 μg/kg). The mean total dose/treatment course was 1,751 μg/kg (median: 240μg/kg, range 70–35,025μg/kg), but varied according to bleed location. As expected, pts with ICHs received higher total doses (mean: 7,279μg/kg; median of 2,250μg/kg) when compared with ECHs (mean: 400μg/kg; median of 140μg/kg 190μg/kg) (p=.06). Overall 78% of the total dose per treatment course was administered within the first 24 hours; however this differed between ICH (34% total/24 hrs) and ECH (88% total/24 hrs).
All ECH was stopped effectively with rFVIIa; 44/45 bleeds were controlled within 24 hours (hrs) and in one hemostasis was achieved within 72 hrs. Twenty-seven episodes required a single treatment dose. Of the 11 ICH bleeds, 6 were reported to be controlled within 24 hrs; one within 72 hrs. Two pts required surgery to control hemostasis. In 2 cases, control of hemorrhage was not explicitly confirmed. One patient with spontaneous ICH died despite reported control of hemostasis. There were no serious adverse drug reactions associated with the rFVIIa treatment.
In summary, in this retrospective review of the US experience accumulated between 2004 and 2008, standard dosing of rFVIIa was found to be safe and effective in the treatment of cranial hemorrhage with an efficacy rate of 100% for ECH and 82% for ICH. The limitations of this study include potential adverse outcome and complications underreporting. Furthermore, neurological and other morbidity data is unavailable. We advocate further prospective documentation of treatment and outcomes.
Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors