Congenital Hemophilia With Inhibitors Research Articles

Thrombotic events with recombinant activated factor VII (rFVIIa) in approved indications are rare and associated with older age, cardiovascular disease, and concomitant use of activated prothrombin complex concentrates (aPCC).

PurposeRecombinant activated factor VII (rFVIIa; NovoSeven® RT; Novo Nordisk A/S, Bagsvaerd, Denmark) is approved in the United States for the treatment of bleeding and perioperative management in congenital hemophilia with inhibitors (CHwI), acquired hemophilia (AH), congenital factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia (GT) with refractoriness to platelets. The aim of the current analysis was to review clinical trials and registries pre- and post-licensure for each indication to establish the estimated rate of thrombosis and then to establish the association of all reported thrombotic events (TEs) with certain risk factors listed for many years in the prescribing information (PI).Patients and methodsA retrospective safety assessment of both clinical trials and registries used to support licensure and postmarketing surveillance was performed. The rate of thrombosis was calculated in the 4 indicated disorders and an assessment of TE risk factors was conducted through a review of all narratives within those indications in the safety database.ResultsIn clinical trials and registries used to support licensure and in postmarketing surveillance, the overall rate of thrombosis was 0.17% of 12,288 bleeding and surgical episodes. The specific risk by indication was 0.11% for CHwI, 0.82% for FVII deficiency, 0.19% for GT, and 1.77% for AH. The most common associated risk factor—“elderly” (29%), defined in the PI as age ≥65 years—was particularly prevalent in patients with AH. TE was also frequently reported with concomitant cardiac or vascular disease (18%) and use of activated prothrombin complex concentrates (18%).ConclusionData show that the rate of TEs within the 4 licensed indications is low, as was originally described in the US PI from 1999 to 2009. It has remained stable over time during postapproval surveillance in multiple US and global registries with active surveillance for safety information across the 4 approved indications.

Thrombotic Events with NovoSeven® RT in Approved Indications Are Rare (0.2%) and Associated with Older Age (>= 65 y), Cardiovascular Disease, and Concomitant Use of aPCCs

Introduction: Recombinant activated factor VII (NovoSeven®RT, Novo Nordisk A/S) is approved for treatment of bleeding and perioperative management in congenital hemophilia with inhibitors (CHwI), acquired hemophilia (AH), congenital factor VII (FVII) deficiency, and Glanzmann thrombasthenia (GT) with refractoriness to platelets. Serious thrombotic events (TEs) have been reported in clinical trials and postmarketing surveillance; however, the incidence of this risk (rate of thrombosis) is considered to be low within labeled indications. While many general risk factors are noted in the prescribing information (PI), the association of reported TEs with certain risk factors noted in the PI has not been established.Methods: A retrospective safety assessment of clinical trials and registries, used to support licensure and postmarketing surveillance, was performed from which the rate of thrombosis could be calculated in the 4 indicated disorders. Further, all postmarketing TE case reports in the Novo Nordisk safety database (including from registries, spontaneous reports, and the literature) were assessed to identify any of the risk factors listed in the PI and the temporal relationship to NovoSeven®RT use (defined as within 48 h given 2- to 3- hour half-life).Results: In clinical trials and registries used to support licensure and in postmarketing surveillance, overall rate of thrombosis was 0.17% of 12,288 bleeding and surgical episodes. There were 21 TEs identified (12 CHwI, 5 AH, 3 FVII deficiency, 1 GT). The specific risk by indication (Table 1) was 0.11% for CHwI (11,121 episodes), 0.19% for GT (518 episodes), 0.82% for FVII deficiency (367 episodes) and 1.77% for AH (282 episodes). Analysis of all postmarketing databases (Table 2) revealed 213 TEs (88 CHwI, 61 AH, 53 FVII deficiency, 11 GT). The majority were reported spontaneously (141), with fewer reported in the literature (47) or solicited in registries or investigator-sponsored studies (25). Of 213 TE cases, temporal relationship was assessed as plausible in 188 (88%) if NovoSeven®RT use was reported within 48 hours prior to TE or timing unknown; timing was more than 48 hours in 25 (12%) of cases. Overall, the most common associated risk factor was “elderly,” defined in the PI as age ≥65 years (29%), and was particularly common in patients with AH and TE (67%). Another common factor was concomitant use of activated prothrombin complex concentrates (aPCC), identified in 18% of all TEs and 34% of TEs in CHwI. Broadly defined cardiovascular disease (including arrhythmias) was noted in 18% of all TEs (36% AH, 15% FVII deficiency, 9% CHwI) and was much more common than specific note of atherosclerotic disease (2%). Other risk factors listed in the PI were uncommon and, in some cases, never identified in TE reports (eg, postoperative immobilization, sepsis, liver disease, disseminated intravascular coagulation, neonates, pregnancy, postpartum hemorrhage, crush injury).Conclusions: Data show that the rate of TEs within licensed indications is low (0.17%), as was originally described in the US PI from 1999-2009. It has remained stable over time during postapproval surveillance in multiple US and global registries, with active surveillance for safety information across the 4 approved indications. In postmarketing safety report assessments of patients with CHwI receiving concomitant treatment with aPCCs, older patients, particularly those with AH who are receiving other hemostatic agents, and patients with a history of cardiac and vascular disease may have an increased risk of developing TE. [Display omitted] DisclosuresRajpurkar:HEMA biologics: Honoraria; Bristol Myers Squibb: Research Funding; Shire: Honoraria; Pfizer: Honoraria, Research Funding; Novonordisk: Honoraria. Croteau:CSL-Behring: Consultancy; Catalyst Biosciences: Consultancy; Genetech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Bioveritiv: Consultancy; Biomarin: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Boggio:Novo Nordisk: Honoraria. Cooper:Novo Nordisk: Employment.

Continuous infusion of recombinant activated factor VII: a review of data in congenital hemophilia with inhibitors and congenital factor VII deficiency.

IntroductionContinuous infusion (CI) of clotting factors as a replacement therapy for perioperative hemostatic protection has been performed for many years, including with factors VIII and IX and recombinant activated factor VII (rFVIIa). This approach provides steady factor levels without requiring frequent administration of bolus doses.AimTo review safety, efficacy, and dosing data regarding CI of rFVIIa for hemostatic management of patients with congenital hemophilia with inhibitors (CHwI) or congenital factor VII deficiency (C7D).Materials and methodsA literature review identified instances of CI of rFVIIa in patients with CHwI or C7D undergoing surgery or experiencing bleeding episodes. Data regarding safety, efficacy, and dosing were extracted.ResultsThe safety and efficacy of 50 mcg/kg/h CI of rFVIIa following a 90 mcg/kg bolus injection, vs a standard bolus injection regimen, was reported for 24 patients with CHwI undergoing elective surgery in an open-label, randomized, Phase III trial. Efficacy was similar between CI and bolus injection groups at all postoperative time points assessed. Additionally, a postmarketing surveillance study reported effective (80%) and partially effective (20%) CI of rFVIIa in a Japanese cohort of ten patients with CHwI who underwent 15 surgical procedures. Finally, the safety and dosing of rFVIIa CI in 193 and 26 patients with CHwI and C7D, respectively, were reported in 11 prospective studies, 10 retrospective studies, and 30 case reports. No unexpected safety findings were reported.ConclusionrFVIIa CI has been performed safely and effectively in patients with CHwI and C7D undergoing surgery and during bleeding episodes in patients with CHwI.

Safety and efficacy of recombinant activated coagulation factor VII in congenital hemophilia with inhibitors in the home treatment setting: A review of clinical studies and registries.

Self-administration of factor and bypassing agents by persons with hemophilia in the home setting is recommended to facilitate earlier intervention after bleeding episodes. The objective of this review was to summarize recombinant activated coagulation factor VII (rFVIIa) safety and efficacy data from clinical trials and patient registries documenting use in the home treatment setting in people with congenital hemophilia with inhibitors (CHwI). A total of 16 studies and registries were identified for inclusion; 14 evaluated on-demand treatment of acute bleeding episodes (865 patients, 9024 bleeding episodes) and 2 evaluated use for secondary prophylaxis (108 patients, 42,861 prophylaxis days). In the on-demand studies, efficacy was consistently high (81%-96%), and thrombotic events were uncommon (n = 3). In the secondary prophylaxis studies, rFVIIa was associated with a 45% to 59% reduction in bleeding episodes and no thrombotic events. These data support the clinical practice of administering rFVIIa in patients in the home treatment setting after initiation under a physician's care.

Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label.

The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven® RT) across pediatric age cohorts is poorly defined. The objective of this analysis was to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling. Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled. All data were stratified by age (<2, 2 to <6, 6 to <12, and 12-16 years) and study category (acute treatment of bleeding episodes or surgery). The pediatric dataset included 172 patients; 144 received rFVIIa for the treatment of bleeding episodes and 28 for the control of bleeding perioperatively. Recombinant FVIIa was effective for 95.4% (1,026/1,076) of the evaluable bleeding episodes and had similar treatment effectiveness across pediatric age groups (range, 94.1-97.2%). The majority received doses of 90 mcg/kg. rFVIIa was effective in achieving perioperative hemostasis across pediatric age groups (range, 91-100%), with greater efficacy observed with the recommended (90 mcg/kg) versus lower dose (35 mcg/kg). A total of 88 pediatric patients experienced a total of 285 adverse drug reactions, similar in type to those reported among adult patients. A total of seven thrombotic events were recorded in seven pediatric patients; only one was confirmed related to rFVIIa upon individual case review. rFVIIa is safe and effective in the treatment of bleeding episodes and prevention of periprocedure bleeding in CHwI with no apparent differences observed among pediatric age groups.

Safety and Efficacy of Recombinant Factor VIIa (rFVIIa) in Congenital Hemophilia with Inhibitors (CHwI) in the Home Treatment Setting: Systematic Review of Clinical Studies and Registries

Background: The FDA approved rFVIIa (NovoSeven®RT) in 1999 for treatment of CHwI patients (pts) and it has been studied in compassionate/emergency use programs, clinical trials, and registries for nearly 30 years in this indication. US prescribing information directs that initially, treatment should be instituted under supervision of a physician. While home treatment is common in hemophilia including patients with inhibitors in clinical studies, scientific publications often omit the treatment location. Recent information requests in relation to policy decisions by payers around home use of rFVIIa prompted systematic analysis of clinical studies and registries where predominant use was in the home setting.Aim: To analyze rFVIIa safety and efficacy data in home treatment in clinical trials and registries.Methods: A systematic review focusing on the efficacy and safety of rFVIIa for the management of congenital hemophilia A and B patients with inhibitors in the home setting was performed. Studies included in the review consisted of clinical trials (phase I-IV) and prospective and retrospective registries evaluating bleed management and prophylaxis.Results: A detailed review identified 14 studies for treatment of bleeding (3 phase II, 2 phase III, 9 phase IV) in the home setting including studies reporting on standard doses (90 mcg/kg), high single doses (270 mcg/kg), and observational studies (dosing per physician direction). These studies captured 865 patients treated for 9,024 bleeding episodes (see Table 1), including 640 patients with 6,999 episodes in studies where efficacy was evaluable. Efficacy was consistently high across studies. The 10-year Japanese post-marketing study (F7HAEM-1947) required all adverse events to be reported irrespective of causality; one patient had visual field defect and suspected cerebral infarction, one central venous occlusion, and two others had events that are not clearly thrombotic (hemolytic uremic syndrome, acute renal failure). The only thromboembolic event (TE) reported in phase II-III studies was in 1 patient in the phase II adept™2 trial, which compared vatreptacog alpha with rFVIIa. Apart from the Japanese study, thrombotic rate was 1/7306 bleeds (0.014%).Table 1On demand treatment of bleeding with rFVIIaTrial IDPhaseNumber of PatientsNumber of BleedsEfficacySafetyF7HAEM-1510II224288%No TEF7HAEM-2068II244591-92%No TENN7128-1907 (Pioneer 1)II2335984%No TEF7HT/USA/1/USA (US Home Trx)III5687792%No TENN1731-3562 (adept™2)III5722793%1 TEHRS/HTRS Registry (2000-2003)IV4279387%No TEHTRS Registry (2004-2008)IV1292,04189-93%No TEF7HAEM-1965 (DOSE)IV35158Not assessed (diary)No TEF7HAEM-3507 (ONE)IV10249685-96%No TENN7025-3601 (SMART-7)IV51511Not reported (interim)No TEF7HAEM-3537 (UKHCDO Registry)IV1391,356Not reported (diaries)No TEF7HAEM-1947IV144*1,718*88%2TE†F7AHEM-1921 (WIRK Registry)IV1426990%No TEF7HAEM-3850IV2713281%-92%No TETotal8659,024* Patients with evaluable efficacy.† One visual field defect with suspected cerebral infarction, one central venous occlusion.Two studies evaluated rFVIIa for secondary prophylaxis (1 phase II, 1 phase IV) (see Table 2). The phase II study captured 22 patients treated with 90 or 270 mcg/kg daily. The phase IV retrospective study captured 86 patients with varied rFVIIa doses that often changed over time. Effective reduction in bleeding was seen in both studies. Across 108 patients treated with prophylaxis at home over 42,861 days, there were no thrombotic events reported.Table 2Secondary Prophylaxis with rFVIIaTrial IDPhaseNumber of PatientsNumber of Prophylaxis DaysEfficacySafetyF7HAEM-1505II221,88545-59% reductionNo TEF7HAEM-3695 (PRO-PACT)IV8640,97646-52%No TETotal10842,861Conclusions: Analysis of data from clinical studies of rFVIIa in home treatment of bleeding and secondary prophylaxis of bleeding demonstrates consistent efficacy for treatment and prevention of bleeding. Thrombotic events were uncommon across ~9,000 bleeding episodes and not reported in ~43,000 prophylaxis days. These data support the safety and efficacy of rFVIIa in the home treatment setting and sufficient evidence for payers to continue its approval in the home management of hemophilia patients. DisclosuresYoung:Kedrion: Consultancy; Bayer: Consultancy; Baxter: Consultancy; Biogen Idec: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria. Escobar:Novo Nordisk Inc.: Consultancy; Baxter: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Biogen: Consultancy; CSL Behring: Consultancy. Pipe:Biogen Idec Inc: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; American Thrombosis and Hemostasis Network: Other: Chair of the Board of Directors; National Hemophilia Foundation: Other: member of the Medical and Scientific Advisory Committee; Novo Nordisk: Consultancy; Baxter: Consultancy. Cooper:Novo Nordisk Inc.: Employment.

Safety of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors: overall rFVIIa exposure and intervals following high (&gt;240 μg kg−1) rFVIIa doses across clinical trials and registries

Recombinant activated factor VII (rFVIIa) is indicated for treatment of bleeding in congenital haemophilia with inhibitors (CHwI) using 90 μg kg(-1) every 2-3 h (EU and US) or a single 270 μg kg(-1) dose (EU only) with ~90% efficacy reported for both regimens. Dosing of rFVIIa varies, and home treatment makes assessment of frequency of doses >90 μg kg(-1), the intervals before additional treatment, and the risk for thromboembolic events (TEs) more difficult. This post hoc analysis assessed the safety and distribution of rFVIIa dosing in CHwI and the impact of >240 μg kg(-1) dosing on subsequent bypassing agent (BPA) dosing interval and frequency. Data regarding on-demand or prophylactic rFVIIa dosing, TE incidence and subsequent BPA dosing after high rFVIIa doses were compiled from multiple sources incorporating safety surveillance. A total of 61 734 rFVIIa doses were reported in 481 patients treated for 3947 bleeds and for 43 135 prophylaxis days. Over half (52%) exceeded 120 μg kg(-1), 37% exceeded 160 μg kg(-1) and 15% exceeded 240 μg kg(-1). Subsequent doses of BPA(s) were administered after 38% of initial and 49% of any rFVIIa dose >240 μg kg(-1), and were most frequently administered ≥24 h after initial (40%) or any (53%) doses >240 μg kg(-1). No TEs were reported. The findings of this analysis show that rFVIIa doses >90 μg kg(-1) are utilized for 'real-world' treatment of children and adults. When additional BPA was administered following an rFVIIa dose >240 μg kg(-1), reported intervals were prolonged, often ≥24 h. No safety issues were identified in the 61,734 doses analysed.

Results of the WIRK prospective, non‐interventional observational study of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors and other bleeding disorders

Recombinant activated factor VII (rFVIIa) has been available for the treatment of acute bleeding and for prevention of bleeding during surgery and invasive procedures in patients with congenital haemophilia with inhibitors (CHwI) and acquired haemophilia since 1996. The study objective was to assess the efficacy and safety of rFVIIa in patients with CHwI, acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia, in a real-life clinical setting. There were no specific inclusion or exclusion criteria; participation was offered to all German haemophilia centres known to use rFVIIa to treat patients with the above indications. Data on rFVIIa use and efficacy for the treatment of acute bleeding episodes and invasive procedures were recorded. Adverse drug reactions and recurrent bleeding episodes were also monitored. In total, 64 patients (50.0% women) received rFVIIa treatment. Patients experienced 281 evaluable bleeding episodes and underwent 44 invasive procedures. In 252 of 281 (89.7%) bleeding episodes, a stop (66.5%) or a significant reduction (23.1%) in bleeding was observed. No bleeding complications were reported for 42 of 44 (95.5%) invasive procedures covered with rFVIIa. A clear positive association was observed between early initiation of rFVIIa treatment for acute bleeding and efficacy. The total cumulative dose and number of injections were 468.3 ± 545.8 μg kg(-1) and 3.6 ± 4.6 respectively. No drug-related adverse events were reported. rFVIIa use in Germany provided effective haemostatic cover without associated adverse events in the management of acute bleeds and invasive procedures across a range of bleeding disorders.

Assessment of individual dose utilization vs. physician prescribing recommendations for recombinant activated factor VII (rFVIIa) in paediatric and adult patients with congenital haemophilia and alloantibody inhibitors (CHwI): the Dosing Observational Study in Hemophilia (DOSE)

Recent data from the Dosing Observational Study in Hemophilia diary study has described home treatment with recombinant activated factor VII (rFVIIa) in congenital haemophilia with inhibitors (CHwI). The current analysis compares prescribed and patient/caregiver-reported rFVIIa administration in paediatric and adult CHwI patients in this study. Patients with ≥ 4 bleeding episodes within a 3-month period prescribed rFVIIa as first-line therapy for bleeding episodes were eligible. Patients/caregivers completed a diary for ≥ 90 days or until the patient experienced four bleeds. Initial, total and mean rFVIIa doses reported for each bleeding episode were calculated and compared with the physician-prescribed doses. Of 52 enrolled patients (25 children; 27 adults), 39 (75%) completed the study. Children and adults had similar mean durations of bleeding episodes. Both patient groups were administered higher initial rFVIIa doses for joint bleeds than prescribed: median (range) 215.2 (74.1-400.0) mcg kg(-1) vs. 200.0 (61.0-270.0) mcg kg(-1) for children, and 231.3 (59.3-379.7) mcg kg(-1) vs. 123.0 (81.0-289.0) mcg kg(-1) for adults. The median infused dose for joint bleeds was higher in adults than children (175.2 vs. 148.0 mcg kg(-1) ), but children received significantly more doses per joint bleed than adults (median 6.5 vs. 3.0). The median total dose per joint bleed was higher in children than adults (1248.7 vs. 441.6). For children and adults, both initial and additional doses administered for bleeds were higher than prescribed. Children received higher total doses per bleed due to an increased number of infusions per bleed.

Patient‐ and caregiver‐reported bleeding symptoms and reasons for starting and stopping treatment with recombinant factor VIIa: analysis of the Dosing Observational Study in Haemophilia (DOSE)

Acute haemorrhage treatment in patients with congenital haemophilia with inhibitors (CHwI) has transitioned to home. Patient/caregiver perceptions of bleeding symptoms and reasons for starting/stopping treatment were investigated. Frequently bleeding CHwI patients (≥ 4 episodes in 3 months) prescribed recombinant factor VIIa (rFVIIa) as first-line therapy, or their caregivers, completed daily diaries for 3-6 months capturing bleeding symptoms and treatment decisions. Thirty-eight patients reported 131 joint, 19 muscle and 44 other bleeding events. Symptoms (all/joint/muscle haemorrhages) included pain (78.9%/90.1%/89.5%), joint swelling (44.8%/65.6%/5.3%), decreased mobility (41.2%/48.9%/68.4%), local warmth (21.1%/26.0%/15.8%), other swelling (16.0%/6.9%/47.4%), irritability (14.9%/16.8%/10.5%), visible bleeding (12.4%/7.6%/5.3%) and redness (10.3%/6.1%/10.5%). Most patients/caregivers recognized when bleeds started (58.4%/58.0%), but were less clear when bleeds stopped (43.5%/33.3%). Medication was commonly started by patients/caregivers when bleeds were identified (73.7%/47.4%) or when concerned bleeds might start (32.9%/27.6%). Common reasons for delays in starting medication by patients included 'I thought it might not be a bleed' (48.9%), 'I wanted to see if the bleed progressed' (46.8%) and 'I thought it was just joint pain' (44.7%). Common reasons for caregivers were: 'I wanted to see if it progressed' (37.9%), 'I didn't have medication' (20.7%) and 'I thought it might not be a bleed' (17.2%). Reasons for stopping medication for patients/caregivers were pain cessation/stabilization (93.9%/54.7%), arrest of swelling progression (60.6%/46.9%) and improved mobility (50.0%/35.9%). Patients/caregivers have difficulty in determining bleed onset and particularly resolution, both quite necessary for treatment decisions and clinical trials. Caregivers' inability to assess resolution in children may lead to longer treatment duration seen in the Dosing Observational Study in Haemophilia (DOSE).

Recombinant activated factor VII safety and efficacy in the treatment of cranial haemorrhage in patients with congenital haemophilia with inhibitors: an analysis of the Hemophilia and Thrombosis Research Society Registry (2004–2008)

Cranial haemorrhage (CH) is a potentially serious complication in patients with severe congenital haemophilia with inhibitors (CHwI). Treatment includes bypassing agents, such as recombinant activated factor VII (rFVIIa). To examine the US experience in treating CH with rFVIIa, a retrospective review of the Hemophilia and Thrombosis Research Society 2004-2008 database was conducted. Among 29 patients with CHwI, 56 of the reported haemorrhages met the study criteria. Of these, 75% were traumatic and 80% were extracranial (ECH). The majority (8/11, 73%) of intracranial haemorrhages (ICHs) developed spontaneously. Conversely, most ECHs (39/45, 87%) followed trauma. ICHs were treated with a median/mean of 23/58 rFVIIa infusions over a median/mean of 7/9 days while ECHs were treated with a median/mean of 1/3 infusions (P = 0.011) over a median/mean of 1/1 day. The median/mean initial rFVIIa doses for all CHs were 106/137 microg kg(-1), and were similar for ICHs and ECHs. All ECHs were effectively controlled with rFVIIa; 44/45 bleeds were controlled within 24 h, one bleed was successfully treated perioperatively, and 27 ECHs required only a single dose. Nine out of 11 ICHs were effectively treated with rFVIIa; six ICHs were controlled within 24 h, one within 72 h and in two cases haemostasis was achieved during the perioperative period. No serious treatment-associated adverse events were reported. One patient died as a result of ICH despite the reported control of bleeding. In conclusion, standard dosing of rFVIIa was found to be safe and effective in treating CH with an efficacy rate of 100% for ECH and 82% for ICH.

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

Abstract 1304Poster Board I-326 IntroductionPatients 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®). MethodsSurgical 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. ResultsThere 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). ConclusionsRecombinant 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% 1400). This analysis confirms the value of corroborating clinical trial results with post-marketing surveillance registries to assess small patient populations with clinically challenging management decisions. DisclosuresCooper:Novo Nordisk: Employment.

Diary Observational Study in Hemophilia (DOSE): Evaluation of Enrolled Population and Overall Diary Data Capture in Congenital Hemophilia Patients with Alloantibody Inhibitors.

Abstract 3484Poster Board III-421 IntroductionTreatment of bleeding episodes in patients with congenital hemophilia (CH) can be complicated by the development of alloantibodies (inhibitors). This results in “difficult to control” bleeding episodes, which could lead to significant joint disease and decreased quality of life (QoL). As the site of treatment has moved from the hemophilia treatment center (HTC) and hospital to the home setting, the correlation between prescribed care and the way patients and their families manage their disease at home and the effects on daily life deserves attention. This analysis reports the overall results of the recently completed DOSE study. MethodsPatients with congenital hemophilia with inhibitors (CHwI) with 4+ bleeding episodes in the prior 3 months who were prescribed rFVIIa (NovoSeven, Bagsvaerd, Denmark) as their first line or recommended therapy for bleeding episodes including breakthrough bleeds on prophylaxis were eligible for the study. The patients or their caregivers captured all bleed treatments, daily activities, QoL [EQ-5D, health and pain visual analog scales (VAS)], family anxiety/stress, and activity changes over a period of at least 90 days or until they captured 4 bleeds. Patients or caregivers recorded data in primary paper diaries with optional internet-based data entry. Participating sites completed registration forms with demographics, hemophilia history, and descriptions of currently prescribed care. ResultsThere were 51 patients enrolled in this study from 18 participating sites. Mean age was 22.6 years (median 16.1), with 27.5% less than age 11, 19.6% ages 11-18, and 39.2% over age 18. The majority were white (70.6%). Mean (SD) weight was 72.4 (43.8) kg (median 61.0 kg). Nearly half (49%) had a central venous access device. The patients were diagnosed with hemophilia A (84.3%) or hemophilia B (15.7%) with inhibitors, with current severity of illnesses described as severe (76.5%) or moderate/severe (19.6%) in most patients. Mean (SD) age at diagnosis was 0.5 (0.7) years (range 0-4 years). Mean (SD) age at first bleed was 0.6 (0.9) years (range 0-6 years). Most subjects had a history of joint bleeds, with muscle, mucosal, and head bleeds also reported. Mean (SD) number of bleeds in the past year was 17.6 (15.4) with mean number of severe bleeds reported as 5.9 (9.2). There were 45.1% reported to have ever had immune tolerance. First line therapy for joint bleeds was rFVIIa in 94.1% with a mean (median) initial dose of 152.2 mcg/kg (120.0), with 33% prescribed 250-270 mcg/kg. Initial dosing for muscle and other bleeds was similar. From the enrolled population, at least 38 patients have completed paper or electronic diaries of 22-180 days duration (median 96 days). There were over 3705 total diary days captured, including 174 bleeding events and 421 bleed treatment days. On average, bleed days accounted for 7.6% of diary days (range 0-68.6%). Of the 174 bleeds, 100 were joint bleeds including 37 target joint bleeds, 19 were muscle bleeds, 4 were mouth/gum bleeds, 2 were in the brain, 1 was in the nose and 1 was in/on the skin, 31 were other. There were instances of two types of bleeds reported during the same episode. Bleed duration was reported as 2.6 (3.0) days (range 1-26). ConclusionsDOSE represents the first large-scale diary study in the small population of patients with congenital hemophilia with high responding inhibitors. In this preliminary analysis of the data, there are several unexpected and previously unpublished results: 1) there is a surprisingly large number of patients with central venous access particularly when considering the mean age of the group, 2) less than half of the patients have undergone immune tolerance despite the fact that the participating centers are all established Hemophilia Treatment Centers, 3) a significant proportion of patients use doses of 250-270 mcg/kg. We expect further detailed analysis to provide valuable data and insight from which hypotheses can be generated for future studies of this rare patient population. Disclosures:Young:Novo Nordisk Inc.: Consultancy, Speakers Bureau. Off Label Use: This abstract describes dosing of rFVIIa that is higher than that in the package insert. Shapiro:Novo Nordisk Inc.: Consultancy, Speakers Bureau. Valentino:Novo Nordisk Inc.: Consultancy, Research Funding. Kessler:Novo Nordisk Inc.: Consultancy. Cooper:Novo Nordisk Inc.: Employment.