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Impact of Acute Bleeding on Daily Activities of Patients with Congenital Hemophilia with Inhibitors and Their Caregivers and Families: Observations from the Dosing Observational Study in Hemophilia (DOSE)

Open ArchivePublished:August 13, 2014DOI:https://doi.org/10.1016/j.jval.2014.07.003

      Abstract

      Objectives

      There is limited understanding of the effects of bleeding episodes on the daily lives of patients with congenital hemophilia with inhibitors and their caregivers. This analysis of the Dosing Observational Study in Hemophilia examined the impact of acute bleeding episodes on work, school, and family activities.

      Methods

      Patients and caregivers participated in a diary study for 90 or more days or until patients experienced four bleeding episodes. All bleed treatments, interference with daily activities, and quality-of-life assessments were captured in daily records. Patients and caregivers reported planned workdays or school days eligible to be “lost” so as to differentiate from days lost because of disability or nonworking status, weekends, and vacations.

      Results

      Diaries were completed for 39 patients (18 adults and 21 children). Bleeding episodes that continued for 3 or more days (16.4%) accounted for most of the major changes to family plans. For the 38 patients with bleeding episodes, 47% of 491 bleed days fell on planned workdays or school days; the remainder fell on weekends, holidays, or nonworkdays or non–school days and therefore did not count as “lost days.” Patients reported a loss of productivity on a greater percentage of eligible bleed days than did caregivers (3.9% vs. 0.8%, respectively). Patients and caregivers reported 13.5%/9.3% fully missed and 3.5%/7.6% partially missed days.

      Conclusions

      This study demonstrated that in hemophilia with inhibitors, bleeding episodes interfere with the daily activities of patients and their caregivers. Furthermore, documenting only lost days underestimated the impact of bleeding episodes because of the high percentage of days without planned work or school.

      Keywords

      Introduction

      Congenital hemophilia is a rare disease that places a considerable burden on patients and their caregivers. Hemophilia A, a deficiency of coagulation factor VIII, accounts for 85% of the cases; hemophilia B is less common and results from a deficiency of factor IX [
      World Federation of Hemophilia
      Guidelines for the Management of Hemophilia.
      ]. The treatment of congenital hemophilia may be complicated by the development of inhibitors or alloantibodies to the clotting factor administered as replacement therapy. Significant inhibitors develop in approximately 15% to 30% of the patients with hemophilia A [
      • Musso R.
      Efficacy and safety of recombinant factor VIII products in patients with hemophilia A.
      ] and in 1% to 3% of the patients with hemophilia B [
      World Federation of Hemophilia
      Guidelines for the Management of Hemophilia.
      ]. Currently, it is estimated that there are 800 to 1000 patients in the United States with congenital hemophilia complicated by inhibitors [

      CDC Universal Data Collection. Summary Report of UDC Activity. National Treatment/Clinical Characteristics (Hemophilia). 2011.

      ].
      Compared with patients without inhibitors, treating the bleeding episodes of patients with inhibitors is more complex, with acute bleeding episodes managed effectively with infusions of bypassing agents (BPAs) such as recombinant activated factor VII (rFVIIa, NovoSeven RT, Novo Nordisk A/S, Bagsvaerd, Denmark) [
      • NovoSeven R.T.
      Coagulation Factor VIIa (Recombinant) Room Temperature Stable [prescribing information].
      ] or plasma-derived activated prothrombin complex concentrates (FEIBA, NF, Baxter AG, Vienna, Austria) [
      • FEIBA N.F.
      (Anti-Inhibitor Coagulant Complex), Nanofiltered and Vapor Heated [package insert].
      ]. As in patients with hemophilia without inhibitors, the treatment of patients with inhibitors has largely switched from the hemophilia treatment center (HTC), where the administration of BPAs is done by HTC staff, to the home, where the administration is done by the patient or the caregiver [
      • Teitel J.M.
      • Barnard D.
      • Israels S.
      • et al.
      Home management of haemophilia.
      ].
      Dosing Observational Study in Hemophilia (DOSE) was a prospective, multicenter, noninterventional, and observational diary study designed to examine the use of BPAs—and specifically rFVIIa—in the home setting [
      • Young G.
      • Solem C.T.
      • Hoffman K.
      • et al.
      Capturing daily assessments and home treatment of congenital hemophilia with inhibitors: design, disposition, and implications of the Dosing Observational Study in Hemophilia (DOSE).
      ]; it also evaluated the correlation of prescribed and actual dosing [
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ] as well as daily assessments of health-related quality of life (HRQOL) [
      • Neufeld E.J.
      • Recht M.
      • Sabio H.
      • et al.
      Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the Dosing Observational Study in Hemophilia.
      ]. DOSE also evaluated the impact of bleeding episodes on patient and caregiver daily activities, absenteeism, and productivity. This article focuses on the planned secondary analysis of the impact of hemophilia and bleeding episodes on work or school and on family activities.

      Methods

      DOSE was conducted between January 2008 and July 2009 at 20 sites in the United States. Its detailed methodology has been described elsewhere [
      • Young G.
      • Solem C.T.
      • Hoffman K.
      • et al.
      Capturing daily assessments and home treatment of congenital hemophilia with inhibitors: design, disposition, and implications of the Dosing Observational Study in Hemophilia (DOSE).
      ], and the primary end point was characterization of treatment of bleeding episodes [
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ]. HRQOL, burden of illness, and loss of workdays or school days were evaluated as planned secondary end points [
      • Neufeld E.J.
      • Recht M.
      • Sabio H.
      • et al.
      Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the Dosing Observational Study in Hemophilia.
      ]. The study was conducted with prior approval by local institutional review boards and had the written consent of the patients or their legal representatives. All patients completed a paper diary, and optionally, patients could directly enter information electronically in real time.
      To be considered for this analysis, male patients had to have hemophilia with inhibitors and at least four bleeding episodes in the previous 3 months, irrespective of whether they were treated primarily on demand or with prophylaxis. They also needed to be prescribed rFVIIa as first-line therapy for the treatment of bleeding episodes. All patients had existing prescriptions for rFVIIa and/or other BPAs for the treatment of bleeding, and were expected to maintain their usual treatment regimens for bleeding episodes and contact their HTCs as part of their normal routines. The routine administration of BPAs (e.g., prophylaxis) on nonbleed days was not recorded. Patients (≥18 years) or caregivers (of children <18 years) were asked to complete daily diary records for at least 90 days or until four bleeding episodes were experienced by the patient [
      • Young G.
      • Solem C.T.
      • Hoffman K.
      • et al.
      Capturing daily assessments and home treatment of congenital hemophilia with inhibitors: design, disposition, and implications of the Dosing Observational Study in Hemophilia (DOSE).
      ]. Specific to this analysis, daily reports also included whether each day was a planned adult patient workday or school day, and in the case of caregiver-completed diaries, independently whether this was a caregiver workday and/or child’s school day (i.e., a day eligible to be lost) to account for adult patients and parents who were not working, for children who were not yet in school, and for weekends and vacations.
      On bleed days, patients and caregivers used a 10-point self-rating scale to evaluate the interference of bleeding on planned activities (0 [none] to 10 [worst change ever]) and a novel, exploratory four-level categorical scale based on patient and caregiver focus groups (i.e., did not change schedule or plans at all, slightly changed schedule, significantly rearranged schedule, or major change in family plans). Absenteeism from planned daily activities was measured by the percentage of missed or unproductive bleed days that occurred on planned workdays or school days for the patient and the caregiver, excluding days on which work or school was not planned. Statistical analyses were largely descriptive and correlative in nature and were performed by Outcome Sciences using SAS 9.2 (SAS Institute, Inc., Cary, NC). Given the limited sample size and the exploratory nature of this analysis, no intergroup analyses were performed.

      Results

       Patients’ Demographic Characteristics and Hemophilia History

      Patients’ demographic characteristics and history have been published previously [
      • Young G.
      • Solem C.T.
      • Hoffman K.
      • et al.
      Capturing daily assessments and home treatment of congenital hemophilia with inhibitors: design, disposition, and implications of the Dosing Observational Study in Hemophilia (DOSE).
      ,
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ,
      • Neufeld E.J.
      • Recht M.
      • Sabio H.
      • et al.
      Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the Dosing Observational Study in Hemophilia.
      ,
      • Gruppo R.A.
      • Kessler C.M.
      • Neufeld E.J.
      • et al.
      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).
      ]. Of 52 patients enrolled, 39 completed daily diaries (or had diaries completed for them by their caregivers); the majority had hemophilia A (85%) and were white (69%). Thirty-seven participants reported using rFVIIa as on-demand–only treatment, 5 were also on immune tolerance therapy, and 12 reported receiving routine prophylaxis with BPAs to prevent bleeding [
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ,
      • Neufeld E.J.
      • Recht M.
      • Sabio H.
      • et al.
      Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the Dosing Observational Study in Hemophilia.
      ,
      • Gruppo R.A.
      • Kessler C.M.
      • Neufeld E.J.
      • et al.
      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).
      ]. For diary completers, the median (range) age was 16.2 (1.6–60.9) years [
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ], with 31% being younger than 11 years and 23% aged 11 to 18 years [
      • Young G.
      • Solem C.T.
      • Hoffman K.
      • et al.
      Capturing daily assessments and home treatment of congenital hemophilia with inhibitors: design, disposition, and implications of the Dosing Observational Study in Hemophilia (DOSE).
      ,
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ]. Participants reported a median of 13 bleeding episodes within the previous year [
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ,
      • Neufeld E.J.
      • Recht M.
      • Sabio H.
      • et al.
      Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the Dosing Observational Study in Hemophilia.
      ]. Most patients were limited in recreational activities, work or school, and/or self-care activities; only 28.2% reported an “unrestricted” functional status [
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ].
      Of 39 diaries (4063 days), 18 were completed by patients (2059 days) and 21 were completed by 19 caregivers (for 21 patients, 2004 days). There were 38 patients who reported 194 bleeding episodes (491 bleed days; median 8.2% of diary days) [
      • Young G.
      • Solem C.T.
      • Hoffman K.
      • et al.
      Capturing daily assessments and home treatment of congenital hemophilia with inhibitors: design, disposition, and implications of the Dosing Observational Study in Hemophilia (DOSE).
      ]; 1 patient did not report any bleeding episodes during the study period. Most bleeding episodes (91%) were treated with BPAs; 18 did not document any treatment with these agents although other treatments such as topical agents could have been used without being captured in the data set [
      • Young G.
      • Shapiro A.D.
      • Walsh C.E.
      • et al.
      Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
      ].

       Impact of Bleeding Episodes on Bleed Day Activities

      Overall, bleeding episodes lasted a median (range) of 31.0 (1.0–509.0) hours. For bleeding episodes that lasted 3 or more days (ranging from 3 to 22 days), there were a total of 187 bleed days that accounted for 38% of all bleed days. On a 0- to 10-point rating scale, the median (range) interference of bleeding episodes in daily activities was 2 (0–10) on the first day of a bleed, 3 (0–10) on the second day of a bleed, and 4 (1–10) on subsequent days. In categorical ratings, planned activities of patients or caregivers were affected on less than half of bleed days (46.3% on the first day of bleeding episodes; 39.3% on the second day; 40.4% on subsequent days). When major changes made to schedules and family plans were reported, changes occurred more often on days 3 to 22 (16.4%) than on day 1 (3.7%) or day 2 (5.4%) (Fig. 1). On a 10-point scale of interference in schedule, scores for interference on day 1, day 2, and day 3+ of a bleeding episode steadily increased, with median scores of 2.0, 3.0, and 4.0, respectively. Interference was similar across all bleed types on day 1; however, on days 3 to 22, joint and “other” bleed types interfered more with patient or caregiver schedules (4.0 and 4.0, respectively) than did muscle bleeds (1.0).
      Figure thumbnail gr1
      Fig. 1Impact of bleeding on daily activities of patients with hemophilia with inhibitors or their caregivers (regardless of treatment).

       Impact of Bleeding Episodes on Productivity and Loss of Work or School

      For the 38 patients with bleeding episodes reported across 491 bleed days, 230 (47%) bleed days fell on planned workdays or school days and 182 (79.1%) patients did not miss work or school. For all patients (adults and children), bleeding resulted in a loss of productivity at work or school on 9 (3.9%) eligible days and a loss of full or partial workday or school day on 31 (13.5%) and 8 (3.5%) days, respectively (Fig. 2A). When considering the underlying treatment strategy, patients did not miss planned work or school on 84 of 112 (75.0%) on-demand bleed days and 56 of 69 (81.2%) prophylaxis breakthrough bleed days. Although not analyzed statistically, hemarthroses and other bleeds seemed to result in more lost workdays or school days than did muscle bleeds (Fig. 2A). For 229 caregiver-reported bleed days, 118 (52%) fell on planned workdays or school days and on 97 (82.2%) caregivers did not miss work or school. Caregivers were unproductive at work or school on 1 (0.8%) eligible day, and they missed full or partial days of work or school on 11 (9.3%) and 9 (7.6%) days, respectively (Fig. 2B). When considering the underlying treatment strategy, caregivers did not miss planned work or school on 30 of 46 (65.2%) on-demand bleed days and 20 of 25 (80.0%) prophylaxis breakthrough bleed days. Although not analyzed statistically, there did not appear to be a bleed type with consistently more lost workdays or school days (Fig. 2B).
      Figure thumbnail gr2
      Fig. 2Productivity and loss of workdays or school days in patients with hemophilia with inhibitors or their caregivers. All, all treatment regimens; ITI, immune tolerance induction therapy; OD, on-demand; PRO, prophylaxis.

      Discussion

      DOSE was designed to understand the decision-making process that occurred in the home-treatment setting, and to gain insights from the experience of patients and caregivers with managing their own or their child’s disease. With the use of daily diary records, it was observed that, regardless of treatment, bleed days were associated with significantly worse HRQOL than nonbleed days [
      • Neufeld E.J.
      • Recht M.
      • Sabio H.
      • et al.
      Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the Dosing Observational Study in Hemophilia.
      ]. Furthermore, adults generally had more chronic arthropathy and thus had a poorer HRQOL than did children [
      • Neufeld E.J.
      • Recht M.
      • Sabio H.
      • et al.
      Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the Dosing Observational Study in Hemophilia.
      ]. In the present study, these findings are further explored by demonstrating that bleeding episodes affected both patients and caregivers, with major changes to family plans occurring more frequently with bleeding episodes that persisted for 3 or more days (i.e., presumably a marker for more severe episodes) or when a visit to the HTC or hospital might occur.
      It is generally thought that home treatment of bleeding episodes may help reduce the burden of disease that results from interference with daily activities for both patients and caregivers. In a previous study, patients and caregivers reported a median of 17.5 and 19.1 missed workdays or school days, respectively, in the past 12 months because of illness related to hemophilia [
      • Brown T.M.
      • Lee W.C.
      • Joshi A.V.
      • et al.
      Health-related quality of life and productivity impact in haemophilia patients with inhibitors.
      ]. In addition, in the preceding 12 months for patients and caregivers in this same study, illness led to a median of 12.5 and 10.0 low-productive days, respectively [
      • Brown T.M.
      • Lee W.C.
      • Joshi A.V.
      • et al.
      Health-related quality of life and productivity impact in haemophilia patients with inhibitors.
      ]. Similarly, DOSE showed that bleed days negatively affected the productivity of both patients with hemophilia with inhibitors and their caregivers. When expressed traditionally as a percentage of total diary days, the impact was perhaps less than anticipated. The high rate of bleeding episodes falling on nonworkdays or non–school days in adult patients suggests that long-term disability, partial employment, underemployment, or unemployment (related or unrelated to disability) and other factors need to be considered when assessing the impact of bleeding in clinical studies and treatment planning. The similarly high rate of bleeding episodes (~50%) falling on nonworkdays or non–school days for caregivers who may have one or more affected children to manage at home suggests that a more comprehensive tool for assessing caregiver burden is needed to assess the burden of hemophilia on the family. It also highlights the need for qualifying lost school days in young pediatric populations (i.e., aged <5 years) where school is not mandated or available and therefore there are no lost days in these young patients; however, bleeding may still place a burden on the family.
      Investigators for DOSE asked patients and caregivers whether a bleed day was a planned workday or school day and if so, whether they did not miss work or school, missed a partial day of work or school, missed a full day of work or school, or were unproductive at work or school. This is similar to the approach used by the Work Productivity and Activity Impairment (WPAI) questionnaire, which was originally designed to measure the effect of general health and symptom severity on work productivity and regular activities [
      • Reilly M.C.
      • Zbrozek A.S.
      • Dukes E.M.
      The validity and reproducibility of a work productivity and activity impairment instrument.
      ] but has since been adapted for various disease states and now includes a specific questionnaire for caregivers [

      Margaret Reilly Associates I. REILLY ASSOCIATES - WPAI General Information. 2002.

      ]. The four types of scores yielded by the WPAI questionnaire are absenteeism (work time missed), which is similar to this analysis of workdays or school days missed; presenteeism (impairment at work/reduced on-the-job effectiveness), for which we measured unproductive days; work productivity loss (overall work impairment/absenteeism plus presenteeism); and activity impairment [

      Margaret Reilly Associates I. REILLY ASSOCIATES - WPAI General Information. 2002.

      ]. The WPAI questionnaire obtains a greater level of detail given that it elicits the number of days and hours worked and missed from work, the number of days that patients and caregivers found performing their work difficult, and the extent to which their work was impaired [
      • Reilly M.C.
      • Zbrozek A.S.
      • Dukes E.M.
      The validity and reproducibility of a work productivity and activity impairment instrument.
      ]. Given that this analysis measured the impact on patients and caregivers through daily diary records, the 7-day recall period of the WPAI questionnaire would have been less practical for the present study.
      The impact of hemophilia on employment was recently assessed in the Hemophilia Experiences, Results, and Opportunities study; this study assessed the impact of hemophilia on employment in 1236 respondents from 10 countries (675 adult patients [189 from the United States], 561 caregivers of affected children [190 from the United States]) [
      • Forsyth A.L.
      • Gregory M.
      • Nugent D.
      • et al.
      Haemophilia Experiences, Results and Opportunities (HERO) Study: survey methodology and population demographics.
      ]. Of the respondents, 60% of the adults were employed (72% in the United States) and 81% reported that hemophilia negatively affected their employment (95% for patients with inhibitors); 72% of the parents were employed (72% in the United States) and 66% reported that hemophilia negatively affected their employment (76% for parents of children with inhibitors). Specific effects on adult patients included selecting a job or training that takes into account their hemophilia-related needs or the fact that they have had to voluntarily leave a job in the past because of their hemophilia. For parents, specific negative effects included selecting a job or training that took into account having to work flexible hours in order to care for a child with hemophilia [
      • Forsyth A.L.
      • Gregory M.
      • Nugent D.
      • et al.
      Haemophilia Experiences, Results and Opportunities (HERO) Study: survey methodology and population demographics.
      ]. Neither DOSE nor the WPAI questionnaire capture any information regarding the impact of the disease on the patients’ or caregivers’ ability to work, on their career choice, or on the specific effects on their career.
      Data interpretation in the present analysis may be limited by several factors, including the small population size and the HTC-based comprehensive care approach. DOSE, however, captured approximately 5% of the estimated US population of patients with hemophilia with inhibitors [
      • Young G.
      • Solem C.T.
      • Hoffman K.
      • et al.
      Capturing daily assessments and home treatment of congenital hemophilia with inhibitors: design, disposition, and implications of the Dosing Observational Study in Hemophilia (DOSE).
      ]. It is possible that adult patients who elected to participate, or parents of affected children electing to participate, were more likely to be not working perhaps because they had partners with health insurance coverage or because they were simply more negatively affected by the burden of treatment. Although the patients’ or caregivers’ partial employment, underemployment, or unemployment in the United States during the 2008 through 2009 time period may be hemophilia-related, that was also the time of peak unemployment due to the Great Recession, which might have been a contributing factor in the number of eligible days for adult patients and caregivers. This possibility suggests the need for further study, which would include a more comprehensive assessment of the impact on parents and affected and unaffected siblings, as well as on the partners and families of adult patients.
      Furthermore, it is plausible that differences exist between patients treated on-demand and those treated prophylactically who have breakthrough bleeding at similar rates. Of the 12 patients who were on prophylaxis, 10 were children, which is consistent with the higher use of prophylaxis in general in pediatric patients in the United States. At the time of DOSE, no BPA was approved for prophylaxis; therefore, it was not possible to prospectively capture differences in the impact on bleed versus nonbleed days (greater activity, less frequent visits). Furthermore, most of the bleeding in patients with hemophilia is joint bleeding, which limits the analysis of other bleed types. Ultimately, this was a small population of patients with great inter- and intrapatient variability (over time), which limits the ability to further analyze by potential confounders.

      Conclusions

      DOSE is the first study to show that patient diaries can be used to monitor both the extent to which patients with hemophilia and caregivers are actively engaged in work or school activities on a daily basis and the impact of hemophilia and bleeding episodes on work or school and on family activities. The significant percentage of days documented that were not planned workdays or school days for patients and parents suggests the limitations of traditional analyses that examine only lost or unproductive time. By assessing the impact on the family, DOSE extends the observations from daily HRQOL assessments that bleed days affect the patient. Furthermore, bleeding episodes that lasted for 3 or more days were more likely to have a negative impact, so future studies should gather more detailed information about potential changes from home to hospital treatment or the need for HTC visits due to these longer lasting bleeding episodes.

      Acknowledgments

      We acknowledge the assistance of Outcome Sciences, a contract research organization that conducted the study and provided statistical analysis under funding by Novo Nordisk Inc. Editorial assistance was provided by Amanda Tricarico, PhD, ETHOS Health Communications, Newtown, Pennsylvania, with financial assistance from Novo Nordisk Inc, in compliance with international guidelines on Good Publication Practice. These data were presented, in part, at the International Society for Pharmacoeconomics and Outcomes Research 2010 Annual International Meeting.

      References

        • World Federation of Hemophilia
        Guidelines for the Management of Hemophilia.
        World Federation of Hemophilia, Montreal, Quebec, Canada2005
        • Musso R.
        Efficacy and safety of recombinant factor VIII products in patients with hemophilia A.
        Drugs Today. 2008; 44: 735-750
      1. CDC Universal Data Collection. Summary Report of UDC Activity. National Treatment/Clinical Characteristics (Hemophilia). 2011.

        • NovoSeven R.T.
        Coagulation Factor VIIa (Recombinant) Room Temperature Stable [prescribing information].
        Novo Nordisk, Princeton, NJAugust 2010
        • FEIBA N.F.
        (Anti-Inhibitor Coagulant Complex), Nanofiltered and Vapor Heated [package insert].
        Baxter AG, Vienna, AustriaFebruary 2011
        • Teitel J.M.
        • Barnard D.
        • Israels S.
        • et al.
        Home management of haemophilia.
        Haemophilia. 2004; 10: 118-133
        • Young G.
        • Solem C.T.
        • Hoffman K.
        • et al.
        Capturing daily assessments and home treatment of congenital hemophilia with inhibitors: design, disposition, and implications of the Dosing Observational Study in Hemophilia (DOSE).
        J Blood Med. 2012; 3: 131-138
        • Young G.
        • Shapiro A.D.
        • Walsh C.E.
        • et al.
        Patient/caregiver-reported recombinant factor VIIa (rFVIIa) dosing: home treatment of acute bleeds in the Dosing Observational Study in Hemophilia (DOSE).
        Haemophilia. 2012; 18: 392-399
        • Neufeld E.J.
        • Recht M.
        • Sabio H.
        • et al.
        Effect of acute bleeding on daily quality of life assessments in patients with congenital hemophilia with inhibitors and their families: observations from the Dosing Observational Study in Hemophilia.
        Value Health. 2012; 15: 916-925
        • Gruppo R.A.
        • Kessler C.M.
        • Neufeld E.J.
        • et al.
        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).
        Haemophilia. 2013; 19: 524-532
        • Brown T.M.
        • Lee W.C.
        • Joshi A.V.
        • et al.
        Health-related quality of life and productivity impact in haemophilia patients with inhibitors.
        Haemophilia. 2009; 15: 911-917
        • Reilly M.C.
        • Zbrozek A.S.
        • Dukes E.M.
        The validity and reproducibility of a work productivity and activity impairment instrument.
        Pharmacoeconomics. 1993; 4: 353-365
      2. Margaret Reilly Associates I. REILLY ASSOCIATES - WPAI General Information. 2002.

        • Forsyth A.L.
        • Gregory M.
        • Nugent D.
        • et al.
        Haemophilia Experiences, Results and Opportunities (HERO) Study: survey methodology and population demographics.
        Haemophilia. 2014; 20: 44-51