What is the role of prophylaxis in the improvement of health-related quality of life of patients with hemophilia?

Hemophilia is a chronic disorder that can negatively affect health-related quality of life (HRQOL). This can be due to a variety of hemophilia-related issues such as bleeding episodes, pain, decreased functional capacity, and impaired performance at school, work, or recreation. Current management recommendations for severe hemophilia include the use of prophylaxis for prevention of bleeding episodes and hemophilia-related complications. Prophylaxis has been shown to reduce bleeds and joint limitation. In addition to clinical measurements such as frequency of bleeds and joint range of motion, it is recognized that the measurement of HRQOL serves as an important outcome in the comprehensive evaluation and care of hemophilia patients. The purpose of this evidence-based mini-review is to answer the question: “In pediatric or adult patients with hemophilia A or B, is prophylaxis associated with improvements in HRQOL?”

To examine the current best evidence for the use of prophylaxis in the improvement of HRQOL among patients with hemophilia, we conducted a PubMed search. Keywords that were used for the search included: “quality of life” and “hemophilia.” Inclusion criteria for articles included were: (1) studies that focused on the use of prophylaxis and its impact on HRQOL (measured using standardized generic and disease-specific instruments) of patients with hemophilia; (2) year of publication: studies published between 1970 and 2013; (3) methods: studies that used empiric study designs including only quantitative methods; and (4) language: studies that were written in English. Reference lists of reviews identified from the search above focusing on “prophylaxis” or “quality of life” in their title were also searched for additional studies.

Of the 432 titles identified, 413 did not fulfill the inclusion criteria and were excluded due to a lack of prophylaxis-specific analyses, a lack of hemophilia-specific analyses, a lack of HRQOL measurements by standardized instruments, or exclusively qualitative or psychometric or cost-effectiveness analytic approaches. Based on the inclusion criteria, a total of 21 studies met the inclusion criteria.^1-21 

The study designs, sample characteristics, and results of the studies are provided in Table 1. Most of the studies were multi-institutional studies conducted within the United States (4 studies)^2,3,10,15  or multi-institutional studies conducted across the United States and multiple European countries (13 studies).^{6,7,9,11-14,16-21}  Four single institutional European studies were also represented.^1,4,5,8  Of the 21 studies, 14 were cross-sectional observational studies.^{2-6,8,10,11,13,15,17,18,20,21}  Seven studies used more robust study designs (ie, randomized prospective trials).^{1,7,9,12,14,16,19}  Several studies were limited in their diagnostic representation, including 3 studies that included only hemophilia patients with inhibitors.^10,12,16  The age of the patients with hemophilia also varied, with 7 adult-only studies,^1,4-6,8,9,19  3 pediatric-only studies,^7,11,17  and the remaining 11 combination adult-pediatric studies.^{2,3,10,12-16,18,20,21} 

A total of 9 different measures were used to assess the HRQOL of hemophilia patients across the 21 studies. The instruments used to measure HRQOL included generic and disease-specific measures of HRQOL. The most frequently used generic HRQOL measure was the Short Form 36 (SF-36) in 9 studies,^{4,5,8,13,15,18-21}  the EQ5D (a measure of HRQOL from the EuroQoL Group) in 5 studies,^1,6,12,14,16  and the Short Form 12 (SF-12) in 3 studies.^2,3,10  Pediatric-specific generic HRQOL measures included the Pediatric Quality of Life Inventory (PedsQL), which was used in 2 studies.^2,3  The German Children's Quality of Life Questionnaire (KINDL) and the Child Health Questionnaire (CHQ) were also used as pediatric-specific generic HRQOL measures in single studies.^11,15  Only 2 adult-focused, disease-specific HRQOL measures were used: MedTap QoL and HaemoQOL.^1,9  Pediatric disease-specific HRQOL measures included the HaemoQOL, which was used in 2 studies.^11,17 

Among adult patients with hemophilia, the impact of prophylaxis on HRQOL is mixed. Duncan et al studied 64 adults and Noone et al studied 80 adults and each found the highest HRQOL in those using prophylaxis.^2,6  Among the domains of HRQOL, physical health was noted to be better among adults on prophylaxis.^2,14,19-21  With respect to pain, the use of prophylaxis among adults was associated with greater pain as reported by Du Triel et al¹⁵  compared with less pain reported by Royal et al and Tagliaferri et al.^14,20  Tagliaferri et al studied 30 adolescent and 54 adult patients receiving prophylaxis in comparison to on-demand therapy and found better HRQOL across all domains with the greatest differences in mobility, usual activities, and pain/discomfort.¹⁴  Noone et al also noted that the use of on-demand therapy was associated with lower scores “self-care.”⁶  Poon et al studied 164 adults and found no association between the use of prophylaxis and HRQOL.³  Collins et al studied 20 adults and also found no significant differences among adults treated with prophylaxis compared with on-demand therapy.⁹ 

The impact of prophylaxis on HRQOL among pediatric patients with hemophilia demonstrates mixed results. In 2011, Gringeri et al studied 45 randomized pediatric patients and found that patients treated on-demand demonstrated impairment in the “family” domain of the HaemoQOL and felt overprotected and less able to participate in work and leisure time.⁷  In 2004, Gringeri et al studied 339 child and adolescents using the HaemoQOL and found that prophylaxis was associated with impaired HRQOL (“feeling” subscale) among children, with less impairment in sport/school subscales in adolescents receiving prophylaxis.¹⁷  Du Treil et al found greater pain in children on on-demand therapy compared with prophylaxis.¹⁵  Bullinger and von Mackensen, in a study of 298 children, found no association between the use of prophylaxis and HRQOL,¹¹  confirmed in studies by Duncan et al and Poon et al.^2,3 

The timing of the start of prophylaxis and the schedule of prophylaxis may play a role an important role in HRQOL. Khawaji et al noted that adults starting prophylaxis before 3 years of age was associated with greater HRQOL across several domains (physical and social health); however, these differences became nonsignificant after age adjustment.⁵  Lindvall et al studied 105 adults and noted that the earlier use of prophylaxis was associated with higher HRQOL with a specific focus on physical health.⁴  Plug et al noted that being born after the introduction of prophylaxis was associated with better physical health compared with those born before the introduction of prophylaxis.¹³  Lindvall et al also assessed the schedule of prophylaxis among 10 pediatric and adult patients and found that daily prophylaxis was associated with diminished HRQOL in the domains of pain and mobility compared with standard prophylaxis, although these findings were not statistically significant.¹ 

The use of prophylaxis in adult and pediatric hemophilia patients with inhibitors was also the subject of evaluation. Hoots et al¹²  and Konkle et al¹⁶  provided reports of a randomized prospective trial of high-dose recombinant FVIIa compared with low-dose recombinant FVIIa prophylaxis in inhibitor patients and demonstrated improvements in HRQOL within the domains of pain and mobility. In a pooled data analysis from the 22 patients, the improvement was not statistically significant. Brown et al also studied the use of prophylaxis in 53 adult and pediatric hemophilia patients with inhibitors and noted that on-demand therapy was negatively associated with physical health and pain,¹⁰  but baseline physical health and pain is known to be poor in this group.

Given the available evidence, we recommend against the use of prophylaxis compared with on-demand therapy to improve HRQOL among adult or pediatric patients with hemophilia (Level 3). This recommendation is based largely on observational and cross-sectional studies assessing the relationship between prophylaxis and HRQOL. Small sample sizes, limited age representation of hemophilia patients in individual studies, and the limited use of both generic and disease-specific HRQOL instruments are also important limitations in the extant literature. Further, the degree to which the intervention itself, such as frequent, invasive intravenous infusions several times weekly, contributes to poorer HRQOL is not quantified. Future studies should use large patient samples and robust study designs, including longitudinal assessments of HRQOL. In addition, these should assess the degree to which prophylaxis itself affects HRQOL and the sample size should be large enough to capture differences among adults, adolescents, and children. Analyses should also include not only generic HRQOL measures, but also disease-specific measures of HRQOL, to provide a rich description of the experiences of living with hemophilia. Given the importance of HRQOL assessment in hemophilia care and the future changing landscape of hemophilia prophylaxis anticipated with the availability of long-acting factors, ongoing data collection comparing current and newer factors will be needed to address the question of for which patients and with which products prophylaxis improves HRQOL among patients with hemophilia.

Conflict-of-interest disclosure: D.B. declares no competing financial interests. M.V.R. is on the board of directors or an advisory committee for Biogen Idec and NHF-MASAC; has received research funding from Baxter, Bayer, Biogen Idec, CSL Behring, and Novo Nordisk; and has consulted for Baxter and Biogen Idec. Off-label drug use: None disclosed.

David Buchbinder, MD, MSHS, Division of Hematology, CHOC Children's Hospital, 455 S Main St, Orange, CA 92868; Phone: 714-532-8459; Fax: 714-532-8771; e-mail: dbuchbinder@choc.org; or Margaret V. Ragni, MD, MPH, Division of Hematology/Oncology Department of Medicine, University of Pittsburgh, Hemophilia Center of Western Pennsylvania, 3636 Boulevard of the Allies, Pittsburgh, PA 15213; Phone: 412-209-7288; Fax: 412-209-7281; e-mail: ragni@pitt.edu.