Effect of etranacogene dezaparvovec on quality of life for severe and moderately severe haemophilia B participants: Results from the phase III HOPE-B trial 2 years after gene therapy.

INTRODUCTION: For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%. AIM: Assess how EDZ affects HRQoL in HOPE-B trial participants. METHODS: HRQoL was evaluated using generic and disease-specific patient reported outcomes (PROs) including the EQ-5D-5L and the Hem-A-QoL questionnaires. Mean domain and total scores were compared 6 months pre- and the first 2 years post-EDZ administration using repeated measures linear mixed models. The percentage of participants with minimal clinically important improvements in HRQoL was also evaluated. RESULTS: Two years post-EDZ, there were nominally significant increases in the least squares (LS) mean score for the EQ-5D-5L Index Value (.04; p = .0129), reflecting better HRQoL. Nominally significant decreases in the LS mean scores, reflecting better HRQoL, were also found for the Hem-A-QoL total score (-6.0; p < .0001) and the Treatment (-13.94; p < .0001), Feelings (-9.01; p < .0001), Future (-6.45; p = .0004) and Work/School (-5.21; p = .0098) domains. The percentage of participants with ≥15-point improvement ranged from 45.83% (95% CI: 31.37%, 60.83%) for Treatment to 13.89% (95% CI: 4.67%, 29.50%) for Family Planning. Results were similar for Year 1. CONCLUSION: In conclusion, gene therapy with EDZ improved HRQoL in the first and second years in several Hem-A-QoL domains, including Treatment, Feelings, Work/School and Future domains, whereas improvement in other aspects of HRQoL were not demonstrated.

Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis.

INTRODUCTION: Head-to-head evaluation of valoctocogene roxaparvovec, the first gene therapy approved for haemophilia A, with emicizumab is not available. Therefore, phase 3 trial data were indirectly compared. AIM: To compare bleeding rates in trials evaluating 6 × 1013  vg/kg valoctocogene roxaparvovec (GENEr8-1; NCT03370913), 1.5 mg/kg emicizumab dosed every week (HAVEN 3; NCT02847637), and FVIII prophylaxis (270-902) in participants with severe haemophilia A (FVIII ≤1 IU/dL). METHODS: Valoctocogene roxaparvovec versus emicizumab and FVIII prophylaxis as used in 270-902 versus emicizumab cross-trial comparisons were performed using matching-adjusted indirect comparison (MAIC). Individual participant data from GENEr8-1 and 270-902 were weighted to equalise aggregate participant baseline characteristics from HAVEN 3. After MAIC weighting, annualised bleeding rates (ABR) and proportions of participants without bleeds were compared for treated bleeds, all bleeds, treated joint bleeds, and treated spontaneous bleeds. RESULTS: After MAIC weighting, ABR for all bleeds was statistically significantly lower with valoctocogene roxaparvovec than emicizumab (rate ratio [95% CI], .55 [.33-.93]). Additionally, significantly higher proportions of participants had no treated joint bleeds (odds ratio [95% CI], 2.75 [1.20-6.31]) and no treated bleeds (3.25 [1.53-6.90]) with valoctocogene roxaparvovec versus emicizumab. When compared with the mainly standard half-life FVIII prophylaxis regimens in 270-902, mean ABRs (except for all bleeds) were significantly lower, and significantly higher proportions reported 0 bleeds for all outcomes with emicizumab. CONCLUSION: Valoctocogene roxaparvovec provided generally lower bleeding rates and higher probability of no bleeds, including treated joint bleeds, than emicizumab. Emicizumab was more effective than FVIII prophylaxis regimens used in 270-902.

Racial and Ethnic Differences in Distress, Depression, and Quality of Life in people with hemophilia.

Hemophilia-related distress (HRD) has been shown to be higher among those with lower educational attainment, but potential racial/ethnic differences have not been previously described. Thus, we examined HRD according to race/ethnicity. This cross-sectional study was a planned secondary analysis of the hemophilia-related distress questionnaire (HRDq) validation study data. Adults aged ≥ 18 years with Hemophilia A or B were recruited from one of two hemophilia treatment centers between July 2017-December 2019. HRDq scores can range from 0-120, and higher scores indicate higher distress. Self-reported race/ethnicity was grouped as Hispanic, non-Hispanic White (NHW) and non-Hispanic Black (NHB). Unadjusted and multivariable linear regression models were used to examine mediators of race/ethnicity and HRDq scores. Among 149 participants enrolled, 143 completed the HRDq and were included in analyses. Approximately 17.5% of participants were NHB, 9.1% were Hispanic and 72.0% were NHW. HRDq scores ranged from 2 to 83, with a mean of 35.1 [standard deviation (SD) = 16.5]. Average HRDq scores were significantly higher among NHB participants (mean = 42.6,SD = 20.6; p-value = .038) and similar in Hispanic participants (mean = 33.8,SD = 16.7, p-value = .89) compared to NHW (mean = 33.2,SD = 14.9) participants. In multivariable models, differences between NHB vs NHW participants persisted when adjusting for inhibitor status, severity, and target joint. However, after household income was adjusted for, differences in HRDq scores were no longer statistically significant (ß = 6.0 SD = 3.7; p-value = .10). NHB participants reported higher HRD than NHW participants. Household income mediated higher distress scores in NHB compared to NHW participants, highlighting the urgent need to understand social determinants of health and financial hardship in persons with hemophilia.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities in health services; diversity, equity, and inclusion; and implementation science.

BACKGROUND: The National Hemophilia Foundation (NHF) conducted extensive all-stakeholder inherited bleeding disorder (BD) community consultations to inform a blueprint for future research. Sustaining and expanding the specialized and comprehensive Hemophilia Treatment Center care model, to better serve all people with inherited BDs (PWIBD), and increasing equitable access to optimal health emerged as top priorities. RESEARCH DESIGN AND METHODS: NHF, with the American Thrombosis and Hemostasis Network (ATHN), convened multidisciplinary expert working groups (WG) to distill priority research initiatives from consultation findings. WG5 was charged with prioritizing health services research (HSR); diversity, equity, and inclusion (DEI); and implementation science (IS) research initiatives to advance community-identified priorities. RESULTS: WG5 identified multiple priority research themes and initiatives essential to capitalizing on this potential. Formative studies using qualitative and mixed methods approaches should be conducted to characterize issues and meaningfully investigate interventions. Investment in HSR, DEI and IS education, training, and workforce development are vital. CONCLUSIONS: An enormous amount of work is required in the areas of HSR, DEI, and IS, which have received inadequate attention in inherited BDs. This research has great potential to evolve the experiences of PWIBD, deliver transformational community-based care, and advance health equity.

Research into how people get their health care, called health services research, is important to understand if care is being delivered equitably and efficiently. This research figures out how to provide the best care at the lowest cost and finds out if everyone gets equally good care. Diversity and inclusion research focuses on whether all marginalized and minoritized populations (such as a given social standing, race, ethnicity, sex, gender identity, sexuality, age, income, disability status, language, culture, faith, geographic location, or country of birth) receive equitable care. This includes checking whether different populations are all getting the care they need and looking for ways to improve the care. Implementation science studies how to make a potential improvement work in the real world. The improvement could be a new way to diagnose or treat a health condition, a better way to deliver health care or do research, or a strategy to remove barriers preventing specific populations from getting the best available care. The National Hemophilia Foundation focuses on improving the lives of all people with bleeding disorders (BD). They brought BDs doctors, nurses, physical therapists, social workers, professors, and government and industry partners together with people and families living with BDs to discuss research in the areas described above. The group came up with important future research questions to address racism and other biases, and other changes to policies, procedures, and practices to make BD care equitable, efficient, and effective.

Cross-sectional study evaluating the association of haemophilia-related distress and clinically relevant outcomes.

INTRODUCTION: In chronic diseases, disease-related distress can impact disease outcomes. Distress and haemophilia-related distress has been demonstrated in people with haemophilia (PwH). The association of haemophilia-related distress on disease outcomes among PwH is unknown. AIM: To study the association of haemophilia-related distress with haemophilia specific outcomes, including adherence to prophylactic therapy, the presence of a target joint, healthcare utilization and work-impairment. METHODS: In a cross-sectional study, adults with haemophilia A or B were enrolled in a study to validate the haemophilia-related distress questionnaire (HRDq). In this planned analysis, univariate and multivariate associations between the HRDq total score and disease outcomes were explored. RESULTS: The 114 participants in this analysis were male, mostly with haemophilia A (92%) and severe disease (52%) with a median age of 31.9 years. On univariate analysis, HRDq total score (5-point change) was associated with the presence of a target joint (P = .002), high healthcare utilization (P = .011), poor adherence (P = .033) and work-impairment (P ≤ .001). After adjustment for age, race, severity and other potential confounders, adherence (aß 0.33, 95% CI .17, .49) and work-impairment (aß 4.69, 95% CI 3.27-6.1) remained statistically significantly associated with HRDq total score. CONCLUSION: Haemophilia-related distress is associated with poor adherence to factor prophylaxis and work-impairment. The direction of the association (causation) is yet to be determined and requires future study.

Physical therapy within US HTCs: A multicentre survey of utilization, practice patterns and pain management approaches.

INTRODUCTION: Practice patterns and utilization of physical therapists (PTs) affiliated with Hemophilia Treatment Centers (HTCs) in the United States (US) are not well known. AIMS: Describe utilization, role responsibilities and practice patterns of US HTC PTs. Identify practice patterns specifically focusing on assessment and treatment of pain. Recognize gaps in utilization and role responsibilities of PTs as part of the multidisciplinary team and suggest guidelines for PT involvement within the HTC. METHODS: Respondents were a subset of a convenience sample of healthcare providers who responded to a non-validated survey developed by a multi-disciplinary panel of haemophilia experts. RESULTS: A 33.0% response-rate (n = 59) representing all regions of US HTCs was achieved. Those working ≥10 hours per week were more likely to provide nutrition education (P = .026) and surgical options education (P < .001). Those who billed insurance for their services during comprehensive visits were more likely to provide education regarding surgical options (P = .046). The majority of PTs (95.0%) evaluated pain regardless of time spent in clinic and felt comfortable treating pain. Fifty-eight percent used a formal pain measurement tool and more likely to use a formal pain measurement tool if billing insurance (P = .004). Top five non-pharmacologic treatments recommended for pain management included splints/braces (84.8%), aquatic therapy (74.6%), orthotics (71.2%), surgical options (47.5%) and yoga (32.2%). CONCLUSIONS: This study demonstrated PT utilization across HTC centres varies widely. Gaps in care may be addressed through salary support, funded education, greater regional/national collaboration of PTs specializing in bleeding disorders and advocacy for insurance coverage for appropriate services.

Postoperative bleeding complications in patients with hemophilia undergoing major orthopedic surgery: A prospective multicenter observational study.

BACKGROUND: Persons with hemophilia (PWH) are at risk for chronic hemophilic arthropathy (HA). Joint replacement surgery may be used to relieve intractable pain and/or restore joint function. OBJECTIVES: This multicenter, prospective, observational cohort study evaluated the rate of bleeding during the postoperative period after total hip (THA) or knee arthroplasty (TKA). PATIENTS/METHODS: We included PWH of any severity ≥18 years of age who were undergoing THA or TKA. Clinical decisions were made at the discretion of the treating physician according to local standards of care. Clinical data were prospectively recorded. Major bleeding was defined as bleeding in a critical site, bleeding that resulted in either a 2 g/dl or greater decrease in hemoglobin during any 24-h period, or transfusion of two or more units of packed red blood cells. RESULTS: One hundred thirty-one procedures (98 TKA and 33 THA) were performed, 39 (29.8%) of which were complicated by major bleeding, including 46% of THA and 25% of TKA. The risk of major bleeding was increased in THA compared to TKA (OR 2.50, p = .05), and by the presence of an inhibitor (OR 4.29, p = .04), increased BMI (OR 4.49 and 6.09 for overweight and obese, respectively, compared to normal BMI, each p < .01), and non-use of an antifibrinolytic medication (OR 3.00, p = .03). Neither continuous clotting factor infusion (versus bolus infusion) nor pharmacologic thromboprophylaxis were associated with bleeding risk. CONCLUSIONS: The bleeding risk remains substantial after THA and TKA in PWH, despite factor replacement. Use of antifibrinolytic medications is associated with decreased risk.

Women and girls with haemophilia receiving care at specialized haemophilia treatment centres in the United States.

INTRODUCTION: Females may have haemophilia with the same factor VIII (FVIII) or factor IX (FIX) levels as affected males. Characterization of females with haemophilia would be useful for health care planning to meet their unique needs. Federally-funded haemophilia treatment centres (HTCs) in the United States contribute data on all individuals with bleeding disorders receiving care to the Population Profile (HTC PP) component of the Community Counts Public Health Surveillance of Bleeding Disorders project. AIMS: To estimate the number of females with haemophilia receiving care at HTCs in the United States and compare their characteristics with those of males with haemophilia. METHODS: HTC PP data collected on people receiving care at an HTC from January 2012 through September 2020 with haemophilia A and B were evaluated by sex for demographic and clinical characteristics. RESULTS: A factor level < 40% was reported for 23,196 males (97.8%) and 1667 females (47.6%) attending HTCs; 51 (.48%) severe, 79 (1.4%) moderate, and 1537 (17.9%) mild haemophilia patients were female. Females were older, more often White, and less often non-Hispanic than males. Females were less likely to have history of HIV or HCV infection, even among those with severe disease, but twice as likely to have infection status unknown. Females with mild haemophilia were more often uninsured than males. CONCLUSIONS: Females with severe or moderate haemophilia are uncommon, even in specialized care centres; however, almost one in five patients with mild haemophilia was female, indicating needs for specialized care based on factor level and history for affected females.

Shortening the Haemophilia Activities List (HAL) from 42 items to 18 items.

INTRODUCTION: The Haemophilia Activities List (HAL) was developed to measure activities and participation in persons with haemophilia (PWH). Shortening the questionnaire may facilitate use of the HAL. AIM: The aim of this study was to determine which items of the HAL are redundant, to construct a shorter version of the HAL, and to determine the construct validity of the HALshort . METHODS: A secondary analysis was performed on pooled data of two published studies using the HAL (seven domains, 42 items, optimum score: 100) in adults with haemophilia A/B. Data were divided into a derivation (62%) and a validation set (38%). Redundant items were identified by evaluation of: floor and ceiling effects, proportions of missing and 'not applicable' responses, inter-item correlations, component loadings in an exploratory factor analysis, internal consistency, and item-total correlations. Correlations with the SF-36 and EQ-5D-5L were used to determine construct validity of the HALshort . RESULTS: Data on 680 PWH were evaluated. In the derivation dataset (n = 420), median age was 30 years (range 18-80), 43% had severe haemophilia and 61% received prophylaxis. Median (IQR) HAL sum score was 65.0 (55.7-88.8). The stepwise procedure resulted in a HALshort of 18 items with a median sum score of 63.3 (54.4-86.7). Construct validity was similar for the HAL and HALshort in the validation dataset (n = 260). CONCLUSION: This clinimetric study resulted in a >50% shortening of the HAL. The 18-item HALshort reduces patient burden and is expected to capture the information on activities and participation. The HALshort needs further validation.

Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single-center report.

BACKGROUND: Emicizumab, a bispecific antibody factor VIII mimetic, is approved for prophylaxis in hemophilia, and has different risks and side effects compared to factor VIII products. OBJECTIVE: To better understand the early impact of emicizumab on our patients at the University of Colorado Hemophilia and Thrombosis Center (UCHTC), we evaluated adverse reactions, factor prophylaxis overlap, and bleeding rates after starting emicizumab through a quality improvement project. PATIENTS/METHODS: A retrospective chart review and structured phone interview were conducted from June to September 2019 for all patients who had started emicizumab at the UCHTC. Data about emicizumab dosing, reactions, bleeding events, and bleeding treatment were collected in 68 children and adults (aged 0.55-79.8 years, on emicizumab a median 213 days; range, 51-1229 days) with hemophilia A (35.3% with past or current inhibitor). RESULTS: Adverse reactions were primarily skin reactions, with no anaphylactic reactions or thrombosis. Bleeding events, defined as pain or swelling treated with factor or supportive measures, demonstrated wide variability, with 25 of 68 experiencing zero bleeds and 5 of 68 experiencing >8 bleeds per year. The most prevalent bleed type was traumatic musculoskeletal bleeding. Bleeding events occurred more often in the first 10 weeks after starting emicizumab, but no time period was without bleeding events. The majority of patients were prescribed every-week or every-2-week dosing, but some had alternative dosing frequency. CONCLUSIONS: Real-world emicizumab use in our center was characterized by variations in prescribing practices and bleeding outcomes and lack of severe adverse reactions.

Patient preferences and priorities for haemophilia gene therapy in the US: A discrete choice experiment.

INTRODUCTION: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments. AIM: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes. METHODS: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post-treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity. RESULTS: A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%). CONCLUSION: People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia.

An evaluation of PROMIS health domains in adults with haemophilia: A cross-sectional study.

INTRODUCTION: The Patient-Reported Outcomes Measurement Information System (PROMIS) provides measures of health status that assess physical, mental and social well-being from the patient perspective. PROMIS measures are used in clinical practice and research across various patient populations but are not yet validated among patients with haemophilia. AIM: Evaluate the sensitivity of PROMIS to indicators of haemophilia clinical severity and compare PROMIS measures to those from other PRO instruments. METHODS: Male adults with haemophilia (n = 115) completed the PROMIS-29 short form which includes 4 questions for each of 7 domains: depression, anxiety, ability to participate in social roles and activities, physical function, pain interference, fatigue and sleep disturbance. Participant responses for each domain were scored on a T-score metric with a mean of 50 and a standard deviation of 10 based on the original PROMIS reference sample of US adults. Participants also completed other generic and haemophilia-specific health-related quality of life questionnaires. RESULTS: Participants who experienced higher pain and depression levels reported significantly worse health in every PROMIS domain compared with their peers. Those who had recently needed to use crutches, visit an emergency department or were currently unemployed or disabled also reported poor PROMIS scores on most domains. Construct validity was supported by correlations between PROMIS domain scores and domain scores reported using the EQ-5D-5L and Haem-A-QoL. CONCLUSION: The PROMIS instrument provides a potentially valuable tool to evaluate the impact of haemophilia and suggests usefulness in research and clinical practice.

Improvements in Communication and Coordination of Care in a Hemophilia Treatment Center.

INTRODUCTION: In response to the increasing complexity of care for patients with bleeding disorders, we established new clinical teams for our hemophilia treatment center (HTC). AIMS: We undertook a quality improvement project to improve the coordination and communication with our patients by establishing primary assignments of clinical staff to individual patients (primary teams). METHODS: A quality improvement project group was formed that established the goals and assignment of primary teams. Patients were surveyed for their knowledge of their primary teams as well as their ability to schedule and contact their primary providers. As a measure of the effects on clinical staff, a balancing survey was also conducted among providers impacted by the clinical assignment of teams. RESULTS: Our results demonstrate improvements across both coordination and communication as reported by patients. Additionally, the assignment of primary teams was met with high satisfaction and improvement in coordination and communication as reported by the clinical staff members of the HTC. CONCLUSIONS: Initiation of a quality improvement project and the creation of a primary team system were feasible at a large HTC and resulted in improvements in both patient-reported and staff-reported outcomes of coordination and communication of care.

Health care resource utilization and cost burden of hemophilia B in the United States.

Hemophilia B is a rare congenital blood disorder characterized by factor IX deficiency. Clinical profiles of hemophilia B range from mild to severe forms of the disease. The objective of this study was to characterize the economic burden associated with differing clinical profiles of hemophilia B from a US health system perspective. Using the IBM MarketScan database (June 2011-February 2019), a claims-based algorithm was developed to identify 4 distinct profiles (mild, moderate, moderate-severe, and severe) in adult males with hemophilia B based on the frequency of hemorrhage events and factor IX replacement claims. Mean annual health care resource use (HRU) and costs were statistically compared between patients with hemophilia B (N = 454) and 1:1 demographic-matched controls (N = 454), both overall and with stratification by clinical profile. Compared with matched controls, patients with hemophilia B had a significantly higher comorbidity burden (Charlson Comorbidity Index, mean ± standard deviation [SD]: 0.9 ± 1.7 vs 0.3 ± 0.9, P < .001). Across all clinical profiles, patients with hemophilia B had significantly higher HRU vs matched controls (mean ± SD: 0.3 ± 0.6 vs 0.1 ± 0.3 inpatient admissions; 0.6 ± 1.2 vs 0.2 ± 0.6 emergency department visits; 17.7 ± 22.9 vs 8.0 ± 11.0 outpatient visits; all P < .001). Annual total health care costs per patient among patients with hemophilia B were more than 25-fold higher vs matched controls (mean ± SD: $201 635 ± $411 530 vs $7879 ± $29 040, respectively, P < .001). Annual total health care costs per patient increased with increasing severity (mean ± SD: mild, $80 811 ± $284 313; moderate, $137 455 ± $222 021; moderate-severe, $251 619 ± $576 886; severe, $632 088 ± $501 270). The findings of this study highlight the substantial burden of illness associated with hemophilia B.

Evidence of a disability paradox in patient-reported outcomes in haemophilia.

INTRODUCTION: People with inherited and long-term conditions such as haemophilia have been shown to adapt to their levels of disability, often reporting better quality of life (QoL) than expected from the general population (the disability paradox). AIM: To investigate the disability paradox in people with haemophilia in the United States by examining preference differences in health state valuations versus the general population. METHODS: We conducted a discrete choice experiment including duration to capture valuations of health states based on patient-reported preferences. Participants indicated their preferences for hypothetical health states using the EQ-5D-5L, where each participant completed 15 of the 120 choice tasks. Response inconsistencies were evaluated with dominated and repeated scenarios. Conditional-logit regressions with random sampling of the general population responses were used to match the sample of patients with haemophilia. We compared model estimates and derived preferences associated with EQ-5D-5L health states. RESULTS: After removing respondents with response inconsistencies, 1327/2138 (62%) participants remained (177/283 haemophilia; 1150/1900 general population). Patients with haemophilia indicated higher preference value for 99% of EQ-5D-5L health states compared to the general population (when matched on age and gender). The mean health state valuation difference of 0.17 indicated a meaningful difference compared to a minimal clinically important difference threshold of 0.07. Results were consistent by haemophilia type and severity. CONCLUSION: Our findings indicated the presence of a disability paradox among patients with haemophilia, who reported higher health states than the general population, suggesting the impact of haemophilia may be underestimated if general population value sets are used.

Outcome measures in Haemophilia: Beyond ABR (Annualized Bleeding Rate).

Options for management of haemophilia are increasing rapidly with completely novel therapeutic approaches that cannot be compared using traditional factor assays. In addition, as prophylaxis regimens have improved, bleeding rates have decreased, and consequently, it is difficult to show an impact of novel therapies on rates of spontaneous bleeding. There is currently an urgent need for a panel of outcome measures to compare therapies that are dissimilar in many essential ways. Conventional objective outcome measures including joint physical examination and joint imaging continue to hold a central importance. Factor assays are essential for evaluation of products derived from native factor genes, but are not applicable to some extended half-life factors or non-factor bypassing agents. Global assays including thrombin generation and chromogenic assays of factor X activation are under investigation for their usefulness in haemophilia assessment. Bleeding rate is a conventional subjective patient-reported outcome that, while decreasing in frequency, is indispensable as an outcome given that the primary manifestation of haemophilia is bleeding. Other patient-reported outcomes such as pain intensity and interference, health-related quality of life and activities and participation are increasingly important to distinguish superior outcomes in comparative trials. This review of outcome measures for haemophilia presents examples of existing outcome measures with an emphasis on their strengths and limitations.

Validation of a new instrument to measure disease-related distress among patients with haemophilia.

INTRODUCTION: In patients with haemophilia, general psychological distress as measured by the National Comprehensive Cancer Network (NCCN) distress thermometer has been associated with pain, disability and increased healthcare utilization. AIMS: To develop and validate a measure of haemophilia-related distress. METHODS: After qualitative interviews, the Hemophilia-Related Distress Questionnaire (HRDq) was developed. To validate the HRDq, adults (≥18 years) with haemophilia were enrolled, reported demographic and clinical information, and completed the HRDq and other questionnaires that measured similar constructs. Analysis included factor analysis and assessment of internal consistency using Cronbach's α, convergent validity using Pearson's correlation coefficient, and discriminant validity by comparing subgroups of patients. Test-retest reliability was assessed using an intraclass correlation coefficient (ICC). RESULTS: Among 130 enrolled participants, 126 (median age=32.7 years) completed the 24 item HRDq in a median time of 5.4 minutes with overall HRDq scores ranging from 2 to 83 (median score=31.5; higher scores indicating higher distress). Assessment of convergent validity demonstrated a strong correlation (ρ>.60) of the HRDq total score with the NCCN Distress Thermometer, Haem-A-QoL total Score, and PROMIS-29 Profile social role domain and a mild to moderate correlation with all other questionnaire domains (.3-.59, p < .05). Distress was higher among those who had less education, were not employed, and were disabled and was not significantly different among those with severe compared with non-severe disease. Assessment of test-retest reliability demonstrated an ICC value of .84 (95% CI .71-.91) for the total score. CONCLUSIONS: The HRDq demonstrates good internal consistency, construct and discriminant validity, and retest reliability with a low responder burden.

In-Hospital Complications and Readmission in Patients with Hemophilia Undergoing Hip or Knee Arthroplasty.

BACKGROUND: Individuals with hemophilia undergoing hip or knee arthroplasty are at risk for complications such as bleeding and infection. However, data on hospital length of stay (LOS) and readmission rates compared with nonhemophilic controls are lacking. This study compared the complication rates, LOS, and unplanned 30-day readmission rates between patients with hemophilia and nonhemophilic controls. METHODS: This retrospective cohort study used the Pennsylvania Health Care Cost Containment Council (PHC4) database from 2007 to 2015 to compare outcomes in patients with hemophilia and nonhemophilic controls undergoing partial and total hip arthroplasty, knee arthroplasty, and revision knee arthroplasty. RESULTS: A total of 118 patients with hemophilia and 3,811 controls were identified. Compared with controls, patients with hemophilia had a higher risk of bleeding complications after hip procedures (38.7% versus 16.1%, p = 0.003), a higher risk of surgical site infection after knee procedures (8.1% versus 1.1%, p < 0.001), longer median LOS after hip (6 versus 3 days, p < 0.001) and knee (5 versus 3 days, p < 0.001) procedures, and higher rates of unplanned 30-day readmission after hip (22.6% versus 4.1%, p < 0.001) and knee (10.3% versus 4.5%, p = 0.018) procedures. The most common reason for unplanned 30-day readmission in patients with hemophilia was bleeding or the patient's underlying coagulopathy (25.1%). CONCLUSIONS: Patients with hemophilia undergoing hip or knee arthroplasty had a higher incidence of postoperative bleeding (hip procedures) and surgical site infections (knee procedures), longer LOS, and higher rates of unplanned 30-day readmission compared with nonhemophilic controls. Key limitations of our study include the potential for inaccurate coding, the relatively small number of patients in the hemophilia cohort, and the uneven distribution of procedure type in the hemophilia and control cohorts. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.