Background:
Von Willebrand disease (VWD) is an inherited bleeding disorder caused by a quantitative or qualitative deficiency of the protein, von Willebrand factor (VWF). There is a lack of clear guidance on best practices to inform the care of people with VWD.
Objectives:
Identify and prioritize the main topics of a collaborative guideline development effort.
Methods:
A scoping survey to prioritize topics to be addressed in a collaborative guideline for VWD was distributed to international stakeholders including patients, caregivers, clinicians, and allied healthcare professionals. The distribution strategy was coordinated by the guideline chairs and representatives of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH). The survey was conducted in English, French, and Spanish. The survey focused on both diagnosis and management of VWD, using 7-point Likert-scale response options and open ended comments. Descriptive analysis of participants and comparative analysis of results by stakeholder subtype (patients/caregivers versus healthcare providers [HCP]), gender, and income setting was performed. Qualitative conventional content data was analyzed utilizing both deductive and inductive coding processes.
Results:
601 participants responded to the survey (49% patients/caregivers, and 51% HCPs). The highest priority topics identified were diagnostic criteria/classification, bleeding assessment tools, treatment options for women, and surgical patients. In contrast, screening for anemia and plasma-derived therapy versus recombinant therapies were rated the lowest priority topics (figures 1 – 2).
Conclusion:
The survey results highlighted areas of importance in the diagnosis and management of VWD across diverse groups of stakeholders and will direct future guideline efforts. The large number responses (601) and discrete comments (9,500) attest to the interest and involvement of the VWD community in this effort.
Objective:
While a new generation of therapies for patients with Hemophilia A are available, it is unclear what patient characteristics, perceptions, and barriers are associated with the decision to switch FVIII replacement therapies. This study assessed patient characteristics, health history, and reasons for switching from a FVIII product with more frequent dosing (³3x infusions/week) to a product with less frequent dosing (≤2x infusions/week) from patient/caregiver and physician perspectives.
Methods:
Data collection was a mix of qualitative and quantitative procedures. The qualitative portion consisted of two online discussion forums: patients (n=17) and caregivers of patients (n=11) receiving a FVIII product dosed ³3x/week, and patients (n=22) and caregivers of patients (n=5) who switched to a product dosed ≤2x/week. The quantitative portion was a retrospective medical chart review (n=207) which captured variables (e.g., bleed rate, treatment history) 6 months pre- and 6 months post-switching to a product with less frequent dosing.
Summary:
Prominent drivers among patients for starting a FVIII product with less frequent dosing included: 1) experiencing diminished effectiveness while on a product dosed ³3x/week resulting in increased breakthrough bleeding, 2) experiencing vein access issues, and 3) beginning prophylaxis as opposed to on-demand infusions after a bleed.
Key barriers to changing included: 1) fears regarding the process of switching being complicated, time consuming, and costly, 2) perceived risks associated with switching, and, 3) possible lack of healthcare provider support.
Physicians were most likely to report that patients switched products because they sought a newer product with twice weekly dosing or less per FDA-approved dosing recommendations (35.3%), followed by patient requested the switch (30.4%), and patient sought a reduction in infusion frequency to improve adherence (27.5%).
Switching to a product with less frequent dosing was associated with improvements in patient-reported bleeding-related outcomes. Patients were more likely to self-administer the treatment post-switch (63.8%) compared with pre-switch (48.8%; p<0.001) and had fewer infusions per week post-switch (2.8 vs. 3.3; p<0.001). Patients’ annualized bleed rate was lower (5.9) post-switch compared with pre-switch (7.7; p<0.001).
Both the number of spontaneous joint bleeds and joint bleeds after trauma or injury were lower (3.2 and 2.7) post-switch (3.6 and 4.3; p=0.044 and p<0.001). The bleeding event was less likely to be classified as moderate or severe (34.5% and 5.9%) post-switch compared with pre-switch (55.0% and 10.0%; p<0.001 and p=0.049). Fewer infusions were required to resolve the bleeding event post-switch (2.6 vs. 3.2; p<0.001).
A prominent reason why patients switch treatment is to improve bleeding-related outcomes. Indeed, we found that switching to a FVIII product with less frequent dosing was associated with improved patient-reported bleeding-related outcomes. These findings are critical for improving patient outcomes and support the FDA mandate to incorporate patient perspectives in the regulatory process.
Objective:
Pain and functional impairment resulting from joint disease in patients with hemophilia (PWH) may impact emotional well-being, resulting in consistent reports of anxiety/depression. The P-FiQ study formally evaluated patient-reported anxiety/depression symptoms and treatment as well as responses to standardized patient-reported outcomes (PROs), and evaluated reliability, validity, and consistency of responses.
Methods:
At a comprehensive care visit, adult male PWH with a history of joint bleeding or pain completed a hemophilia history and 3 patient-reported outcomes (PROs) assessing anxiety/depression and quality of life (QoL): EQ-5D-5L, Brief Pain Inventory (BPI), and SF-36v2. PROs were assessed for reliability, consistency, and correlation with factors including patient-reported characteristics.
Summary:
A total of 381 PWH (median age, 34 years) were enrolled in P-FiQ; 77% had hemophilia A, 23% had hemophilia B, and 9% had inhibitors. Fewer than half (44%) were currently receiving routine infusions to prevent bleeding. More than half were employed full-time (53%), and 65% were married or had a long-term partner. Depression was reported by 19% and anxiety by 14%. On the EQ-5D-5L anxiety/depression item, 43% reported feeling anxious or depressed “today.” On BPI, most participants indicated that pain interfered in the previous week with mood, sleep, and enjoyment of life, and more than half (54%) indicated interference with relations with other people. On SF-36v2 (range 0- 100, higher scores indicate better QoL), median mental health summary score was 50.7; subdomains were similar (vitality, 49.0; social functioning, 45.6; role emotional, 55.9; mental health, 52.8). Emotional problems resulted in reduced time spent on work/activities (40%) and accomplishing less than they would like (47%). More than half (55%) had felt downhearted or depressed, and a large majority (93%) had felt tired in the past 4 weeks. Sixty percent of participants indicated that their physical or emotional problems had interfered with their normal social activities with family, friends, and other contacts. Similar items across PROs correlated with one another, and PRO scores (EQ-5D-5L anxiety/depression, SF-36 mental health) were significantly (P<0.05) correlated with self-reported anxiety/depression.
Conclusion:
Anxiety and depression in adults with hemophilia have been consistently reported in other studies and were identified in P-FiQ by self-report and across several PRO instruments. Emotional problems were reported to interfere with normal social activities and productivity. While the unmet need to address mental health in PWH has received increased recognition, it is not typically assessed formally. When compared with pain, management strategies and/or referral relationships may also not be as formally established. The findings presented here highlight the potential value of simple screening tools (eg, EQ-5D-5L) and opportunities to encourage patient dialogue about mental health within the comprehensive care setting and in referral networks.
Objective:
People with hemophilia frequently experience joint bleeds, resulting in pain and functional impairment. The P-FiQ study formally evaluated patient-reported pain descriptions, responses to standardized patient-reported outcomes (PROs) related to pain, and pain management strategies.
Methods:
Participants completed a pain/hemophilia history and 5 PRO instruments. Pain was assessed via 3 PRO instruments: EQ-5D-5L, Brief Pain Inventory v2 Short Form (BPI), and Short Form-36 v2 (SF- 36v2), and these instruments were assessed for reliability, consistency, and correlation with factors including patient-reported characteristics.
Summary:
P-FiQ enrolled 381 adult males with mild-severe hemophilia and a history of pain and/or joint bleeding. Most (65%) self-reported having arthritis/bone/joint problems. Thirty-two percent of participants reported experiencing both acute and chronic pain, 35% chronic pain only, 20% acute pain only, and 15% no pain. Of those reporting acute pain, most described the sensation as “sharp” (77%) or “aching” (65%); for those reporting chronic pain, most described the pain as “aching” (80%) or “nagging” (50%). Ankles (37%) and knees (24%) were commonly reported as the most painful joints. Many participants with acute/chronic pain reported using acetaminophen (62%/55%) or nonsteroidal anti-inflammatory drugs (34%/49%) to treat their pain in the past 6 months. Some participants indicated having moderate/severe/extreme (28%/12%/2%) pain/discomfort “today” as measured by the EQ-5D-5L pain/discomfort domain. For BPI (scale 0-10, 10 is most severe pain), median pain severity scores were 6.0 for worst pain, 3.0 for average pain, 2.0 for current pain, and 1.0 for least pain. Median BPI pain interference scores indicated interference with general activity (3.0), mood (3.0), walking ability (3.0), normal work (3.0), and enjoyment of life (2.0). On SF-36, most participants (90%) reported experiencing bodily pain, and 75% indicated that pain interfered with normal work in the last 4 weeks. Assessments of pain on PROs were highly correlated with one another. The following formal PRO assessments were associated with self-reported pain: pain/discomfort domain of EQ-5D-5L, BPI worst pain, least pain, average pain, and current pain, and SF-36 bodily pain. Greater extent of lifetime routine infusions was also associated with EQ-5D-5L pain/discomfort and SF-36 bodily pain.
Conclusion:
Pain severity and interference in people with hemophilia were identified consistently across several PROs, and correlated with patient-reported pain. In the comprehensive care setting, greater use of formalized assessment tools over time would improve dialogue and pain assessment between healthcare professionals and patients, document and validate the presence and extent of pain, establish and monitor individual goals for pain management interventions, and encourage the exploration of various pain management strategies and the evaluation of their overall quality and effectiveness.
Objective:
To assess the effect of digital monitoring on bleeding rates in patients with hemophilia A using prophylaxis.
Methods:
A total of 294 eligible patients with hemophilia A were included in our observational study. Eligible patients used clotting factor concentrates and had no active inhibitors. Patients used a digital health tool powered by MicroHealth to log bleeds and infusions via smartphone, texting, or online. The study observational period was August 2014 to January 2015. Patients using the tool could choose to invite their care professionals for monitoring. For each patient, Hemophilia Treatment Center (HTC) monitoring was defined as having at least one HTC professional: 1. Linked to the patient and with online access to the infusion logs; 2. Receiving notifications when the patient had bleeds and/or had adherence below a threshold, and; 3. Having two or more patients under monitoring. There were a total of 35 and 259 patients in the monitoring and non-monitoring groups, respectively.
We conducted Bayesian analysis using linear mixed models and a negative binomial distribution to compare the relative risk of bleeding rates for patients with and without HTC monitoring.
Summary:
Patients using HTC monitoring had a relative bleeding rate of 0.60 vs. patients without monitoring, which is equivalent to a 40% reduction in bleeding rates for monitored patients (95% credible interval: 0.38—0.96).
Patients on the monitoring and no monitoring groups were comparable except that the monitoring group had 23% more pediatric patients (p<0.001). However, bleeding rates between pediatric and adults were comparable (p=0.500). Subgroup analysis showed no differences in the reductions of bleeding rates due to monitoring between pediatric-only and adult-only subgroups (p=0.353).
Conclusions:
The use of digital tools for chronic care monitoring is a growing global trend.
A reduction in the annualized bleeding rate of 40% (~2 bleeds a year) is both statistically and clinically significant and may have a cumulative protective impact on patients’ long-term outcomes. Observational studies are subject to sample bias, however, patients in both groups were technologically savvy and motivated enough to track their condition using a digital health tool. Given that this intervention is free, safe, and fits the accountable care model, we encourage clinicians to explore its adoption. Confirmatory studies on this topic are encouraged.
Objective:
Personalizing treatment to a patient’s lifestyle and promoting overall health and wellness in persons with hemophilia (PWH) is essential to optimizing outcomes. There is limited evidence that correlates how activity and infusions impact bleeding episodes and further data on this relationship is needed. The research objective of SPACE is to prospectively explore the association between activity level, timing of infusion, and occurrence of a bleeding episode in PWH using novel technology.
Methods:
This six-month prospective, observational study includes PWH A or B in the United States currently receiving ADVATE or RIXUBIS between the ages of 13 and 65 years. Enrolled PWH use a smartphone eDiary application to log information on activities, infusions, and bleeding episodes. As an additional measurement of activity, enrollees are given a FitBit, a consumer-based activity tracker that measures steps taken and calories burned. Activity types are assessed based on their level of perceived risk for collision, according to the NHF “Playing It Safe” brochure. We report here current study status and descriptive analysis of baseline data.
Results:
The interim analysis included 15 patients with a median age of 19 (Range: 13 to 47). At baseline, 87% of patients were on prophylaxis and 13% treated on-demand treatment. Fifty-three percent of patients had 0 target joints at baseline. Eighty-seven percent of patients indicated that they had discussed activity participation with their physician. Sixty-seven percent of patients considered themselves ‘very satisfied’ or ‘satisfied’ with their level of activity. Data collected from the FitBit indicated that patients in SPACE walked on average 7,367 (SD: 3250) steps per day and burned 979 (SD: 398) calories from their activity. For patients on prophylaxis, the mean number of days per week doing mild, moderate and strenuous activity were 3.57, 2.64, and 1.5 respectively. Of the data reported on bleeding episodes, 40% of patients reported no bleeds at the time of the interim analysis. Forty percent of patients did not report having a bleed at the time of the interim analysis. Of all bleeds reported, 34% were associated with physical activity.
Conclusions:
Current data from SPACE demonstrates that subjects are active and participating in various activities. Continued data will provide better understanding of the types of activities and infusion schedules that may be associated with risk as well as protective effects on bleeding episodes by infusing prior to activity. A personalized approach to treatment based on physical activity levels may minimize bleeding risk in PWH.
Objective:
To assess pain and functional impairment through 5 patient-reported outcome (PRO) instruments in non-bleeding adults with hemophilia.
Methods:
Adult men with hemophilia (mild-severe) with history of joint pain/bleeding completed a hemophilia/pain history and 5 PROs (EQ-5D-5L with visual analog scale [VAS], Brief Pain Inventory v2 [BPI-SF], International Physical Activity Questionnaire [IPAQ-SF], SF- 36v2, and Hemophilia Activities List [HAL]) during routine visits. Initial patients were asked to complete the PROs again after their estimated 3-4 hour visit (retest population). PRO scores were calculated from published algorithms. Generally, higher scores indicate better health- related quality of life (HRQoL) and functional status, and greater pain severity/interference.
Summary:
381 Patients were enrolled between October 2013 and October 2014; 164 of the initial 187 completed the retest and are reported here. Median time for completion of the initial survey/PROs was 36.0 minutes and 21.0 minutes for the PRO retest. Most retest subjects had hemophilia A (74.4%) and were white-non-Hispanic (72.6%). Median (Q1, Q3) age was 33.9 (26.9, 46.0), 48.7% were married, 62.6% had some college or graduate education, 80.7% were employed, and 61.0% were overweight or obese. HCV (49.4%) was more common than HIV (16.5%); 61.0% self-reported arthritis/bone/joint problems. Median EQ-5D- 5L VAS was 80.0 (0-100 scale), and EQ-5D-5L health index 0.80 (-0.11-1 scale); 61.6% reported any problems with mobility (29.3% reported moderate/severe problems), 55.8% with usual activities (18.4% moderate/severe), and 22.0% with self-care (4.3% moderate/severe). 73.2% reported pain-discomfort (43.3% moderate/severe), and 41.1% anxiety-depression (14.7% moderate/severe). For BPI, median pain severity was 3.0 (0-10 scale) and pain interference 2.9 (0-10 scale); median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Pain most impacted general activity, mood, walking ability, and normal work, and least impacted relations with other people. Ankles were the most frequently reported site of pain. Median IPAQ total activity was 693.0 MET/min/week; 49.3% reported no activity in the prior week. Median SF-36v2 scores (0-100 scale) were lower for physical health (39.6) than for mental health (51.6). Median overall HAL score was 76.1 (0-100 scale); complex lower extremity activities were the most impacted activity domain.
Conclusions:
These 5 PRO instruments provide different levels of detail describing the impact of hemophilia on pain and function, and consequently, have varied burdens of administration. PRO data from the retest population demonstrate that most adults with hemophilia experience pain and functional impairment that impacts HRQoL, highlighting the importance of assessments and patient dialogue.
Objective:
Clinical knowledge gaps of hemophilia can affect patient outcomes through delayed diagnosis/referral as well as improper monitoring and interventions. A study was undertaken to identify and characterize clinical practice gaps and confidence levels in the management of hemophilia specific to pediatricians.
Methods:
Building upon a previous assessment developed in 2014, an updated global, hemophilia-specific continuing medical education-accredited clinical practice assessment survey was developed utilizing current evidence-based consensus guidelines and best practices, including guidelines from the National Hemophilia Foundation and the World Federation of Hemophilia. The assessment included both knowledge- and case -based, multiple-choice questions that healthcare providers completed confidentially on-line between March 23, 2015 and April 9, 2015. Areas such as appropriate triggers for initiating prophylaxis and use of physical therapy were assessed. Responses from pediatric providers were de- identified and aggregated prior to analysis.
Summary:
660 pediatricians (30% of total respondents) completed the survey, from the following locales: North America (36%), Asia (23%), Europe (15%), Middle East (10%), Africa (7%), Central/South America (6%), and Australia (4%). Academic (31%), private practice (27%), community hospital (19%), community clinic (12%), and hemophilia treatment center (3%) practice settings were identified. Analysis of pediatricians who indicated professional interaction with hemophilia patients (87% of pediatrician respondents) demonstrated knowledge gaps including (% incorrect responses): classification of severity of hemophilia (37%); optimal use of prophylactic therapy, e.g., when to initiate (31%), at what dose (53%), prophylaxis in active patients (26%); likelihood of inhibitors (75%); using bypassing therapy (58%); comprehensive care model (61%); supporting overall joint health and quality of life (70%); and adherence (60%). A low level of confidence in the ability to identify when to use prophylaxis was reported among 31% of pediatricians. The top barriers to the administration of prophylaxis identified by the pediatric providers included lack of availability of FVIII or FIX concentrates, lack of venous access, and insurance coverage (29%, 22%, and 21% for respondents, respectively).
Conclusions:
This study demonstrated gaps in knowledge and confidence about the assessment and optimal care of hemophilia for pediatricians, suggesting that further education specific to the needs of these providers is warranted.
Objective:
To evaluate the effect of bleeding episodes on hemophilia patient burden of illness using observational data.
Methods:
Between 2005-2007 and 2009-2012, the Hemophilia Utilization Group Studies Va and Vb, respectively, recruited patients from ten Hemophilia Treatment Centers (HTCs) in eleven states. Adult patients or parents of children with hemophilia A or B completed an initial survey assessing socio-demographics, clinical characteristics, and treatment regimen. Work absenteeism, underemployment due to hemophilia, and unpaid hemophilia-related caregiver time were recorded at regular intervals over two years to estimate indirect costs using the human capital approach. Direct costs were estimated using healthcare services utilization and drug dispensing records. All costs were annualized and converted to 2014 US dollars. Annual mean bleeding episodes were calculated from patient-reported number of bleeds recorded in follow-up interviews, and used to stratify patients into bleeding categories of 0, 1-3, 4-6, 7-9, and 10+ bleeds. Associations between bleeding episodes and healthcare utilization, work productivity losses, and total costs were analyzed in patient subgroups based on both severity and treatment regimen.
Results:
Of 477 recruited patients, 352 with complete healthcare utilization and dispensing records and at least three months of follow-ups were included. A larger proportion of hemophilia A patients had severe disease and used prophylaxis compared to those with hemophilia B, but no socio-demographic variables differed significantly between the groups. Among severe patients, adults compared to children and episodic treatment compared to prophylaxis users had significantly more average annual bleeds [respective mean(standard deviation): 16.24(13.9) vs 5.54(9.47), p<0.0001 and 15.69(12.65) vs 8.39(11.1), p<0.0001]. Nearly two-thirds of the 82 severe patients using episodic treatment (63.4%) had 10 or more annual bleeds. Higher bleeding categories (more annual bleeds) were significantly associated with higher annual mean indirect costs for mild/moderate patients using episodic treatment [mean range across categories: $423-$21,434 (p=0.0003)] and severe patients on prophylaxis [$6,467-$14,890 (p=0.005]. Increased bleeding was also significantly associated with higher mean total costs in episodic treatment users with mild/moderate disease [$17,373- $136,552 (p<0.0001)] and severe disease [$83,957-$226,614 (p=0.008)]. Across all subgroups, increased bleeding was associated with more emergency room visits, outpatient procedures, and missed days of work, oftentimes reaching statistical significance.
Conclusions:
A larger proportion of severe hemophilia patients treating episodically have poor bleed management compared to those on prophylaxis. Overall, higher bleeding frequency is associated with both higher direct and indirect costs for individuals with hemophilia A and B across disease severity and treatment regimen.
Objective:
Patient satisfaction with healthcare services enhances patient experience, improves outcomes, and is increasingly mandated by public and private payers. While many US Hemophilia Treatment Centers (HTC) periodically assess patient satisfaction, the lack of a uniform survey hampered national measurement. To remedy this knowledge gap, the US HTC Network implemented a national patient satisfaction survey in 2015.
Methods:
A Regional HTC Coordinator workgroup devised, piloted, and finalized a two-page survey for self-administration online, at clinic, or at home, in English or Spanish and mailed to households. Survey content and format were based on national health surveys to enhance comparability and scientific robustness, informed by legacy regional HTC surveys. Questions assessed patient demographics; satisfaction with services, team members, and care processes; and Healthy People 2020 adolescent transition objectives. Surveys included open ended questions to obtain qualitative data. Respondents were anonymous but identified with their respective HTCs. Participation was voluntary. Persons with genetic bleeding disorders who had HTC contact in 2014 were eligible. During February 2015, 124/130 HTCs sent surveys to 27,563 households. Parents completed surveys for children under age 15. No reminders were sent. Data were entered and analyzed at a central site and aggregated at national, regional and HTC levels.
Results:
Over 4800 households (17.4%) returned surveys by April 30, 2015. National analyses on 4332 surveys reveal that 96.6% were ‘always’ or ‘usually’ satisfied with HTC care. Over 80% were ‘always’ satisfied with the core HTC team members. Three quarters of 12-17 year olds were ‘always’ satisfied with HTC encouragement regarding becoming more independent, and how the HTC discussed caring for a bleeding disorder upon reaching adulthood. Eighty– 90% were ‘always’ or ‘usually’ satisfied with care processes, e.g. shared decision making, care coordination, ease of obtaining timely information and services, and being treated respectfully. Insurance and language were ‘always’ a problem for 20%. 29.0% of respondents were female and 10.3% Hispanic. 83.4% were Caucasian, 5.8 African- American, 3.1% Asian/Pacific Islander or Native Hawaiian, 4.3% Multiple races, and 4% Other. Over half had severe or moderate FVIII or FIX deficiency or VWD Type 3. Ages ranged from newborns to 96 years: 38% under 18, 20% age 18 – 34, and 42% over age 35.
Conclusions:
Implementing a National Patient Satisfaction Survey for the US HTCN is feasible, and provides valuable information. Satisfaction with HTC services is high, but insurance and language ‘always’ pose problems for one fifth. Further analyses will examine regional differences.
