Bleeding Disorders Conference

Introduction/Background:

Maintenance of oral health is frequently challenging for US adults with a bleeding disorder. Underlying causes are due mainly to (1) lack of dental insurance and (2) lack of knowledge among dentists about how to perform safely either primary dental care or oral surgery. Without regular care, patients are at risk for advanced dental disease, which is associated with chronic inflammatory conditions, including type 2 diabetes and cardiovascular disease. Research indicates that controlling periodontal disease reduces inflammatory markers throughout the body, including synovial joints.

Materials and Methods:

The Gulf States Hemophilia and Thrombophilia Center (GSHTC) in Houston, Texas serves a diverse urban population; historically, about 50% of adult patients receive no dental care. In October 2019, GSHTC added adult dental exams to comprehensive care services. Patients are evaluated by University of Texas School of Dentistry residents and scheduled for routine or specialized dental procedures as needed. To assess the scope of dental needs in the GSHTC patient population, we examined the range of procedures recommended and the proportion of patients reporting oral health care problems. We report here preliminary results from the initial six months of adult dental services, October 2019 – March 2020. 

Results:

In this period, 171 adults with a bleeding disorder received dental evaluations, and 146 completed the Oral Health Impact Profile (OHIP-14). The OHIP-14 is a validated survey instrument consisting of 14 questions measuring seven dimensions of oral health: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability and handicap. Responses are rated on a 5-point Likert scale: 0=never, 1=hardly ever; 2=occasionally, 3=fairly often; 4=very often/every day. Total OHIP-14 scores can range from 0 to 56 and are calculated by summing the values for the 14 items. Higher scores indicate worse and lower scores indicate better health-related quality of life (HRQoL). Scores ranges from 0-52; 80 (55%) individuals had a score of 0-1 (no oral health problems); 48 (33%) scored between 2-9, and 18 (12%) had scores of 10 or greater. Since October 2019, nearly all adult patients seen in clinic have received a dental evaluation; approximately 40 patients in need of dental care have received treatment or a treatment plan. Procedures include deep cleaning, regular/surgical extractions, fillings, scaling, root planing, crowns, bridges and root canal, all of which require infusion of factor concentrate prior to treatment.

Conclusion:

A substantial proportion of patients who completed the OHIP-14 reported reduced HRQoL related to poor oral health; subsequent dental examination confirmed the urgent need for treatment in these individuals. Continued administration of the OHIP-14 will monitor the impact of dental treatment on patient HRQoL. Ultimately, we hope to provide evidence of the need for widespread inclusion of adult dental care among US Hemophilia Treatment Centers.

Objectives:

Von Willebrand disease (VWD) is the most common bleeding disorder in children and adolescents. Its varied clinical presentation contributes to challenges and delays in diagnosis and management. We characterized diagnosis, bleeding, and treatment patterns in children (2-11yrs) and adolescents (12-17yrs) with VWD.

Methods:

This retrospective database analysis utilized data from IQVIA PharMetrics Plus Database of medical insurance claims for VWD patients (ICD-9 286.4) from 01/01/2006 to 06/30/2015. Patients included had ≥2 medical claims for VWD and continuous enrollment for ≥2 years, to ensure higher likelihood of definitive VWD diagnosis, before/after their 1st VWD claim. Pre-diagnosis period included 18mos of data before diagnosis. Post-diagnosis period included 7-24mos post-diagnosis data. Data from the first 6-month post-diagnosis period were excluded due to data variability, suggestive of treatment optimization. Descriptive statistics were used to summarize patient demographic/clinical characteristics, including types of bleeding episode (BE), rates, outcomes; treating physician specialty; and type of VWD treatment, in both pre-/post-diagnosis periods.

Results:

475/1087 patients identified were children (43% female; mean age at diagnosis 6.9yrs; 612 were adolescents (74% female; mean age at diagnosis 14.9yrs). The top 3 treating physician specialties seen by children in the pre-/postdiagnosis periods, respectively, were hospitalists (21%/9%), primary care physicians (16%/7%), and hematologists (11%/3%). Adolescents were mostly seen by hospitalists (30%/15%), primary care physicians (25%/16%), and obstetrician gynecologists (19%/15%). 11% of children and adolescents saw a hematologist prior to diagnosis, compared with 3% and 5%, respectively, post-diagnosis. A 17%/15% decrease in bleed claims in the pre-/post-diagnosis period was observed among children (40%/23%) and adolescents (59%/44%), respectively. The most common type of BE among children in the pre-/post-diagnosis periods was epistaxis (19%/10%). Heavy menstrual bleeding was the most common BE among adolescents in both the pre-/post-diagnosis periods (40%/30%; in females 54%/40%). Epistaxis was the second most common BE among adolescents in both the pre-/post-diagnosis periods (11%/7%), and in females (9%/5%), but highest among males (17%/12%). Overall, VWD-related treatment claims increased between the pre-/post-diagnosis periods for both children (12%/23%) and adolescents (31%/50%). The most prescribed treatments for bleed management in children were aminocaproic acid (ACA), desmopressin (DDAVP) and nasal cauterization (pre-diagnosis: 5%, 4% and 4%, respectively; post-diagnosis: 11%, 13% and 3%, respectively). For adolescents, the most prescribed treatments, pre- and post-diagnosis respectively, were oral contraceptives (22% and 33%, DDAVP (9% and 19%) and ACA (4% and 11%).

Conclusions:

This analysis demonstrates a decrease in BE claims following VWD diagnosis and a rise in ACA and DDAVP treatment claims in both children and adolescents, and in oral contraceptive claims among female adolescents. Nevertheless, a considerable proportion of children and adolescents continue to experience BEs 6mos post-diagnosis. This emphasizes the need for treatment optimization and improvement in care and management of patients in these age groups.

Swimming is an important life skill that benefits hemophilia patients medically and psychosocially. As a recipient of the NHF " Social work Excellence Grant" our HTC has implemented a swim program for patients with hemophilia and other bleeding disorders. We currently have 17 children enrolled and are also monitoring these children by conducting before and after physical therapy and QOL examinations. 

Objective:

Immune tolerance induction (ITI) is the standard of care for inhibitor eradication and restoration of factor VIII (FVIII) responsiveness in subjects with severe hemophilia who develop high-titer inhibitors. Retrospective data support the use of recombinant FVIII Fc fusion protein (rFVIIIFc) in ITI (Carcao et al. Haemophilia. 2018) but this has yet to be confirmed in prospective studies. This study presents preplanned interim results of verITI-8 (NCT03093480).

Methods:

VerITI-8 is a single-arm, nonrandomized, open‐label, ethics-approved study of rFVIIIFc (200 IU/kg/day) for first-time ITI. Eligible subjects had a history of high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL) and provided informed consent. The primary endpoint is time to tolerization, defined by negative inhibitor titer (<0.6 BU/mL) at two consecutive visits; incremental recovery ≥66% of expected at two consecutive visits; and rFVIIIFc half‐life ≥7 hours. ITI failure is defined as not meeting the above criteria by Week 48. This interim analysis was planned when ≥10 subjects had received ≥6 months of rFVIIIFc ITI.

Summary:

Fifteen subjects were screened as of the December 5, 2018 cutoff, while 14 subjects enrolled and had received ≥1 dose of rFVIIIFc for ITI. The median (range) age at start of ITI was 2.6 (0.8–16.0) years and historical peak inhibitor titer was 29.6 (6.2–256.0) BU/mL. Six subjects have been successfully tolerized, with a median (range) time to first negative titer, normal incremental recovery, and tolerization of 2.3 (1.7–15.6), 6.0 (4.3–28.1), and 11.7 (8.1–32.0) weeks, respectively. Seven subjects continue to receive rFVIIIFc ITI (median [range] time on ITI: 16.0 [0.1–35.6] weeks) and 1 subject has failed. No adverse events related to rFVIIIFc have been reported.

Conclusions:

Early results from this prospective/ongoing study of first-time ITI indicate that rFVIIIFc may offer rapid time to tolerization in some subjects with severe hemophilia A and high-titer inhibitors. Achieving tolerance faster can improve quality of life and reduce costs.
 

Objective:

Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life FVIII therapy approved for treatment of adults and children with hemophilia A. A-LONG parent (NCT01181128) and ASPIRE extension (NCT01454739) Phase 3 studies evaluated safety and efficacy of rFVIIIFc for prevention and treatment of bleeding episodes for previously treated subjects with severe hemophilia A. A subgroup analysis was performed using A-LONG and ASPIRE interim data cut 3 and including subjects ≥50 years of age.

Methods:

Subjects were assigned to one of the following treatment regimens: individualized prophylaxis (IP; 25–65 IU/kg rFVIIIFc every 3–5 days), weekly prophylaxis (WP; 65 IU/kg every 7 days), modified prophylaxis (MP; tailored dosing if IP and WP were suboptimal), and episodic treatment (ET; on-demand dosage dependent on type and severity of bleeding episode). Subjects could change treatment groups at any time in ASPIRE and may appear in more than one treatment regimen. For this subgroup analysis outcomes included inhibitor development, the annualized bleeding rate (ABR), ABRs for subjects with target joints and target joint resolution, hemophilia quality of life questionnaire for adults (Hem-A-QoL), modified hemophilia joint health score (mHJHS), and cumulative exposure.

Summary:

Twenty-one subjects ≥50 years of age (median [range] age, 57 [50–65] years) in A-LONG and/or ASPIRE received rFVIIIFc (IP, n = 14; WP, n = 7; MP, n = 3; ET, n = 3). Baseline median (interquartile range [IQR]) ABR was 13 (6–22) for subjects who received pre-study prophylaxis and 27 (19–43) for subjects who received pre-study ET. No subjects developed inhibitors. Median (IQR) ABRs on treatment (with n ≥5) were 1.77 (0.35–5.26; IP) and 2.01 (0.25–4.76; WP). On-treatment ABRs (median [IQR]) for subjects with target joints (with n ≥5) were 1.39 (0.00–5.26; IP) and 2.01 (0.25–4.76; WP). All 49 evaluable target joints were resolved during prophylactic treatment. Mean (standard deviation) change from baseline in total Hem-A-QoL score and mHJHS was –1.9 (10.9) and –9.2 (11.43), respectively, for subjects who were always on prophylactic rFVIIIFc treatment. Subjects had a median (IQR) of 4.05 (3.04–4.26) years of treatment with rFVIIIFc and 293 (227–364) cumulative rFVIIIFc exposure days. There was no increase in weekly factor consumption.

Conclusions:

For previously treated subjects ≥50 years of age with severe hemophilia A, rFVIIIFc prophylaxis for approximately 4 years resulted in low ABRs and improved/sustained joint health without inhibitor development and without increase in factor consumption, suggesting that rFVIIIFc prophylaxis in adults ≥50 years of age has overall clinical benefits irrespective of baseline status. These data were similar to the overall study population.

Objective:

We conducted a pilot study using a single open-ended question to elicit patient-perceived challenges and management strategies in individuals with bleeding disorders. The de-identified responses and themes expressed in this study were analyzed. The identification of perceived challenges and management strategies in individuals with bleeding disorders offers the opportunity to improve value based care.

Methods:

This retrospective, cross-sectional cohort study used a sample of convenience at The Hemophilia Center at OHSU. Study population included 20 participants. Inclusion criteria included: ages seven to eighty nine, diagnosed with a bleeding disorder and seen during any outpatient Hemophilia Center clinic visit between March 1, 2017 and April 30, 2018. Participants were included if, during the course of their clinical care, they answered the question, “What is the most significant (or greatest) challenge you have in managing your bleeding disorder and what do you do about it?” Data extracted included question response, age, type and severity of bleeding disorder. Responses were analyzed for themes by the investigators and using qualitative data analysis software. Coded demographic data was correlated.

Summary:

Seven challenge themes were identified: activity restrictions, infusions, emotion/stress, pain, future plans, education and access. Management themes included: self-advocacy, parent directed, activity modification or avoidance, acceptance, inquiry, asking for assistance, planning ahead, resiliency, and peer supports. Younger participants’ (9-17 years) challenges included activity restriction and infusions with management strategies of self-advocacy, activity avoidance and modification. Participants aged 18-57 years highlighted challenges with access to care, infusions, emotion/stress, pain, education and future planning. Management strategies in this group were focused on acceptance, planning ahead, peer support and resiliency. Analysis based on severity of bleeding disorder revealed that subjects with severe hemophilia reported infusions and activity restriction as their most significant challenge, with self-advocacy and activity modification management strategies. Participants with moderate hemophilia reported challenges centered on activity restriction and education of peers, with management strategies being self-advocacy and planning ahead. There were no differences in themes identified when analyzed based on type of bleeding disorder.

Conclusions:

This study characterizes the unique challenges and management strategies described by individuals with bleeding disorders. The themes highlighted the importance of patient voice and can be used to inform individual care decisions.

Objective:

BAY 81-8973 (Kovaltry®) is a full-length, unmodified recombinant human factor VIII (FVIII) for prophylaxis and treatment of bleeds in patients with hemophilia A. Safety and efficacy of BAY 81-8973 in children, adolescents, and adults were established in the LEOPOLD clinical trials. This analysis reports interim data from the LEOPOLD Kids extension study for patients with ≥100 exposure days (EDs) to BAY 81-8973 in the main study plus extension study.

Methods:

In LEOPOLD Kids, boys aged ≤12 years with severe hemophilia A and ≥50 EDs to FVIII received BAY 81-8973 (25–50 IU/kg) ≥2 times/wk for ≥50 EDs. Patients completing the main study could enroll in an ongoing extension study for ≥100 EDs.

Summary:

Of 51 patients who completed the main study, 46 (90.2%) entered the extension study (aged <6 years, n=22; aged 6–12 years, n=24). Patients were treated for a median (range) of 1494 (175–1989) days and accumulated 546 (67–1011) EDs in the extension study. Median (quartile [Q]1; Q3) dose per prophylaxis infusion was 37.7 (33.1; 41.8) and 30.9 (29.1; 34.9) IU/kg for younger and older patients, respectively; annual prophylaxis dose was 4984 (3679; 6529) and 4089 (3283; 5555) IU/kg. Median (Q1; Q3) annualized number of total bleeds was 2.0 (0.2; 4.2) and 1.8 (0.5; 3.0) for younger and older patients, respectively; annualized total bleed rate was 3.0 (0; 6.0) and 0 (0; 6.4) for these patients in the main study. Median (Q1; Q3) annualized total bleeds within 48 hours of prophylaxis infusion was 0.8 (0; 1.7) and 1.0 (0.1; 1.6) in younger and older patients in the extension study. Response was excellent/good in 337/405 bleeds (83.2%); data were missing for 22 (5.4%) bleeds. Most bleeds (93.5%) were mild/moderate and were spontaneous (42.4%) or trauma related (53.6%). One patient experienced a mild treatment-related serious adverse event (transient very low FVIII inhibitor titer concurrent with acute infection and positive immunoglobulin G anticardiolipin) and remained in the extension study. No change in treatment was required, and the patient was clinically well.

Conclusions:

Data from the LEOPOLD Kids extension study show that BAY 81-8973 provides safe and effective long-term prophylaxis in children with severe hemophilia A treated for a median of 4.1 years, confirming safety results observed in the main study.

Objective:

Report results of an open-label international study that collected retrospective data on compassionate use of high-purity plasma-derived FX concentrate (pdFX) in subjects with hereditary factor X (FX) deficiency (FXD).

Methods:

This study included subjects with hereditary FXD (irrespective of severity) who received compassionate use pdFX as routine prophylaxis (RP), on-demand (OD) treatment, short-term prevention, and/or perisurgical hemostatic cover. Dosing was at the investigator’s discretion and tailored to each patient. Data from date of first compassionate use dose until data cutoff (31 December 2015) were collected retrospectively.

Summary:

All 15 enrolled subjects from 12 study centers received ≥1 pdFX dose for compassionate use. Of these, 13 subjects were aged ≥12 years (mean, 22.8 years) and 2 were aged <12 years, 8 (53.3%) were female, 12 (80.0%) were white, 3 (20.0%) were Asian. All subjects had moderate or severe FXD (FX activity [FX:C] <5 IU/dL).Of the 15 patients, 7 received only RP, 7 received only OD, and 1 alternated between OD and RP. The 8 subjects on RP received a total of 1239 RP infusions (mean, 154.9 infusions/subject, range 39–492), with a mean dose/infusion/subject of 32.5 IU/kg. The 2 subjects aged <12 years received larger RP doses than the 6 older subjects (mean doses/infusion/subject of 51.1 vs 26.3 IU/kg).Twelve subjects (8 OD, 4 RP; all aged ≥12 years) reported 88 bleeds (34 minor, 7 major, and 47 not rated); 37 bleeds were menorrhagic, 28 were traumatic, 17 were spontaneous, 4 were other, and 2 had unknown cause. pdFX efficacy was rated as effective for the 79 bleeds (including 1 subdural hematoma) treated with OD pdFX. Mean pdFX dose was 22.2 IU/kg/infusion/subject, with a mean of 9.5 infusions/subject to treat a bleed. More bleeds occurred in the OD than in the RP population.Two subjects underwent 1 dental procedure each, with only 1 presurgical pdFX dose required per patient; a third surgery, a portacath insertion, required 6 infusions to prevent postoperative bleeding. Two successful pregnancies/childbirths were also reported, with no abnormal bleeding complications or efficacy/safety concerns reported.The mean duration of compassionate use was 87.6 weeks for the 15 subjects, with a range of 15–211 weeks (0.3–4.0 years). Over the 1373 infusions administered across 25.2 subject-years, investigators rated overall pdFX efficacy as excellent in 14 (93.3%) subjects and good in 1 (6.7%) subject. No adverse drug reactions, safety concerns, infusion site reactions, tolerability issues, or inhibitor development were reported during pdFX compassionate use.

Conclusions:

The higher bleed rate in OD versus RP use and the treatment duration (up to 4 years) support the efficacy and safety of pdFX demonstrated in prospective clinical studies and its continued use in the treatment of subjects with hereditary FXD.

Objectives:

Emicizumab, a bispecific humanized monoclonal antibody in development to address unmet medical needs in persons with hemophilia A with inhibitors (PwHAwI), bridges FIXa and FX to replace the function of missing FVIIIa, needed for effective hemostasis. This study assessed efficacy, safety and PK of emicizumab prophylaxis in PwHAwI.

Methods:

Study NCT02622321 was conducted at 43 centers/sites, and enrolled PwHAwI ≥12 y.o. Participants (pts) receiving prior episodic bypassing agents (BPAs) were randomized (2:1) to emicizumab prophylaxis vs no prophylaxis (Arm A vs B). Primary endpoint compared treated bleed rates in Arm A vs B. PwHAwI receiving prior prophylactic BPA received emicizumab prophylaxis in Arm C. Emicizumab was injected subcutaneously at 3 mg/kg/wk for 4 wks, and 1.5 mg/kg/wk thereafter.

Summary:

109 male PwHAwI were enrolled; median age 28 (range 12–75) yrs. Median (range) emicizumab treatment exposure was 24.0 (3.0–47.9) wk overall and 29.5 (3.3–47.9) wk in Arm A. Statistically significant, clinically meaningful reductions (87%) in treated bleed rates were observed between emicizumab prophylaxis vs no prophylaxis (Arm A vs B) (annualized bleeding rate [95% confidence interval] 2.9 [1.69 to 5.02] versus 23.3 [12.33 to 43.89], P<0.0001), and in all secondary bleed-related endpoints (spontaneous, joint, target joint, and all bleeds). Of note, a 79% reduction in treated bleed rate was seen with emicizumab prophylaxis (Arm C) vs BPA prophylaxis prior to study entry in a non-interventional study (NCT02476942; intra-individual comparison, P=0.0003). Overall, 67.3% of PwHAwI on emicizumab prophylaxis had zero treated bleeds. Statistically significant, clinically meaningful improvements in health-related quality of life (HRQoL) and health status were seen for Arm A vs B. Emicizumab was well tolerated. Total of 198 adverse events (AEs) were reported in 103 pts; most common AEs were injection-site reactions (15%), and 12 serious AEs were reported in 9 (8.7%) pts. Thrombotic microangiopathy and thrombosis (2 pts each in primary analysis) were reported and associated with high cumulative aPCC doses averaging >100 U/kg daily for >24 hr prior to event onset. No events occurred with emicizumab prophylaxis alone. Both TMA events resolved once aPCC treatment was stopped, and the thrombotic events did not require anticoagulation; 2 pts resumed emicizumab without sequelae (1 with TMA, 1 with thrombosis). No antidrug antibodies were detected. Mean trough emicizumab concentrations >50 μg/mL were achieved after 4 loading doses (3 mg/kg/wk) and sustained with maintenance doses of 1.5 mg/kg/wk.

Conclusion:

Emicizumab prophylaxis prevented or substantially reduced bleeds in PwHAwI and meaningfully improved HRQoL. Emicizumab had acceptable safety without excess thrombotic risk in the absence of concomitant aPCC. PK levels were sustained with once- weekly maintenance doses. These promising data could support a paradigm shift in the management and lives of PwHAwI.

Objective:

The aim of this study was to determine if the young boys with hemophilia at our clinic have gross motor delays that may have been missed during the annual physical therapy evaluation. By identifying delays, our clinic can improve the standard of care and promote gross motor development in our patients to enhance their ability to be physically active and protect their joints and muscles from injury.

Method:

Over a one year period, boys with hemophilia A or B between the ages of 4 to 14 were tested by the physical therapist at our clinic using the Bruinink’s-Oseretsky Test of Motor Proficiency, Second Addition, BOT2. The BOT2 is a valid and reliable gross motor test for 4 to 21 year olds and is widely used to detect mild to moderate motor delays. The five gross motor subtests used in this study included upper extremity (UE) coordination, bilateral coordination, balance, strength, running speed and agility (run/agility). A total of 42 boys completed the study with scores distributed between three age groups: Group 1=4-7 year olds; Group 2=8- 11 year olds; and Group 3=12-14 year olds. Exclusion criteria included a bleed within the last week that was unresolved or other physical limitation preventing participation. All severities of hemophilia were included in the study, but were not separately analysed in the results.

Results:

Each age group mean scores for the subtests were within the normal mean range of 15±4 except for strength in Group 2. Group 1 had some participants score above average for four of the subtests, while Group 2 and 3 only scored above average on one subtest. Group 1 had 6-18% score below average on four of the subtests while Group 2 had 27-47% and Group 3 had 30-50% score below average on all 5 subtests. No adverse events or bleeds occurred during or as a result of the gross motor testing.

Conclusion:

At our Hemophilia Treatment Center, more than 50% of the boys tested had gross motor dels. The percentage of boys showing deficits increased and persisted after age 7. This reinforces the need to include some standardized gross motor testing during the annual physical therapy evaluation of our patients with hemophilia to identify boys with scores below average and make referrals at an early age to prevent persisting gross motor delays.

Objective:

Functional impairment from recurrent joint bleeding in people with hemophilia results in joint pain and reduces quality of life. The P-FiQ study formally evaluated patient- and site-reported functional assessment including responses to generic and hemophilia-specific patient-reported outcomes (PROs) tools. Psychometric analyses were used to evaluate reliability, validity, and consistency of responses.

Methods:

Adult males with hemophilia and a history of joint pain or bleeding completed a hemophilia history and 5 PROs assessing function: EQ-5D-5L, Brief Pain Inventory v2 Short Form (BPI), International Physical Activity Questionnaire (IPAQ), Short Form-36 v2 (SF-36v2), and Hemophilia Activities List (HAL). PROs were assessed for reliability, consistency, and correlation, with factors including patient-reported characteristics.

Summary:

A total of 381 adults (median age, 34 years; range, 18-86 years) were enrolled in P-FiQ. Most participants (66%) and sites (59%) reported functional disability in the past 6 months (CDC-UDC scale). Patients self-reported arthritis/bone/joint problems (65%) and history of joint procedures or surgeries (50%). On EQ-5D-5L, most reported problems “today” with mobility (61%) and usual activities (53%) but fewer with self-care (19%). On BPI, similar median pain interference scores (0- 10 scale, 10 is complete interference) were reported with general activity (3.0), walking ability (3.0), and normal work (3.0). On IPAQ, physical activity was reported by 49% of respondents over the prior week, with more reporting walking (35%) than moderate (16%) or vigorous (16%) activities. On SF-36v2, activities in the past 4 weeks that were most frequently limited were vigorous activities (80%), bending, kneeling, or stooping (67%), walking more than a mile (61%), and climbing several flights of stairs (59%). Physical problems caused participants to limit kinds of work/activities (69%), accomplish less than they would like (66%), have difficulty in performing work/activities (65%), and reduce time spent on work/activities (62%). On HAL, greater difficulties were seen for lower vs upper extremity functions/activities; within the lying/sitting/kneeling/standing domain, the most frequent problems in the previous month were squatting for a long time (74%), kneeling (73%) or standing (72%), and kneeling/squatting (70%). Similar items across different PROs were correlated with one another. Self- reported functional impairment was significantly differentiated by BPI pain interference, IPAQ total activity, SF-36v2 physical functioning, and all HAL domains and summary scores.

Conclusion:

PRO instruments assessing functional status range from simple/generic (EQ-5D-5L) to complex/disease-specific (HAL) and provide varying levels of detail. Greater use of formal PRO instruments in the clinical setting may improve dialogue between health care professionals and patients/caregivers and inform proactive approaches to specifically target patient identified functional limitations (eg, HAL) and identify areas for further targeted management strategies.

Objectives:

Contemporary real-world data on units dispensed and expenditures associated with use of standard half-life (SHL) and extended half-life (EHL) factor VIII replacement products in U.S. patients with hemophilia A are limited. This exploratory analysis of real-world administrative data was conducted to determine units dispensed and factor replacement product-related direct expenditures associated with currently marketed recombinant SHL and EHL FVIII products, and to examine inter-product switches.

Methods:

De-identified claims data from the commercially available Truven Health MarketScan® Research US claims database were used to identify direct expenditures and number of international units (IUs) dispensed for all patients with a diagnosis code of ICD-9 286.0/ICD-10 D66 who used SHL (SHL group) and/or EHL (EHL group) during the study period from Aug 1, 2014 to Jan 31, 2017. Data on switching from an SHL to an EHL factor VIII replacement product were captured in patients with continuous pharmacy enrollment for whom claims data were available for at least 1 calendar quarter and up to 1 year before and after the index date of a product switch. Descriptive statistics were used to analyze results.

Summary:

Cross-sectional analysis.
The SHL group comprised 415 patients, among whom six distinct SHL FVIII products had been dispensed, and the EHL group included 91 patients, among whom two EHL FVIII products had been dispensed. The age distribution of the two groups was similar (p =0.57), although the proportion of patients under 18 years of age was somewhat higher in the SHL group than in the EHL group (46.9% vs 36.2%). The median FVIII product dispensation per calendar quarter was 46,409 IU (IQR, 12,760-87,670 IU) (SHL) versus 67,375 IU (IQR, 50,524-98,264 IU) (EHL). Median expenditures per calendar quarter were substantially higher for EHL ($135,519; IQR, $100,320-186,557) than for SHL ($61,152; IQR, $18,593-115,845).

Switching analysis.
Of the patients in the EHL group, 29 had switched from one of three SHL FVIII products to one of two EHL FVIII products during the study period. The total median IU dispensation per calendar quarter increased following the switch from 58,598 IU (pre-switch, SHL) to 68,036 IU (post-switch, EHL; 16% increase), as did the factor-related expenditure ($76,553, SHL, versus $141,101, EHL; 84% increase).

Conclusion:

Real-world data derived from a large claims database, unadjusted for treatment regimen or hemophilia severity, reveal marked differences in metric units and expenditures among hemophilia A patients to whom SHL and/or EHL products were dispensed. Switching from an SHL to an EHL FVIII replacement product was associated with a substantial increase in units dispensed and factor expenditures. Further analyses, incorporating essential clinical characteristics, should be explored.

Objective:

To provide genotyping and enrollment into the My Life, Our Future research repository for individuals with Hemophilia and potential carriers by offering a community based outreach program.

Methods:

Utilizing the ATHN dataset, potential participants who had not been previously genotyped were identified. In addition, a recruitment letter was prepared and sent to invitees of the local NHF Chapter Annual Dinner. Interested subjects were instructed to contact the genetic counselor, who discussed the project and scheduled them in 15 minute research timeslots. A hospital mobile unit, stocked with medical supplies and a centrifuge, was obtained to provide a site for registration, phlebotomy and processing of specimens. Staff for the event included the following: three staff to consent participants; four staff providing venipunctures, two staff to process specimens, two staff to assist with registration and a driver for the mobile unit. Funding was secured through NHF to support the genotyping day.

Summary:

Fifteen subjects, including 3 males and 12 females, scheduled appointments for the 4-hour recruitment time period. In addition, three subjects were added the day of the project and a waiting list was started for those wishing to enroll at a future event. In total, 17 subjects were enrolled from 9 families. In several cases, family members from different generations enrolled, including an at-risk carrier female, her mother and grandmother. Ages of participants ranged from 4-91. All participants chose to participate in the research repository. One participant’s specimen had to be destroyed due to a mislabelled MLOF ID (an add-on subject). It took approximately 10 hours to prepare for the event including 2 hours of planning related to the mobile unit (5 staff) and 8 hours to develop the recruitment letter, prepare the IRB amendment, mail letters, schedule participants, prepare consent packets, obtain MLOF ID numbers, and arrange phlebotomy kits (4 staff). It took 5 hours and 12 staff to successfully implement the program on the genotyping day. In comparison, we typically process on average two patients per 4 hour comprehensive clinics held two times per month, with 2 staff involved with other concurrent job assignments.

Conclusions:

The outreach program is an effective way to recruit individuals for genotyping and participation in the MLOF research repository. Participants were excited to participate and inquired about future events. The event provided a relaxed atmosphere with extended family members present, allowing for multi-generational and diverse recruitment. When considering a genotyping day versus scheduled clinic time, additional preparation time is needed to arrange logistics and avoid error, but the number of participants is significantly increased.

Objective:

To evaluate efficacy of IB1001 for perioperative management of bleeding under surgical circumstances in hemophilia B patients.

Methods:

The efficacy of IB1001 for perioperative management has been evaluated in a prospective, open-label, multicenter international study where 17 subjects (16 male PTPs and one female hemophilia B carrier) underwent 20 major surgical procedures. The PTPs were defined as patients with a minimum of 150 exposures to another factor IX preparation. The subjects had severe or moderately severe (factor IX level ≤ 2 IU/dL) hemophilia B without inhibitors, with exception of one mild hemophilia B female carrier. Efficacy of IB1001 was based on the surgeon’s assessment including estimation of blood loss as ‘less than expected’, ‘expected’, or ‘more than expected’ at the time of surgery and assessment of hemostasis at 12 and 24 hours post-surgery as ‘superior’, ‘adequate’, or ‘poorly controlled’. Transfusion requirements were also monitored.

Summary:

Thirteen major procedures in 12 male subjects were managed by bolus regimen, and 6 major procedures in 4 male subjects were managed by continuous infusion regimen. Mean loading dose for 13 major procedures managed by bolus regimen was 120 ± 11.4 IU/kg and mean maintenance bolus dose (given every 12 hours) was 59.7 ± 12.2 IU/kg. During the 24 hours following surgery, factor IX levels were successfully maintained over 60%, as intended. Factor IX levels at pre-infusion were 59.7% ± 15.9% at 12 hours after surgery and 54.4% ± 16.5% at 24 hours after surgery. For a major procedure in one female carrier, the bolus dose was 110 IU/kg, while the mean maintenance dose was 44.9 ± 7.0 IU/kg. Mean loading dose for 6 major procedures managed by continuous infusion regimen was 95.4 ± 14.5 IU/kg and the mean maintenance infusions were 7.1 ± 4.0 IU/kg/hr. In all major procedures, blood loss at the time of surgery was ‘expected’ or ‘less than expected’ as assessed by the surgeon. IB1001 was rated by the surgeon as ‘superior’ or ‘adequate’ in controlling hemostasis post-surgery, including 8 knee arthroplasties, two elbow arthroplasties, one knee amputation, one percutaneous Achilles tendon lengthening, one open inguinal hernia repair, one tibiotalar fusion, two arthroscopic synovectomies, three debridements and one total hysterectomy/bilateral oopherectomy. There were no transfusions required perioperatively.

Conclusions:

At the time of surgery, blood loss was expected or less than expected after IB1001 treatment, while post-surgery effective hemostasis control was achieved following IB1001 treatment in hemophilia B patients.

Objectives:

This trial evaluated the hemostatic efficacy, pharmacokinetics, and safety of a recombinant VWF (rVWF) in adults with severe von Willebrand disease (VWD) (type 3 [VWF:Ag ≤ 3 IU/dL], severe type 1 [VWF:RCo< 20 IU/dL], 2A [VWF:RCo< 20 IU/dL], 2N [FVIII:C<10% ], 2B, or 2M).

Methods:

Bleeds were to be treated initially with rVWF and rFVIII (1.3:1 ratio), followed by rVWF alone (as long as FVIII:C >40%). Hemostatic efficacy was evaluated using a pre- defined 4-point rating scale (none=4, moderate=3, good=2, excellent=1). PK parameters for rVWF vs. rVWF:rFVIII were assessed in a randomized crossover design, and a 6-month repeated PK evaluation for rVWF alone.

Summary:

Of 31 subjects assigned to bleed treatment, 22 (17 type 3, 4 type 2A and 1 type 2N) experienced 192 bleeding episodes (several in multiple locations) that were treated with rVWF: 106 occurred in mucosal tissue (including 32 menorrhagic, 42 nasopharyngeal, 26 mouth/oral bleeds), 59 joint bleeds, 6 gastrointestinal bleeds, and 37 in other locations. Treatment success (mean efficacy rating <2.5) was achieved in all 22 subjects (100%; Clopper-Pearson exact 90% confidence interval: 87.3 to 100.0). ‘Excellent’ ratings were given for 186/192 (96.9%) bleeds (119/122 minor, 59/61 moderate, 6/7 severe, 2/2 unknown severity) and the remaining 3.1% were ‘good’. One infusion was effective in 81.8% of bleeds (median [range]: 1 [1-4] overall; 2 [1-3] for severe bleeds). The subject’s own assessment of treatment efficacy (an exploratory endpoint), was ‘excellent’ within 8 hours after the first infusion for 125/134 (93.3%), ‘good’ for 8/134 (6.0%) and ‘moderate’ for 1/134 (0.7%) bleeding episodes. A substantial increase in FVIII:C and sustained stabilization (> 40% by 6 hours, rising to >80% 24 hours post-infusion) was observed after infusion with rVWF. PK parameters for VWF Ristocetin cofactor (VWF:RCo, a surrogate for the platelet-dependent function of rVWF) were similar when rVWF was infused alone (mean T1/2 21.9 h vs. 19.6 h with rVWF:rFVIII). Eight adverse events (tachycardia, infusion site paraesthesia, ECG t wave inversion, dysgeusia, generalized pruritis, hot flush, chest discomfort and increased heart rate) in 5 subjects were assessed as related to rVWF. No inhibitor or anti-VWF binding antibody development was observed, and there were no thrombotic events or severe allergic reactions.

Conclusions:

rVWF was safe, well-tolerated and effective in the treatment of a variety of bleeding presentations in severe VWD. The sustained stabilization in FVIII:C after the initial infusion enables subsequent infusion of rVWF without rFVIII, when multiple infusions are required.

Introduction and Objectives:

In the phase 3 A-LONG and Kids A-LONG studies, subjects with severe hemophilia A receiving rFVIIIFc prophylaxis 1-2 times/week had low annualized bleeding rates (ABRs), with comparable pre-study and on-study weekly factor consumption for subjects previously on FVIII prophylaxis. This report evaluated the effect of rFVIIIFc on subjects’ physical activity across a variety of age groups using a subject-reported assessment.

Methods:

Subjects eligible for A-LONG (≥12 y) and Kids A-LONG (<12 y) were previously treated males with severe hemophilia A (<1 IU/dL endogenous FVIII activity). Subjects in A- LONG were enrolled into 1 of 3 arms: Arm 1, individualized prophylaxis; Arm 2, weekly prophylaxis; or Arm 3, episodic treatment. All subjects in Kids A-LONG received rFVIIIFc prophylaxis. There were no restrictions regarding physical activity. Physical activity assessments were conducted at Weeks 7, 14, 28, 38, 52, and end of study (A-LONG) and Weeks 2, 7, 12, 17, 22, 26, and end of study (Kids A-LONG). At each visit after their first rFVIIIFc dose, subjects were asked to report any changes in their activity levels relative to their prior study visit as: more (or more intensive), fewer (or less intensive), or about the same amount of physical activities. To summarize each subject’s change in physical activity during the study compared to baseline, subjects’ reports were classified into four groups: less, the same, more, or undetermined.

Results:

A total of 165 and 71 subjects enrolled in A-LONG and Kids A-LONG, respectively. Overall, the majority of subjects in A-LONG reported more or the same amount of physical activity, and few subjects reported less physical activity during the study (less, the same, more, undetermined in Arm 1 [n=117], 8%, 36%, 51%, 5%; Arm 2 [n=23], 9%, 48%, 39%, 4%; Arm 3 [n=23], 9%, 52%, 26%, 13%, respectively). Results were generally similar for subjects in Kids A-LONG (for subjects aged <6 y [n=35], 3%, 26%, 66%, 6%; for subjects aged 6 to <12 y [n=34], 9%, 26%, 56%, 9%).

Conclusions:

The majority of subjects in A-LONG and Kids A-LONG reported similar or increased physical activity levels during the studies, while maintaining low ABRs. These self- reported data suggest that subjects across a variety of age groups with severe hemophilia A who are transitioning to rFVIIIFc may maintain or increase physical activity levels, while reducing infusion frequency and maintaining similar weekly factor consumption, without compromising efficacy.

Objectives:

The objective of this study was to compare the rate of prophylaxis between severe hemophilia B and severe hemophilia A patients.

Methods:

A retrospective cross sectional study was conducted using a large US specialty pharmacy dispensing database and 16 months of data (January 2013 to April 2014). Patients with ICD-9 diagnosis codes 286.0 (hemophilia A) or 286.1 (hemophilia B), who filled a prescription for any FVIII or FIX product were included. Prophylaxis patients were defined by having at least one prophylaxis dispensing record, while on-demand patients were defined by those without any prophylaxis dispensing record during the study period. Descriptive statistics were used to report patient characteristics and the percent of prophylaxis and on-demand patients by hemophilia A and B. Logistic regression was used to compare the rate of prophylaxis between severe hemophilia A and severe hemophilia B, while controlling for age.

Results:

A total of 1565 hemophilia A patients and 376 hemophilia B patients were included in the analysis. A higher percentage of hemophilia A patients had severe hemophilia than hemophilia B patients (63.1% vs. 45.0%, P<0.0001). The mean age for severe hemophilia patients was 24.6 and 22.8 years, respectively (P=0.04). Overall, more severe hemophilia A patients were on prophylaxis compared to severe hemophilia B patients (80.3% vs 73.4%, P=0.04)). When controlling for age, severe hemophilia A patients were significantly more likely to be on prophylaxis compared to severe hemophilia B patients (OR=1.63, P=0.02).

Conclusion:

Severe hemophilia B patients were less likely to be prescribed prophylaxis compared to severe hemophilia A patients. Efforts should be made so the benefits of prophylaxis are extended to more hemophilia B patients.

Objective:

To assess subjective and objective outcomes of total joint arthroplasty (TJA) as a treatment for hemophilic arthropathy, and to assess the safety and efficacy of perioperative pharmacologic thromboprophylaxis as a means to prevent venous thromboembolism in this population.

Methods:

We performed a retrospective chart review to identify patients with congenital bleeding disorders who underwent TJA between 1987 and 2012. We collected data on range of motion (ROM) and pain before and after surgery and on early and late complications (bleeding, infection, thrombosis). Data are presented descriptively using median values and ranges where appropriate.

Summary:

We identified 38 procedures (29 knees (TKA) and 9 hips (THA) in 28 patients (26 male, 2 female) with hemophilia A (n = 21), hemophilia B (n = 4), factor 11 deficiency (n = 1) and von Willebrand disease (n = 2). Median age at operation was 42 years (range, 17 – 74) for TKA and 45 years (range, 18 – 71) for THA. Inhibitors were present in one patient with hemophilia A (1.5 B.U.) and one patient with factor 11 deficiency (0.5 B.U.). All patients were treated with hemostatic agents appropriate to their disorders for up to 4 to 6 weeks post- operatively. Complete data at 2 months post-operatively are available for 27 TKA patients, of whom, 7 (23%), demonstrated improvement in ROM (median 15 degrees, range 5 - 25). At 1.5 years post-operatively, 17/29 (59%) TKA patients showed improvement in ROM (median 15 degrees, range 4 - 58) and 100% reported decreased knee pain. All 9 THA patients demonstrated improved ROM at 2 months post-operatively. Eight (89%) demonstrated gains in internal rotation (median, 45 degrees, range 15 – 45), 9 (100%) in external rotation (median 30 degrees, range 15 – 45), 5 (56%) in flexion (median 35 degrees, range 27 – 55), 7 (78%) in extension (median 15 degrees, range 3 – 95), and 7 (78%) in abduction (median 15 degrees, range 10 – 25).

We were able to contact 22 of 28 study subjects (79%), accounting for 31 of 38 (82%) procedures. Patients who underwent 25 of the 29 TKAs (86%) and 6 of the 9 THAs (67%) agreed to provide answers to yes/no questions about their experience with TJA. 25 of 25 (100%) TKA subjects reported improvement in pain and stated that if given the opportunity to go back and revisit their decision, would make the same decision to have the surgery. 24 of 25 (96%) TKA subjects reported improvement in their joint function after the surgery. 6 of the 6 THA subjects we contacted stated that they experienced improvement in joint pain and function as a result of the surgery, and 5 of 6 (83%) stated that they would choose to have the surgery if they had to choose again.

Low molecular weight heparin was administered post-operatively in 29 of 38 procedures (76%). Thromboprophylaxis was discontinued in 3 patients for non-joint bleeding (one hematuria, two cases of hypotension and anemia). There were no symptomatic VTE. Early complications included 5 cases of cellulitis and 2 hemarthroses in patients not receiving thromboprophylaxis. Late complications included two patients with aseptic loosening in prosthetic knees leading to TKA revisions, one with a subsequent joint infection requiring surgical debridement and one patient with a worsening flexion contracture requiring TKA revision.

Conclusions:

While there are risks associated with TJA in patients with bleeding disorders, our data suggest they are outweighed by the benefits manifesting as decreased pain and improved function. Pharmacologic thromboprophylaxis appears safe in this population; whether it is necessary is unknown and should be a subject of future trials.

Objective:

Age is a major risk factor for cardiovascular disease. Comprehensive care and the improved safety of factor replacement therapy and therapeutic approaches, such as prophylaxis, have increased life expectancy for people with hemophilia people with hemophilia (PwH).

PwH may acquire cardiovascular risk factors (such as diabetes, hypertension, hyperlipidemia, obesity and renal disease) as a consequence of advancing age, lifestyle and hemophilia- related conditions, yet little information is available on cardiovascular risk assessment among PWH.

The ADVANCE Working Group, an expert panel of European hemophilia centers supported by an educational grant from Bayer Healthcare, convened to raise awareness of age-related comorbidities among PwH. There are currently no evidence-based guidelines for antithrombotic management in PwH presenting with acute coronary syndrome (ACS). ADVANCE met to perform a review of the current European Society of Cardiology guidelines, and to consider how best they should be adapted for PWH.

Methods:

Structured communication techniques based on a Delphi-like methodology were used to achieve expert consensus on key aspects of clinical management.

Summary:

The main final statements are: a) ACS and myocardial revascularization should be managed promptly by a multidisciplinary team that includes a hemophilia expert; b) Each comprehensive care center for adult PwH should have a link to a cardiology centre with an emergency unit and 24 hour availability of PCI; c) PCI should be performed as soon as possible under adequate clotting factor protection; d) Bare metal stents are preferred to drug eluting stents; e) Anticoagulants should only be used in PwH after replacement therapy; f) Minimum trough levels should not fall below 5-15% in PwH on dual antiplatelet therapy; g) The duration of dual antiplatelet therapy after ACS and PCI should be limited to a minimum; h) PwH receiving antiplatelet therapy should be offered gastric protection; i) The use of GPIIb- IIIa inhibitors is not recommended in PwH other than in exceptional circumstances; j) The use of fibrinolysis may be justified in PwH when primary PCI (within 90 minutes) is not available ideally under adequate clotting factor management.

Conclusion:

It is hoped that the results of this initiative will help to guide optimal management of ACS in PwH.