Annualized Bleeding Rate Research Articles

Follow-up of More Than 5 Years in a Cohort of Patients with Hemophilia B Treated with Fidanacogene Elaparvovec Adeno-Associated Virus Gene Therapy

Follow-up of More Than 5 Years in a Cohort of Patients with Hemophilia B Treated with Fidanacogene Elaparvovec Adeno-Associated Virus Gene Therapy

Prophylactic Treatment with Rurioctocog Alfa Pegol Results in a Dose-Dependent Normalization of Biomarkers of Joint Health in Severe Hemophilia a: An Exploratory Analysis from the Propel Study

Prophylactic Treatment with Rurioctocog Alfa Pegol Results in a Dose-Dependent Normalization of Biomarkers of Joint Health in Severe Hemophilia a: An Exploratory Analysis from the Propel Study

Pharmacokinetic-Guided Prophylaxis with Rurioctocog Alfa Pegol Improves Bleeding Rates over Standard Prophylaxis: Real-World Observational Data from the Ahead German Study

Pharmacokinetic-Guided Prophylaxis with Rurioctocog Alfa Pegol Improves Bleeding Rates over Standard Prophylaxis: Real-World Observational Data from the Ahead German Study

Effectiveness of Monthly Low-Dose Emicizumab Prophylaxis without 4-Week Loading Doses Among Patients with Hemophilia a with and without Inhibitor: A Case Series Report

Introduction: Emicizumab is a humanized, bispecific, monoclonal antibody proven as an effective prophylaxis for patients with hemophilia A with and without inhibitor. After the weekly loading of 3 mg/kg for 4 doses followed by maintenance dose of 1.5 to 6 mg/kg at 1 to 4-week intervals, the equivalent factor VIII was maintained at approximately 15% and showed an effective prophylaxis in reducing annual bleeding rate. Due to the health care resource constraint, the dose of emicizumab was reduced to maintain the prophylaxis factor VIII at 1-3%.Methods: The effectiveness of monthly low dose emicizumab prophylaxis without 4 loading doses was evaluated among patients with hemophilia A with and without inhibitor for at least 6 months. The bone mineral density (BMD), ultrasonography of bilateral ankle, elbow and knee as well as Hemophilia Joint Health Score (HJHS) were initially evaluated and planned to be repeated after one year treatment. The vitamin D level was determined initially, and vitamin D supplement was prescribed for 3 patients with low vitamin D levels at 13.3, 23.2 and 24.6 ng/mL. Moreover, the quality of life assessment using Hemo-QoL and CHO-KLAT was performed in 3-month intervals.Results: Five patients without inhibitor (3 severe, 2 moderate) and 1 patient with severe hemophilia A with inhibitor enrolled in the study. They all behaved in low bleeding risk circumstances such as avoidance of contact sport. Their ages ranged from 4 to 40 years of age. The youngest boy had difficulty at peripheral venous access for regular prophylaxis while the remaining 4 patients without inhibitor experienced frequent breakthrough bleeding episodes while receiving a low dose prophylaxis at 500 to 1,000 units of factor VIII concentrate twice weekly. All refused to receive more frequent prophylaxis. For patient with inhibitor, the high inhibitor titer of 65 Bethesda units (BU) declined during the 2 years of immune tolerance induction (ITI) at the intermediate dose of 100 units/kg of extended half-life factor VIII concentrate 3 times weekly. His lowest inhibitor was at 10 BU and was documented as failed ITI. He experienced frequent bleeding at the muscles and joints for which bypassing agents could not be adequately provided.For the baseline study, 2 patients had low BMD Z score ≤-2.0 while the remaining 4 patients had normalized BMD Z score >-2.0. The ultrasonography of bilateral ankle, elbow and knee at anterior, medial, lateral and posterior/inferior spaces revealed joint distension reflecting varying-degree synovial hypertrophy and/or bleeding component of 0-14.0, 0-9.8, 0-9.4, 0-12.8; 0-14.4, 0-17.8, 0-10.7, 0-18.6 and 0-23.8, 0-15.3, 0-17.1, 0-12.9 millimeter, respectively. Varying-degree hyperemia from the ultrasonography reflecting active inflammation of synovium was found in 4 ankles, 6 elbows and 4 knees of the total 36 joints in 4 of 6 patients. The HJHS scores ranged from 6 in the youngest patient to 56 in the patient with inhibitor. All patients except the 4-year-old boy had 1 to 3 target joints.All the studied patients received 1 each of the whole vial of emicizumab at 30, 75, 105 mg monthly except 3 patients receiving 60 mg monthly which was equal to 1.1 to 1.6 mg/kg of emicizumab. The monthly trough levels of emicizumab determined by a modified one stage factor VIII assay using emicizumab calibrator were maintained at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3% (0.3% FVIII per µg/ml of emicizumab). The bleeding rate was markedly decreased from 4-8 episodes monthly to 0-1 episode monthly. The monthly zero bleeding rate was found among 4 patients. Moreover, the swollen target joint gradually dissolved. Their quality of life markedly improved evaluated by the Hemo-QoL and CHO-KLAT. They could attend regular school and work happily. The HJHS and ultrasonography have not been repeated yet.Conclusion: The monthly low dose emicizumab prophylaxis of the whole vial at 1.1 to 1.6 mg/kg without loading dose could achieve emicizumab trough levels at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3%. It showed effective prophylaxis among patients with hemophilia with and without inhibitor who performed low bleeding risk activity. The 3 aspects of body functions and structures, activities and participation were gradually improved. DisclosuresNo relevant conflicts of interest to declare.

Longitudinal Efficacy and Safety of N8-GP for Prophylaxis and Bleed Control in US Patients

Introduction: N8-GP is an extended half-life recombinant factor VIII product indicated for use in patients with hemophilia A. The pathfinder trials evaluated routine prophylaxis and bleed control in previously treated patients aged ≥12 years (pathfinder2) and patients aged <12 years (pathfinder5), including an extension trial (pathfinder8). The objective of the present analysis was to compare the efficacy and safety of N8-GP in US vs global (including US) patients.Methods: In the pathfinder2 trial, patients aged ≥12 years with severe hemophilia A were administered N8-GP 50 IU/kg every 4 days (Q4D) as routine prophylaxis or 20 to 70 IU/kg as on-demand treatment. Patients aged <12 years received prophylaxis with N8-GP 60 IU/kg twice weekly in the pathfinder5 trial, and bleeding episodes were treated with 20 to 75 IU/kg. In the pathfinder8 extension trial, the investigator decided on which treatment arm the patient should be allocated based on previous treatment regimen and taking into account bleeding tendency.Results: See Table for efficacy in prophylaxis (median annualized bleeding rates [ABRs]) and bleed treatment (success rate). Median ABRs tended to decrease from 0.84 (global) and 0.86 (US) in pathfinder2 to 0.00 (global) and 0.00 (US) in pathfinder8 in patients aged ≥12 years on the prophylaxis regimen. In addition, in patients aged <12 years, median ABRs decreased from 0.81 (global) and 0.76 (US) in pathfinder5 to 0.00 (global) and 0.49 (US) in pathfinder8. Treatment success rates for US patients were comparable to those for global patients across trials and 100% were rated “excellent” or “good” for patients aged <12 years in pathfinder8.Overall, there were 59 treatment-related adverse events (AEs) in patients on the prophylactic regimen in pathfinder2, 13 of which occurred in US patients, and 11 treatment-related AEs in patients treated on-demand, 3 of which occurred in US patients. In pathfinder5, there were 16 treatment-related AEs, 7 of which occurred in US patients. In pathfinder8, there were 6 treatment-related AEs in patients aged ≥12 years, 3 of which were in US patients. In addition, there was 1 treatment-related AE in a non-US patient aged <12 years. AEs included rash, redness, and injection site reactions. Across trials, 1 previously treated patient (an 18-year-old, from a US site) with an intron 22 inversion developed a low-titer inhibitor at 93 exposure days to N8-GP and was withdrawn when the titer progressed to >5 Bethesda units. The patient returned to their previous FVIII product, and their inhibitor status was negative at follow-up.Conclusions: Efficacy of N8-GP was sustained during the main and extension pathfinder trials in both global and US patients. In addition, a favorable safety profile was maintained throughout the course of the program. [Display omitted] DisclosuresWheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Kearney: Grifols: Research Funding; Daiichi Sankyo: Research Funding; CVS Pharmacy: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Wufsus: Novo Nordisk Inc: Current Employment. Ostrow: Novo Nordisk Inc: Current Employment. Lentz: Novo Nordisk Inc: Consultancy, Honoraria, Research Funding.

Indirect Treatment Comparison of Damoctocog Alfa Pegol versus Turoctocog Alfa Pegol as Prophylactic Treatment in Patients with Hemophilia A.

PurposeTo assess the efficacy and FVIII consumption of BAY 94-9027 versus N8-GP in prophylaxis in adolescent and adult patients with severe hemophilia A (HA).Patients and MethodsA systematic literature review was conducted to identify studies on the efficacy of BAY-94-9027 and N8-GP for prophylaxis in patients with HA aged ≥12 years without a history of inhibitors. Eight studies met systematic literature review inclusion criteria, but only data from PROTECT VIII on BAY 94-9027 and PATHFINDER 2 on N8-GP could be used for an indirect comparison. Matching-adjusted indirect comparison (MAIC) and simulated treatment comparison were performed.ResultsNo significant differences (unadjusted and adjusted) were observed in the mean annualized bleeding rate (ABR) for any bleed and proportion of patients with zero bleeds when comparing BAY 94-9027 to N8-GP. The adjusted treatment difference [incidence rate ratio (IRR)] in terms of ABR was 1.11 (95% CI, 0.85–1.44). The odds ratio (OR) of any bleed, measuring the relative effect of BAY 94-9027 versus N8-GP on the proportion of patients with zero bleeds, was 1.03 (95% CI, 0.60–1.77). FVIII consumption was significantly lower in BAY 94-9027 [mean adjusted difference=−1292.57 IU/kg/year (95% CI, ‒2152.44 to ‒432.70)]; a 26.7% reduction in consumption of BAY-94-9027. The results of the sensitivity analyses were similar to the main analysis for mean ABRs, percentages of patients with zero bleeds, and significant reduction in rFVIII consumption. For patients on BAY 94-9027 every-5-days and every-7-days, no differences versus every-4-days N8-GP were observed for the mean ABR for any bleed [IRR=0.90 (95% CI, 0.68‒1.20)] and proportion of patients with zero bleeds [OR=1.06 (95% CI, 0.56‒2.02)].ConclusionBAY 94-9027 prophylaxis demonstrated 26.7% lower annual consumption when compared to N8-GP with similar efficacy in terms of ABR and percentage of patients with zero bleeds.

A survey of physicians’ treatment switching practice in people on long-term prophylaxis for hemophilia in five European countries

Objective Recombinant factor VIII and factor IX Fc fusion proteins (rFVIIIFc and rFIXFc) were developed with an extended half-life (EHL) to improve the management of people with hemophilia A (PwHA) and B (PwHB), respectively. Methods This survey gathered physician-reported treatment decisions and physician views on outcomes in PwHA or PwHB who switched to rFVIIIFc or rFIXFc in the 12 months prior to study completion. Results Physicians (N = 37) considered bleeds, pharmacokinetic parameters, joint health and adherence the most important factors to assess both in routine care and when deciding to switch to an EHL therapy. In the 12 months prior to study completion, 37 physicians switched 113 PwHA to rFVIIIFc and 25 physicians switched 36 PwHB to rFIXFc. Most PwH (>90%) had moderate or severe hemophilia and many (>60%) switched within 6 months of the survey. The main reason for switching PwHA to rFVIIIFc was to allow fewer injections (49%), while the main reason for switching PwHB to rFIXFc was the product becoming available for use (36%). Overall, 96% of PwHA and 89% of PwHB who were switched remained on these EHL products at the time of survey. Mean total weekly dose, injection frequency and annualized bleeding rate were reported to have reduced following switching. Conclusion This survey provides valuable insight into reasons for, and challenges to, the use of EHL products in clinical practice. Physicians perceived that switching to treatment with rFVIIIFc or rFIXFc can improve quality of life, treatment burden, disease control and adherence.

Efficacy safety and immunogenicity of rurioctocog alfa pegol for prophylactic treatment in previously treated patients with severe hemophilia A: a systematic review and meta-analysis of clinical trials.

Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A. Methods: This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales. Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04-3.14) and 92% (95% CI = 85%-97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety. Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.

Predictors of adverse clinical outcomes in atrial fibrillation patients with concomitant renal impairment under rivaroxaban therapy

Abstract Background Atrial fibrillation (AF) increases the risk of stroke and mortality, and concomitant renal impairment confers a worse prognosis. However, those factors that may limit the use of direct-acting oral anticoagulants in AF patients with renal impairment have not been further investigated, as they confer a higher risk of adverse events in this patient population. Purpose To investigate predictors of adverse clinical outcomes in AF patients with renal impairment who were treated with rivaroxaban. Methods The EMIR study is an observational, multicenter study including patients with AF treated with rivaroxaban for at least the previous 6 months. During 2.5 years of follow-up, the occurrence of thromboembolic events (the composite of isquemic stroke, transient ischemic attack, systemic embolism and myocardial infarction [MI]), major bleeding (ISTH definition) and major adverse cardiovascular events (MACE: fatal/non-fatal MI, myocardial revascularization and cardiovascular death) were recorded. For the present analysis, creatinine clearance (CrCl) was estimated by using the Cockroft-Gault equation and renal impairment was defined as a CrCl &amp;lt;60 mL/min. Results 1433 patients were included (44.5% female; mean age 74.2±9.7 years), of which 498 (35.1%) had CrCl &amp;lt;60 mL/min. The mean CHA2DS2-VASc and HAS-BLED were 3.5±1.5 and 1.6±1.0, respectively. During the follow-up, 7 (1.4%) patients with CrCl &amp;lt;60 mL/min suffered a thromboembolic event, 16 (3.2%) suffered major bleeding, and 19 (3.8%) suffered a MACE. Compared to patients with normal renal function, patients with CrCl &amp;lt;60 mL/min showed a higher annual rate of major bleeding (0.62%/year vs. 1.87%/year; p=0.003) and MACE (0.62%/year vs. 1.97%/year; p=0.002). Multivariate analyses demonstrated that the CHA2DS2-VASc score (OR 1.84; 95% CI 1.11–3.07) was associated with a higher risk of thromboembolic events; whereas the HAS-BLED score (OR 2.25; 95% CI 1.41–3.59) and any dependency level (OR 3.42; 95% CI 1.17–9.98) were associated with a higher risk of major bleeding; and male sex (OR 3.55; 95% CI 1.08–11.63) and heart failure (OR 4.67; 95% CI 1.62–13.51) with a higher risk of MACE. The use of antiplatelet agents was also independently associated with an increased risk of thromboembolic events and MACE (OR 12.28; 95% CI 2.50–60.18; and OR 8.72; 95% CI 2.86–26.59; respectively). Conclusions Rivaroxaban showed excellent results in moderate renal impairment. However, the annual rate of major bleeding and MACE was higher in AF patients with impaired renal function. In patients with AF and renal impairment, male sex, the presence of heart failure, dependency, the concomitant use of antiplatelets, and greater comorbidity according to the CHA2DS2-VASc and HAS-BLED, were associated with higher risk of adverse clinical outcomes. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer

PHARMACOKINETIC-GUIDED PROPHYLAXIS FOR PEOPLE WITH HEMOPHILIA A

Pharmacokinetic (PK)-guided prophylaxis for people with hemophilia A (PwHA) treatment has been related to fewer bleeding and cost savings have been reported. myPKFiT®is a populational PK tool available for this purpose, developed for α-octocog (Advate®, Takeda) analysis. We evaluated the impact of myPKFiT®-guided prophylaxis in PwHA on replacement costs and bleeding episodes. Men with severe (FVIII < 1%) or moderate (FVIII 1%-5%) HA without inhibitors and treated with Advate®were invited at two Southern Brazilian Hemophilia Treatment Centers. Inclusion criteria involved ≥ 50 exposure days, age 1-65 years, weight 12-120 kg, bleeding-free for ≥ 2 weeks, and last surgical procedure ≥ 6 months. PwHA who developed inhibitor (> 0.6 BU/mL at two time-points) during the study period were excluded. Anthropometric and hemophilia-related data were obtained using a standardized form. PK analysis was performed according to myPKFiT®recommendations, using one-step test. After PK analysis, PwHA were approached to adjust their regimen according to bleeding phenotype, arthropathy, and physical exercise. Replacement regimen and FVIII disposal (from now called consumption) were assessed before and after treatment adjustment. PwHA younger than 15 years were evaluated for 6 months, while those 15 years or older were evaluated for 12 months. Annualized bleeding rate (ABR) was calculated from the reported treated bleeding episodes. FVIII disposal (from now reported as consumption) was adjusted by weight (kg) and monthly. The cost of 1 IU of Advate®was based on the median date of the evaluated periods, which was July/2019. We converted the price in Real into American Dollar, considering the currency at the date that the Brazilian Ministry of Health purchased the product. A total of 37 PwHA were included. In the younger group (n = 20), 75% were severe, and 65% had no hemophiliac arthropathy. Half of these patients were on primary prophylaxis. Two PwHA had a previous history of successful immune tolerance induction. Among the older group (n = 17), 76% were severe, 1 PwHA was treated exclusively on-demand before adjustment, none were on primary prophylaxis, and 12% had no hemophiliac arthropathy. One participant developed inhibitor during the study. Median [interquartile range, IQR] tranged from 9.5 [8.0-10.0] h, among younger individuals, to 10.5 [9.0-11.0] h, among the older ones. Three PwHA from the older group were excluded from the cost analyses: 1 developed inhibitor during follow-up, 1 was treated exclusively on-demand before PK-analysis, and 1 was prescribed plasma-derived FVIII few months after adjustment. From the remaining 34 PwHA, all individuals were advised about behavior and time of infusion, according to their bleeding phenotype, arthropaties, and physical exercise. Among younger PwHA, monthly total FVIII replacement cost increased after PK-based adjustment (p < 0.0001), while reducing costs of episodic therapy (p = 0.05) and increasing costs of prophylaxis (p < 0.0001). Median [IQR] ABR reduced from 3.0 [0.5-10.0] to 1.0 [0.0-2.0]. Among older PwHA, although monthly total and prophylactic costs did not change between the periods, costs of episodic treatment reduced (p = 0.039). ABR did not change either. PK-adjusted prophylaxis was related to increased treatment costs among PwHA < 15 years, but not among individuals ≥ 15 years. Although ABR reduced after adjustment among younger PwHA, no ABR change was evidenced among older participants.

Joint health state in relation to different clinical, laboratory, and radiological variables of hemophilia A patients

Abstract Background Haemophilic (HF) arthropathy is a major complication in haemophilia. Collagen factors are responsible for maintaining the integrity of the vessel wall in the joint. Our goal was to assess the haemophilia joint state and its relation to the clinical, laboratory &amp;radiological data. Methods This cross-sectional study included 50 hemophilia A patients recruited from the Pediatric Hematology / Oncology unit, Children’s Hospital, Ain Shams University,Cairo,Egypt. Assessment of joint status clinicallyand radiologically by X-rays&amp; ultrasound was performed. Results 48% of the studied hemophilia A patients had one, 40 % had two target joints or more. The elbow and knee are the most frequently affected joints (46%,62% respectively).There were no significant differences between inhibitor positive and inhibitor negative patients regarding the number of target joints.However, inhibitor positive patients had significantly lower annual bleeding rate; moreover, none of inhibitor positive patients had surgeries done and none were on celecoxib. There were no significant differences between inhibitor positive hemophilia A patients and inhibitor negative regarding US total score, hem QOL, total HJHS and total FISH score. Patients with 2 target joints had significant higher annual bleeding rate, worse quality of life score, higher total HJHS score compared to those with one or without target joints. Conclusion In our study, we argued the lack of significant difference between inhibitor positive and inhibitor negative Hemophilia A patients as regards the occurrence of hemophilic arthropathy. Nevertheless, patients with ≥ 2 target joints had worse annual bleeding rate, quality of life &amp; total HJHS score.

RESULTS FROM A 52-WEEK, NONINTERVENTIONAL STUDY OF BRAZILIAN INDIVIDUALS WITH SEVERE HAEMOPHILIA A RECEIVING PROPHYLAXIS: RATES OF BLEEDING, FVIII USE, AND QUALITY OF LIFE

Regular prophylaxis with exogenous Factor VIII (FVIII) is recommended for individuals with severe haemophilia A (HA), but standardised data on bleeding, FVIII use, and quality of life (QoL) for this population in routine clinical practice are scarce. In a prospective, multinational, noninterventional study, male participants age ≥18 years with severe HA (FVIII ≤1 IU/dL) receiving prophylactic FVIII were followed for at least 6 months. Bleeding and FVIII use were reported weekly. Annualised bleeding rate (ABR) and FVIII infusion rate were calculated for participants with ≥6 months follow-up and combined with retrospective data from 6 months prior to baseline. Adverse events (AEs) were collected monthly. Participants completed the haemophilia-specific health-related QoL questionnaire for adults (Haemo-QoL-A) at baseline. This abstract presents a sub analysis of the study's Brazilian population. For all 54 Brazilian participants, median (range) age was 27 (18–47) years. For the 41 (76%) Brazilian participants with ≥6 months follow-up, mean (standard deviation [SD]; median) ABR for treated bleeds was 2.42 (4.05; 0.80) bleeds per year and mean (SD; median) annualised FVIII infusion rate was 167.87 (60.22; 155.17) infusions per year. Mean (SD; median) ABRs of treated traumatic, spontaneous, and joint bleeds were 0.90 (1.6; 0.0), 1.52 (3.3; 0.0), and 1.91 (3.29; 0.0) bleeds per year, respectively. Median (range) percentage of follow-up time adherent with prescribed prophylaxis frequency in Brazilian participants was 94.7%(49%-100%). Mean (SD) Haemo-QoL-A total transformed score (0–100) score was 70.3 (15.1) The lowest mean (SD) domain scores (representing lower QoL) in all Brazilian participants were for treatment concern 45.7 (30.85), physical functioning 66.9 (21.33), and consequences of bleeding 68.1 (22.92). AEs were reported in 22 (40.7%) participants, with the most common AEs being haemophilic arthropathy, nasopharyngitis, and synovitis, each reported in 2 (3.7%) Brazilian participants. Two serious AEs (oesophageal haemorrhage and haematoma) were reported, each by single participant (1.9%). Despite high prophylaxis adherence, participants reported breakthrough spontaneous and joint bleeding and impaired physical functioning. Additional haemostatic options for severe HA are needed.

A Prospective Observational Study of Antihemophilic Factor (Recombinant) Prophylaxis Related to Physical Activity Levels in Patients with Hemophilia A in the United States (SPACE).

IntroductionHigh collision-risk physical activity can increase bleeding risk in people with hemophilia A, as can increasing the time between factor VIII (FVIII) administration and physical activity. FVIII prophylaxis may be tailored to planned activities to prevent activity-related bleeding.AimTo explore the relationship between physical activity levels, FVIII infusion timing, and occurrence of bleeding in patients with severe/moderately severe hemophilia A without FVIII inhibitors receiving antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA).MethodsSPACE was a 6-month, prospective, multicenter, observational outcomes study (NCT02190149). Enrolled patients received an eDiary application and a wearable activity tracker, which recorded physical activity, rAHF infusion, and occurrence of bleeding. Physical activity risks were ranked using National Hemophilia Foundation criteria.ResultsFifty-four patients aged 11–58 years (n = 47 prophylaxis, n = 7 on-demand) were included in the analysis. Patients had a mean (SD) 8.14 (10.94) annualized bleeding rate, and recorded 4980 intervals between an rAHF infusion and physical activity; 1759 (35.3%) of these intervals were ≤24 hours. Analysis of recorded eDiary data showed that the risk of activity-related bleeding did not significantly increase with time between last infusion and activity, but did increase with higher-risk physical activities. Analysis of activity tracker recorded data showed that the risk of bleeding reported by patients as spontaneous increased with prolonging time (≤24 to >24 hours) from last infusion to physical activity start (odds ratio 2.65, p < 0.05). Joint health data collected at baseline were not included in the regression analysis because of small sample size; therefore the study could not assess whether patients with more joint disease at baseline were at higher risk of injury-related and reported spontaneous occurrence of bleeding.ConclusionThese results show that activities with a high risk of collision lead to an increased risk of bleeding. Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding.

Health and treatment outcomes of patients with hemophilia in the Netherlands, 1972–2019

IntroductionWe conducted six cross‐sectional nationwide questionnaire studies among all patients with hemophilia in the Netherlands from 1972 until 2019 to assess how health outcomes have changed, with a special focus on patients >50 years of age. MethodsData were collected on patient characteristics, treatment, (joint) bleeding, joint impairment, hospitalizations, human immunodeficiency virus and hepatitis C infections, and general health status (RAND‐36). ResultsIn 2019, 1009 patients participated, of whom 48% had mild, 15% moderate, and 37% severe hemophilia. From 1972 to 2019, the use of prophylaxis among patients with severe hemophilia increased from 30% to 89%. Their median annual bleeding rate decreased from 25 to 2 bleeds. Patients with severe hemophilia aged <16 years reported joint impairment less often over time, but in those aged >40 years joint status did not improve. In 2019, 5% of all 1009 patients were positive for the human immunodeficiency virus. The proportion of patients with an active hepatitis C infection drastically decreased from 45% in 2001 to 2% in 2019 due to new anti‐hepatitis C treatment options. Twenty‐five percent had significant liver fibrosis even after successful therapy. Compared to the general male population, patients aged >50 years reported much lower scores on the RAND‐36, especially on physical functioning. Discussion/ConclusionOur study shows that increased use of prophylactic treatment and effective hepatitis C treatment have improved joint health and nearly eradicated hepatitis C infection in patients with hemophilia in the Netherlands. However, patients still suffer from hemophilia‐related complications, especially patients aged >50 years.

Real-World Data on Bleeding Patterns of Hemophilia A Patients Treated with Emicizumab.

Emicizumab (Hemlibra™) is approved for prophylaxis of hemophilia A (HA) patients. The HAVEN studies addressed bleeding reduction in emicizumab-treated patients, but real-world data on bleeding patterns during emicizumab therapy are lacking. We aimed to compare the occurrence of breakthrough bleeding at different time points, starting from emicizumab initiation. This longitudinal prospective observational cohort study included HA patients (n = 70, aged 1 month to 74.9 years) that completed at least 18 months of follow-up in our center. We analyzed the number of spontaneous and traumatic bleeds during selected time points of the study (“bleeding periods”). The percentage of traumatic and spontaneous bleeding episodes was not significantly different among “bleeding periods” (P = 0.053 and P = 0.092, respectively). Most trauma-related treated bleeds resulted from either hemarthrosis (53%) or head trauma (33%). Spontaneous bleeding episodes were mostly hemarthroses (80%). Potential associations of the patients’ age, annualized bleeding rate before emicizumab treatment, and the presence of inhibitors with spontaneous bleed occurrence were analyzed with binomial logistic regression. The odds of bleeding while on emicizumab increased by a factor of 1.029 (P = 0.034) for every one year of age. Conclusions: Our real-world data revealed that the risk of bleeding persists, especially in older patients, despite therapy with emicizumab. These data may help clinicians in counselling their patients and in planning their management.

Emicizumab in pediatric hemophilia: Bleeding and surgical outcomes from a single-center retrospective study.

Real-world data describing emicizumab prophylaxis in pediatric hemophilia A is limited with current literature providing a heterogenous approach to procedural management. We performed a retrospective review on the 28 patients who have been treated with emicizumab prophylaxis at Texas Children's Hospital from 2018 to 2021. After starting emicizumab, the mean annualized bleeding rate reduced from 3.61 to 0.44. Seven surgical procedures were performed in the cohort, and all treated with pre- and postoperative factor replacement resulting in one minor bleeding event. We demonstrate a successful experience with emicizumab prophylaxis and safe perioperative approach with a focus on minimizing postoperative bleeding.

Patient preferences for gene therapy in haemophilia: Results from the PAVING threshold technique survey.

ObjectivesThe aim of the Patient preferences to Assess Value IN Gene therapies (PAVING) study was to investigate trade‐offs that adult Belgian people with haemophilia (PWH) A and B are willing to make when choosing between prophylactic factor replacement therapy (PFRT) and gene therapy.MethodsThe threshold technique was used to quantify the minimum acceptable benefit (MAB) of a switch from PFRT to gene therapy in terms of ‘Annual bleeding rate’ (ABR), ‘Chance to stop prophylaxis’ (STOP), and ‘Quality of life’ (QOL). The design was supported by stakeholder involvement and included an educational tool on gene therapy. Threshold intervals were analysed using interval regression models in Stata 16.ResultsA total of 117 PWH completed the survey. Mean thresholds were identified for all benefits, but substantial preference heterogeneity was observed; especially for the STOP thresholds, where the distribution of preferences was bimodal. Time spent on the educational tool and residence were found to impact MAB thresholds. The most accepted (88% of PWH) gene therapy profile investigated in this study comprised of zero bleeds per year (vs. six for PFRT), 90% chance to stop prophylaxis, no impact on QoL, and 10 years of follow‐up on side effects (vs. 30 for PFRT).ConclusionsResults from this study proved the value of educating patients on novel treatments. Moreover, preference heterogeneity for novel treatments was confirmed in this study. In gene therapy decision‐making, preference heterogeneity and the impact of patient education on acceptance should be considered.

Low dose long-acting factor VIII prophylaxis in pediatric and young adult patients with hemophilia A: Short-term single-center experience from a developing country

Objectives: High dose factor prophylaxis in hemophilia has been proven to prevent joint bleeds in the western world effectively. We look for a cost-effective and feasible way for Indian patients to reduce the dose and frequency of factor infusion. Data on prophylaxis with a low dose, long-acting factor infusion twice a week dosing schedule is limited. The purpose was to study the efficacy and safety of long-acting factor VIII (Eloctate) for secondary/ tertiary prophylaxis in pediatric and young adult patients with moderate and severe hemophilia A. Materials and Methods: Thirty-eight patients with moderate and severe hemophilia A with an age range from 1 to 25 years were included in the study. During the initial 4 months, they received therapeutic doses of ELOCTATE (Factor VIII with Fc Fusion Protein) on an episodic basis after a clinical bleed. In the next 4 months, they received prophylactic intravenous ELOCTATE at the dose of 20 units/kg body weight twice a week. Annual bleeding rates (ABR), school absenteeism, emergency visits, joint scores, and adverse events were compared during both periods. Results: The total number of joint bleeds during the episodic treatment and prophylaxis period was 608 and 67, respectively. ABR was 47.9 during the episodic treatment period and 5.3 during prophylaxis showing an 88.9% reduction in joint bleeds. School/college absenteeism and emergency visits were significantly reduced during prophylaxis. No significant adverse events were noted during prophylaxis. Conclusion: Low dose, twice a week, and long-acting recombinant factor VIII-Fc (Eloctate) prophylaxis can be a reasonable options for patients with hemophilia A in developing countries.

A multicentre real-world data study to assess the bleeding rate and management of patients with haemophilia A and factor VIII inhibitors in Argentina.

The development of inhibitors against factor VIII (FVIII) concentrates is a severe complication of treatment for patients with haemophilia. We investigated annualized bleeding rates (ABRs) in patients in Argentina with haemophilia A with inhibitors and analysed potential differences between treatment strategies. This multicentre, retrospective, real-world data, cohort design study comprised ambulatory paediatric and adult patients with congenital haemophilia A and FVIII inhibitors treated according to standard clinical practice, with 12-months follow-up. Of 69 included patients, 39 (56.5%) received on-demand treatment, 13 (18.8%) received prophylactic treatment, and 17 (24.6%) received immune tolerance induction (ITI) therapy. The mean overall ABR was 7.68 ± 8.18, with similar rates for on-demand (8.59 ± 9.69), prophylaxis (5.54 ± 4.71), and ITI (7.24 ± 6.23) subgroups. In the negative binomial regression model, prophylactic treatment [incidence rate ratio (IRR) 0.41, 95% confidence interval (CI): 0.21-0.79, P < 0.01] and ITI (IRR 0.47, 95% CI: 0.27-0.81, P < 0.01) therapy were significantly associated with a decrease in the ABR compared with on-demand treatment. Age (IRR 0.96, 95% CI: 0.94-0.97, P < 0.01), number of target joints (IRR 1.21, 95% CI: 1.11-1.31, P < 0.001), and history of recurring bleeding (IRR 2.3, 95% CI: 1.19-4.57, P = 0.012) were significantly and independently associated with ABR. The ABR in standard clinical practice was lower than that reported in controlled clinical trials. Patients undergoing prophylaxis and ITI therapy showed reduced ABRs compared with on-demand treatment, after controlling for bleeding predictor variables.

Individualized prophylactic treatment of patients with hemophilia A to improve effectiveness and optimize product consumption on the example of octocog alpha and rurioctocog alpha pegol. A systematic literature review

Objective: to review the data on the efficacy and consumption of octocog alfa and rurioctoctog alfa pegol in standard prophylaxis and individualized prophylaxis in hemophilia A patients based on published international data.Material and methods: a systematic literature search and review were performed. Among 25 sources identified within the systematic search 7 relevant sources describing the comparison of treatment with octocog alfa and rurioctocog alfa pegol in adult and pediatric patients with severe and moderate hemophilia A based on personalized assessment of the pharmacokinetic curve using the interactive tool myPKFit versus the standard (non-personalized) dosage regimen were selected. Data on individual patients, as well as data from secondary subgroups defined by age, bleeding rate, risk of bleeding associated with the daily physical activity were combined and analyzed.Results. In observational studies, adjustments of the dose and administration of octocog alfa in patients with severe hemophilia based on personalized assessment of the pharmacokinetic curve using myPKFit resulted in the reduced consumption and/or increased efficacy of prophylaxis — a reduced annual bleeding rate. In an extended controlled study of rurioctocog alpha pegol a trend toward reduced bleeding rate and increased mean annual consumption of the drug was reported in patients who received myPKFit guided prophylaxis compared to a non-personalized treatment regimen. In the single-cut studies, myPKFiT use resulted in the regimen revisions in less than a quarter of patients.Summary. Personalized dosing for octocog alpha and rurioctocog alpha pegol based on pharmacokinetic curve built using pharmacokinetic population model enables reasonable dose adjustments and improves outcomes.