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A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study)
Abstract
Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia.
This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period.
Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg(-1) 3 × week) or episodic therapy with ≥25 IU kg(-1) every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated.
Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy.
This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life.
... The annual consumption of FVIII was used to estimate the costs associated with the use of the myPKFiT ® device in the 1-year prior and after its implementation. We decided to estimate only the cost associated with FVIII consumption because, in this population, this represents up to 95% of the overall costs [29][30][31]. Hence, the annual costs related to FVIII consumption were computed by multiplying the mean of UI used by the price per IU of FVIII, as indicated by the Italian Medicine Agency (AIFA). ...
... The incremental costeffectiveness ratio (ICER) between the period prior and after the use of the myPKFiT ® device was estimated by adopting the perspective of the Italian National Health Service (NHS). The ICER was expressed as cost in euros (EUR) per bleed avoided [29][30][31]. ...
... Finally, ICER was estimated as the variation in costs between pre-and post-use of myPKFiT ® device divided by the variation in the ABR and AJBR events within the same timeframe. Results were expressed as cost in euros per bleed avoided [29][30][31]. ...
Background and Objectives: This study aimed to assess the effectiveness and costs associated with pharmacokinetics-driven (PK) prophylaxis based on the myPKFiT® device in patients affected by hemophilia A (HA) in Italy. Materials and Methods: An observational retrospective study was conducted in three Italian hemophilia centers. All patients with moderate or severe HA, aged ≥ 18 years, capable of having PK estimated using the myPKFiT device, and who had had a clinical visit between 1 November 2019 and 31 March 2022 were included. Differences in clinical, treatment, health resources, and cost data were assessed comparing post-PK prophylaxis with pre-PK. The incremental cost-effectiveness ratio (ICER) was estimated as cost (EUR) per bleed avoided. Results: The study enrolled 13 patients with HA. The mean annual bleeding rate decreased by −1.45 (−63.80%, p = 0.0055) after the use of myPKFiT®. Overall, the consumption of FVIII IU increased by 1.73% during follow-up compared to the period prior the use of the myPKFiT. Prophylaxis based on the myPKFiT resulted in an ICER of EUR 5099.89 per bleed avoided. Conclusions: The results of our study support the idea that the use of PK data in clinical practice can be associated with an improvement in the management of patients, as well as clinical outcomes, with a reasonable increase in costs.
... Of these, two studies were randomized, controlled, but openlabel. The JOS study 14 included patients on primary prophylaxis, while the ESPRIT study enrolled patients on both primary and secondary 15 . The remaining studies described secondary prophylaxis data. ...
... On this study 15 , the mean clotting factors consumption was 8,852 IU/patient/month in the prophylaxis group, versus 3,981 IU/patient/month in the episodic treatment. Half of the patients in the prophylaxis group required central venous access placement, and none in the episodic group. ...
... On this investigation 15 , prophylaxis at a dose of 30 IU/kg 3 times a week significantly reduced the frequency of bleeding, especially hemarthrosis. Even so, the incidence of joint bleeding was considered significant, for being four times higher than the previously described study 14 . ...
Hemophilia is an inherited X-linked coagulopathy defined by a deficiency or abnormality in the clotting function of factor VIII (Hemophilia A) or factor IX (Hemophilia B). Prophylaxis – the regular administration of therapeutic products to maintain hemostasis and prevent bleeding – is the mainstream of treatment. Addressing the development and scientific evidence for administrating prophylaxis is the goal of this review. Prophylaxis is the therapeutic modality of choice for people with severe hemophilia, being considered, in principle, a lifelong treatment. It should have an early onset, ideally as a primary, or at least secondary. Even lifelong tertiary prophylaxis seems to offer benefit, although further studies are still lacking. Individualized strategies should lead to an optimization of the dilemma between better joint outcomes versus involved costs.
... Prophylactic treatment was a key factor contributing to eventfree survivor prognosis and optimal therapy for persons with hemophilia. 24 Gringeri et al. [50]/2011/Italy/ Peer-reviewed journal article ...
... Three treatment-comparative cohort studies had a median of 5 of 9 stars on the original NOS for cohort studies. The only randomized controlled trial, conducted by Gringeri et al. [50], had an overall low risk of bias on the Cochrane RoB 2.0 tool ("some concerns" in the domain "deviation from the intended intervention"). The results of the risk of bias assessment according to the study design are presented in Table 2 [6,27-54]. ...
... HRQoL, health-related quality of life; QoL, quality of life. a Fourteen subgroups from 13 studies (considering both arms from the randomized trial by Gringeri et al. [50]); 268 patients assessed in 11 countries. b Fifteen subgroups; 534 patients assessed in 13 countries. ...
Background:
Various instruments have been used to assess health-related quality of life (HRQoL) in children and adolescents with hemophilia A.
Objective:
We systematically reviewed the literature to summarize HRQoL measurement instruments and outcomes in this population.
Methods:
MEDLINE, Embase, Cochrane CENTRAL, and LILACS databases were searched. Studies published from 2010 to 2021, reporting HRQoL assessed by generic or hemophilia-specific instruments in individuals aged 0 to 18 years were included. Two independent reviewers performed screening, selection, and data abstraction. Data were meta-analyzed using the generic inverse variance method with the random-effects model for single-arm studies reporting instrument-specific mean total HRQoL scores. Prespecified subgroup meta-analyses were performed. Heterogeneity among studies was assessed using the I 2 statistic.
Results:
Six instruments were identified in 29 studies meeting the following inclusion criteria: 4 generic instruments (PedsQL [5 studies], EQ-5D-3L [3 studies], KIDSCREEN-52 [1 study], and KINDL [1 study]) and 2 hemophilia-specific instruments (Haemo-QoL [17 studies] and CHO-KLAT [3 studies]). The overall risk of bias was moderate to low. There was a substantial variability in the primary outcome (mean total HRQoL score) among studies using the same instrument (Haemo-QoL), with scores ranging from 24.10 to 89.58 on a scale from 0 to 100 (higher scores indicating higher HRQoL). Meta-regression with 14 studies using the Haemo-QoL questionnaire demonstrated that 79.34% (R 2 ) of the observed 94.67% total heterogeneity (I 2 ) was explained by the proportion of patients receiving effective prophylactic treatment.
Conclusion:
HRQoL assessment in young people with hemophilia A is heterogeneous and context specific. The proportion of patients on effective prophylactic treatment is positively correlated with HRQoL. The review protocol was registered prospectively with PROSPERO (CRD42021235453).
... All patients with ICH received supportive treatment; none required neurosurgical intervention. Clotting factor concentrate was administered for a median duration of 12 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) days in subjects with hemophilia A without FVIII inhibitor, and 14 (10)(11)(12)(13)(14)(15)(16) days in subjects with hemophilia B. The doses and durations of CFC are summarized in Figure 1. During hospitalization, 16 patients clinically improved while There was one severe hemophilia A patient with a history of positive FVIII inhibitor during previous treatment and a family history of positive FVIII inhibitor. ...
... All patients with ICH received supportive treatment; none required neurosurgical intervention. Clotting factor concentrate was administered for a median duration of 12 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) days in subjects with hemophilia A without FVIII inhibitor, and 14 (10)(11)(12)(13)(14)(15)(16) days in subjects with hemophilia B. The doses and durations of CFC are summarized in Figure 1. During hospitalization, 16 patients clinically improved while There was one severe hemophilia A patient with a history of positive FVIII inhibitor during previous treatment and a family history of positive FVIII inhibitor. ...
... To date, several published trials on prophylaxis for hemophilia have shown that it effectively prevents recurrent joint bleeding, which would lead to arthropathy and disability, compared to on-demand treatment. 14,15 However, on-demand treatment is still applied in Indonesia due to high cost and limited financial support. For patients receiving CFC as on-demand treatment, short-term intermittent prophylaxis is indicated following an ICH episode, with the objective to prevent recurrent life-threatening bleeding. ...
Background Intracranial hemorrhage (ICH) is one of the major bleeding events causing mortality and long-term morbidity in children with hemophilia, especially those who receive on-demand therapy.
Objective To evaluate the outcome of children with hemophilia after ICH receiving short-term intermittent prophylactic treatment.
Methods This retrospective study was conducted in the Department of Child Health, Dr. Cipto Mangunkusumo Hospital, Jakarta. Children £18 years of age with hemophilia presenting with ICH between 2015-2020 were included. We recorded patients’ demographics, type and severity of hemophilia, the presence of factor VIII (FVIII) inhibitor, brain CT scan, treatment, and outcomes of these patients. Patients who received short-term intermittent prophylaxis using clotting factor concentrate (CFC) post-ICH episodes were observed for ICH recurrence.
Results There were 19 episodes of ICH experienced by 18 patients, consisting of 16 patients with hemophilia A and 2 with hemophilia B. Patients’ median age was 4 years (range 0-16 years). Hemophilia was classified as severe in 13 patients, moderate in 4 patients, and mild in 1 patient. Thirteen episodes were preceded by head trauma. The most common clinical manifestation was seizures (13.2%). The most common type of ICH was subdural hematoma. Two patients died and 2 patients had neurological sequelae during hospitalization. The median dose of short-term intermittent prophylaxis using CFC (n=16) was 20 IU/kg of FVIII twice a week and 30 IU/kg of FIX twice a week, for a median duration of 8 weeks (range 5-12 weeks). One patient who did not adhere to the prophylaxis regimen had recurrent ICH at a similar location 6 months after the first episode.
Conclusion Our findings suggest that short-term intermittent prophylaxis is important to prevent the recurrence of ICH in children with hemophilia.
... Prophylaxis is the standard of care for most children with hemophilia to prevent spontaneous bleeding and joint deformities. Between 1970 and 1990, the superiority of prophylaxis over on-demand treatment in patients with severe hemophilia has been demonstrated in many studies [4][5][6][7][8][9] including the randomized control trial of Manco-Johnson, et al. [8] and the ESPRIT study [9]. In contrast to on-demand treatment, prophylaxis has demonstrated to reduce the number of bleeds per year as well as the risk of life-threatening hemorrhages in patients with hemophilia [10]. ...
... Prophylaxis is the standard of care for most children with hemophilia to prevent spontaneous bleeding and joint deformities. Between 1970 and 1990, the superiority of prophylaxis over on-demand treatment in patients with severe hemophilia has been demonstrated in many studies [4][5][6][7][8][9] including the randomized control trial of Manco-Johnson, et al. [8] and the ESPRIT study [9]. In contrast to on-demand treatment, prophylaxis has demonstrated to reduce the number of bleeds per year as well as the risk of life-threatening hemorrhages in patients with hemophilia [10]. ...
... It has important long-term implication in resource constraint countries like India where episodes can effectively be treated with very low dose prophylaxis. The median number of joint bleeds in the prophylaxis group where high doses of prophylaxis was used was 0.05 in joint outcome study [8] and 0.20 events per [9] which were also similar to that of our study. ...
Introduction:
Low dose factor VIII prophylactic therapy in hemophilia has not been well established till date. This randomized controlled trial compared the efficacy of twice vs. thrice weekly schedule of low dose prophylactic factor VIII in children with hemophilia A as evaluated by the bleeding rate and clinico-radiological evaluation.
Methods:
Thirty-three children with severe hemophilia A (≤18 years) were randomized into two groups. Baseline evaluation included detailed history, clinical (HJHS 2.1 score and FISH score) and radiological examination (Pettersson score and ultrasound score). Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose being 10 U/kg in both groups. All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at the end of follow up were recorded.
Results:
We analyzed 14 children in twice weekly prophylaxis group and 16 children in thrice weekly prophylaxis group. Statistically insignificant difference was found between the bleeding rates in both the groups after prophylaxis with the median values of monthly bleeding rate being 0.17 and p-value of 0.79. The differences between the initial and final clinical and radiological scores within each group were found to be statistically significant. There was no significant difference in the clinical and radiological scores in between the groups.
Conclusion:
Twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A. Lay summaryHemophilia A is one of the most common congenital coagulation factor deficiencies. Low dose factor VIII prophylaxis is recommended for hemophilia in resource-poor settings to reduce the bleeding episodes and improve the quality of life, although the optimal schedule for the same has not been well established. A randomized controlled trial on 33 children with hemophilia A (≤18 years) was done to compare the efficacy of twice versus thrice weekly schedule of prophylactic factor VIII. Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose in both groups being 10 U/kg. They were evaluated by the bleeding rate and clinical (HJHS 2.1 score and FISH score) and radiological scores (Pettersson score and ultrasound score). All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at end of follow up were recorded. When analyzed, statistically insignificant difference was found between the bleeding rates after the two prophylaxis regimes. There was a significant improvement between initial and final clinical and radiological scores in both the groups and no difference was recorded in between the groups. To conclude, twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A.
... Current recommendations encourage early initiation of prophylactic treatment regimens. Evidence supporting prophylactic regimens was elucidated through multiple observational and randomized trials [34,39]. However, the reported outcomes have largely focused on joint bleeds and subsequent arthropathy but not on the risk of ICH. ...
... The ESPRIT study demonstrated similar findings, with bleeding events significantly reduced in the prophylaxis arm. Children on prophylaxis therapy had fewer hemarthroses compared with episodic therapy (0.20 in the prophylaxis arm vs. 0.52 per month for episodic therapy, P <0.02) [39]. The SPINART trial was designed to evaluate routine prophylaxis with sucrose-formulated rFVIII (rFVIII-FS) compared with on-demand treatment in patients ages 12-50 years with severe hemophilia A [41]. ...
Purpose of Review
Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies.
Recent Findings
ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient’s pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD.
Summary
Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications—intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.
... Pain and disability have been reported as the most prevalent problems in large cohort studies among individuals with hemophilia in association or not with chronic hemophilic arthropathy [30][31][32]. Bleeding control can be defined as fewer than 4 annual spontaneous bleeding events, but PwHA on primary prophylaxis may suffer substantially fewer bleeding events [33]. On the other hand, patients with on-demand treatment can have up to 20-50 bleeding events per year [4,34]. ...
... Our data showed that PwHA on regular prophylaxis who started later in life (>7 yrs) had more than 3 bleeding events per year, a finding that has been previously reported in this population (7.4 bleeding events a year). This fact enhances the need for further individual adaptation of treatment regimens under a new concept of personalized treatment [33]. Although prophylaxis-based therapy was frequently observed in this study (76%), only 4 patients mentioned practicing self-infusion during the focus group. ...
Collecting and interpreting self-reported outcomes among people with hemophilia A supports the understanding of the burden of the disease and its treatment to improve holistic care. However, in Colombia, this information is limited. Therefore, this study aimed to describe the knowledge, perception and burden of hemophilia A from the patients' perspective. A cross-sectional study was conducted in the context of a hemophilia educational bootcamp held from November 29th to December 1st, 2019, in Medellin, Colombia. The bootcamp was organized by a hemophilia patient association responsible for contacting and inviting patients with hemophilia A (PwHA). Information on patients' health beliefs, treatment experiences, and health-related quality of life (HRQoL) was obtained through focus groups, individual interviews and the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire. A total of 25 moderate or severe PwHA were enrolled in this study and completed the PROBE questionnaire. Acute pain was the most frequently reported symptom, with 88% of the patients reporting the use of pain medication. Difficulty with activities of daily living was reported by 48%. Furthermore, 52% reported having more than 2 spontaneous bleeding events in the last year. Treatment was administered at home for 72% of patients, with regular prophylaxis as the most common treatment regimen. In terms of overall HRQoL, the median EQ-5D VAS score was 80 (IQR: 50-100). PwHA in Colombia still suffer from disease complications related to bleeding events, pain and disability that affect their HRQoL, which highlights the need to develop patient-centered initiatives to improve the wellness of this population.
... Regular infusion of FVIII is a strategy to target the trough FVIII level of more than 1%. Thus, severe haemophilia A patients will have none or fewer spontaneous bleeding events like those with moderate and mild haemophilia A. In addition, the current findings aligned with previous studies conducted in developing countries (5)(6)(7)(8)(9)(10)(11). ...
... This treatment option allows patients to be involved in high impact sports and activities, thus increasing their physical abilities. The ankle joint is subjected to greater weight-bearing since it is the first to absorb the forces of weightbearing and body motion, thus, increasing bleeding incidence (5). ...
Background:
Haemophilia A is a bleeding disorder caused by inadequate clotting factor VIII (FVIII). There are two main modes of treatment approach in severe haemophilia A patients either with on-demand or prophylaxis therapy with clotting factor FVIII concentrates. In this study, a comparison was made between the bleeding incidence rate of the on-demand and prophylaxis group in severe haemophilia A patients at Ampang Hospital, Malaysia.
Methods:
A retrospective study involving patients with severe haemophilia was conducted. The patient's self-reported bleeding frequency was retrieved from the patient's treatment folder from January to December 2019.
Results:
Fourteen patients received on-demand therapy, while the other 24 patients received prophylaxis treatment. The total number of joint bleeds in the prophylaxis group was significantly lower compared to the on-demand group (2.79 bleeds versus 21.36 bleeds [P < 0.001]). Furthermore, the total annual usage of FVIII was higher in the prophylaxis group compared to the on-demand group (1,506 IU/kg/year [± 905.98] versus 365.26 IU/kg/year [± 223.90], P = 0.001).
Conclusion:
Prophylaxis FVIII therapy is an effective treatment in reducing the frequency of bleeding joints. However, this treatment approach is associated with high cost due to the high consumption of FVIII.
... This benefit of lower bleeding risk has been demonstrated before in clinical trials comparing prophylaxis with on-demand treatment, showing that prophylactic CFRT reduces risk of total hemorrhage by more than 70%, keeping the mean annual bleeding rate at lower than 4 episodes per patient. 5,[32][33][34] Observational studies have also shown similar results, namely that prophylaxis can reduce any bleeding events. 8,18,35 Nagae et al 18 35 have demonstrated in their studies that coagulation factor prophylaxis reduces the annual bleeding event rate to lower than 5 events per patient. ...
... Other studies that indicated joint benefits had an average follow-up of 5 years or longer, increasing their probability of detecting more outcomes. 5,14,32,33,39 The study had several strengths. First, it utilized population-based data to conduct the analysis and thus was representative of the whole PWHA population in Taiwan. ...
Purpose
Taiwan launched reimbursement of prophylactic coagulation factor replacement therapy (CFRT) for patients with severe hemophilia type A (severe PWHA) in 2014. However, since then, the effectiveness of prophylactic CFRT in real-world practice has not been evaluated thoroughly. This study aimed to evaluate the effectiveness of prophylactic CFRT in severe PWHA cases on the outcome of bleeding risks.
Patients and Methods
We included male, severe PWHA cases from a nationwide, population-based database in Taiwan. Given that the database lacked details of the dosing regimen for prophylactic CFRT, we applied group-based trajectory modeling using the proportion of days covered (PDC) by CFRT from 2014 to 2015 in order to classify patients. A high PDC level corresponded to a greater proportion of time under CFRT, thus implying that the patient was probably receiving prophylactic therapy. We followed up patients from January 01, 2016 until occurrence of any bleeding events, death or December 31st 2017.
Results
We identified a total of 420 severe PWHA and classified them into high- (n = 88), medium- (n = 181) and low- (n = 151) PDC groups. The mean (±SD) PDC values of the three groups were 0.78 (±0.1), 0.40 (±0.1) and 0.12 (±0.1), respectively. Using Cox regression models with propensity score adjustment, we found patients with medium- (hazard ratio: 0.69; 95% CI: 0.56–0.89) or high-PDC (0.45; 0.36–0.68) under CFRT had reduced risks of any bleeding, compared to the low PDC group.
Conclusion
The findings demonstrated the effectiveness of prophylactic CFRT in the prevention of bleeding events in real-life severe PWHA.
... Although on demand therapy could stop bleeding, it did not prevent the debilitating damage that began within hours of an acute bleed [4]. ESPRIT was a pivotal randomized control clinical trial demonstrating the efficacy of prophylactic treatment versus on demand treatment for those with HA [5]. Additionally, this study along with the Joint Outcome Study, demonstrated that prophylactic treatment led to fewer major bleeding episodes and was more effective when initiated early in life [5,6]. ...
... ESPRIT was a pivotal randomized control clinical trial demonstrating the efficacy of prophylactic treatment versus on demand treatment for those with HA [5]. Additionally, this study along with the Joint Outcome Study, demonstrated that prophylactic treatment led to fewer major bleeding episodes and was more effective when initiated early in life [5,6]. Prophylactic treatment has led to a significant reduction in the number of bleeding episodes, as well as overall reduction and prevention in life threatening bleeding such as intracranial hemorrhage, frequency of emergency room visits, and hemarthrosis [7]. ...
Introduction
Hemophilia A is a severe bleeding disorder affecting about 1 in 5,000 males. The gold standard for prophylaxis and treatment of acute bleeding has been factor (F) VIII concentrate. A multitude of treatment modalities are now available and under clinical investigation.
Areas covered
This review discusses ongoing/recently completed early-phase clinical trials registered on ClinicalTrials.gov in patients with hemophilia A through April 2022. These new pipeline therapies are focused on addressing the safety and efficacy of new factor-related products, non-factor related products, and gene therapy options for hemophilia.
Expert opinion
Current standard of care effectively prevents and treats acute bleeding and has significantly improved the quality of life in hemophilia. The biggest challenges in the improvement of care are treatment-related burden and the burden of cost in developing countries. New drugs under development are likely to enter practice by the end of this decade and address many of the unmet needs particularly of those with severe disease. Data is limited in unique populations (e.g. congenital/inherited FVIII inhibitors, non-severe hemophilia A, women/girls with hemophilia and children) which are important areas for future research; additional clinical trials and long-term outcome data are necessary prior to incorporating these new therapies in our treatment arsenal.
... 6 Early initiation of FVIII prophylaxis has been shown to provide protection against joint damage. 80,81 In hemophilia A, clinical assessment of joint structure and function is commonly performed using the Hemophilia Joint Health Score (HJHS) in children and adolescents. 6 In the simoctocog alfa clinical trial program, HJHS was used to assess joint health in previously treated children in GENA-03 and GENA-13. ...
People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy. However, a major challenge of FVIII therapy is the development of neutralizing anti-FVIII antibodies (FVIII inhibitors). Simoctocog alfa (Nuwiq®) is a human cell line-derived recombinant FVIII (rFVIII) whose immunogenicity, efficacy, and safety have been studied in 167 children with severe hemophilia A across two prospective clinical trials and their long-term extensions. In 105 previously untreated children, the inhibitor rate of 16.2% for high-titer inhibitors (26.7% for all inhibitors) was lower than published rates for hamster cell line-derived rFVIII products. There was no inhibitor development in previously untreated children with non-null F8 mutations and in previously treated children. In a case series of 10 inhibitor patients, 8 (80%) underwent successful immune tolerance induction with simoctocog alfa with a median time to undetectable inhibitor of 3.5 months. In an analysis of 96 children who enrolled in the extension studies and received long-term simoctocog alfa prophylaxis for up to 5 years, median spontaneous, joint, and total annualized bleeding rates were 0.3, 0.4, and 1.8, respectively. No thromboembolisms were reported in any of the 167 children, and there were no treatment-related deaths. Optimal care of children should consider several factors, including minimization of inhibitor development risk, maintaining tolerance to FVIII, highly effective bleed prevention and treatment, safety, and impact on long-term outcomes such as bone and joint health. In this context we review the pediatric clinical data and ongoing studies with simoctocog alfa.
... When selecting treatment for haemophilia B, it is important to consider that other direct and indirect non-medication factors, such as recurrent bleeding rates, diminished work productivity and hospitalisation, may convey a disproportionate economic and/or humanistic burden on patients and their caregivers [17,33,49,50]. Other evidence supporting the use of EHL FIX prophylaxis compared with SHL FIX on-demand include primary prophylaxis is demonstrated to significantly improve longterm clinical outcomes versus on-demand therapy in patients with severe haemophilia [11,12,52]; on-demand therapy may incur higher lifetime healthcare costs versus prophylaxis due to higher non-medication costs (e.g. rehabilitation and surgery) [53]; patients with haemophilia B may have fewer bleed-related hospitalisations when treated with EHL FIX versus SHL FIX [49]; and patients with severe haemophilia B receiving prophylaxis may have higher HRQoL versus those treated with on-demand [54]. ...
Recombinant factor IX (rFIX) and recombinant FIX Fc fusion protein (rFIXFc) are standard half-life and extended half-life FIX replacement therapies, respectively, and represent established treatment options indicated for adults and children with haemophilia B. These FIX replacement therapies can be administered as prophylaxis (to prevent bleeding) or ‘on-demand’ (to stop bleeding). This analysis aimed to estimate the cost-effectiveness of once-weekly prophylaxis with rFIXFc versus on-demand treatment with rFIX in patients with haemophilia B without inhibitors in the Italian healthcare setting.
A Markov model was developed to assess a hypothetical cohort of adolescent or adult male patients (≥ 12 years) with haemophilia B (FIX level of ≤ 2 IU/dL) without inhibitors. Model inputs were derived from the pivotal phase 3 clinical studies for rFIXFc and rFIX, published literature and assumptions when published data were unavailable. The model employed a lifelong time horizon with 6-monthly transitions between health states, and it estimated total costs, total quality-adjusted life years (QALYs), number of bleeds, number of surgeries and incremental cost-effectiveness ratio.
rFIXFc prophylaxis was associated with lower total costs per patient (€5,308,625 versus €6,564,510) and greater total QALYs per patient (15.936 versus 11.943) compared with rFIX on-demand; rFIXFc prophylaxis was therefore the dominant treatment strategy. The model also demonstrated that rFIXFc prophylaxis was associated with fewer incremental bleeds (− 682.29) and surgeries (− 0.39) compared with rFIX on-demand.
rFIXFc prophylaxis provides improved health outcomes and lower costs, and represents a cost-effective treatment option compared with rFIX on-demand for adolescent and adult male patients with haemophilia B. This comparative assessment of cost-effectiveness should help to inform both clinicians and healthcare policy makers when making treatment decisions for patients with haemophilia B.
... tus affectation at the end of follow-up (HJHS and HEAD-US = 0). When evaluating data from the most recent publications, we see that the percentage of joint involvement has presented an important variability, from 29% reported in 2011 by Gringeri et al.,22 with a median score of five according to the Pettersson score to 35% described by Warren et al in 2020.23 in the JOS-C, in the group of patients on early prophylaxis. The age of initiation of prophylaxis in both groups had been 4.2 (0.8-7) and 1.3 (0.4), with a median AJBR of 1 and 1.6, respectively. ...
Introduction:
Tailored prophylaxis is the current treatment regimen for patients with severe haemophilia A. Recently, published guidelines describe two possible approaches, based on clinical characteristics or estimation of pharmacokinetic parameters. However, both have strengths and weaknesses, and their characteristics need to be integrated to optimize treatment appropriately. In this paper, we present a model that considers together the characteristics of prophylaxis and the relevance of each.
Methods:
The age at initiation of prophylaxis, number of bleeding events, treatment regimen, therapeutic adherence, FVIII trough levels, and joint status were analyzed in 59 patients followed at La Paz University Hospital between January 2000 and December 2019.
Results:
The mean duration of primary prophylaxis of 113.37 ± 57.79 months. Eighty-three percent (n = 49) had no joint status involvement at the end of follow-up (HJHS and HEAD-US = 0). The median ABR was 0.7 (IQR 0.2 -1.0) and 54.2% presented trough levels of FVIII during follow-up >1 IU/dL. 72,9% engaged in some type of physical activity and overall adherence was over 85% in all patients evaluated. The regression analysis performed, considering all these factors, showed that the initiation of prophylaxis before 21 months of age was the most relevant protective factor against the appearance of joint involvement (OR 88.33 p.031 CI 95% 1.49-5224.40) CONCLUSION: Early initiation of prophylaxis was the most relevant factor in the protection of joint status. More comprehensive analysis models adapted to the characteristics of each population, are needed to adequately individualize treatment.
... However, at present, prophylaxis in children has signi cantly improved, and we also found that children who received prophylaxis had fewer joint bleeding events than did those who received on-demand treatment. Imaging studies showed that 6 patients (29%) treated with prophylaxis had signs of joint disease, while 14 patients (74%) treated with intermittent treatment had signs of joint disease (P < 0.05) [27]. Therefore, it is essential to promote prophylactic treatment to enhance the protection of patients' joints and improve their overall quality of life. ...
Aim
To increase the attention given to low-income hemophilia patients, and to reduce the annual bleeding rate and incidence of hemophilia arthropathy, ultimately improving quality of life.
Methods
Clinical data from 171 low-income hemophilia patients were collected from January 2017 to December 2019 in Shandong Province. The data includes age, education, employment status, activity of factor Ⅷ/Ⅸ and inhibitor, therapeutic regimen, virus infection, and annual bleeding rate (ABR). The translated and validated Chinese version of the Haemophilia Quality of Life questionnaire for adults (Haem- QoL-A), Hemophilia Joint Health Scores (HJHS) and annualized FⅧ or prothrombin complex (PCC) consumption were applied.
Results
In our study, a total of 171 male patients—131 adults and 40 children—were included, and the median age was 30 years. The average annual income of these patients' families was ¥6181.52. Among the patients with initial bleeding, the median age was 1 year. A total of 133 (77.8%) patients were diagnosed with hemophiliac arthropathy. Eight out of 150 patients had a hemophilia A inhibitor, while only 1 patient had a hemophilia B inhibitor. Among the 171 patients, only 6 children received low-dose prophylaxis. In terms of viral infections, twenty patients (11.7%) were infected with transfusion-associated viruses. The median ABR was 20 bleeding events/year (2-100). The mean Haemo-QoL-A score was 62.3\(\pm 14.5\). The mean total HJHS in children was 8.1\(\pm 7.1\), and that in adults with HA/HB was 40.1\(\pm 20.0\) (P<0.05). The annual per capita factor dosage of the 171 low-income hemophilia patients was calculated to be 6182 IU/year.
Conclusions
In low-income hemophilia patients, the incidence of joint deformity is greater, the incidence of hemophilia inhibitors is lower, and the rate of virus infection through blood transfusion is lower; these findings are attributed to nonstandardized treatment. Moreover, the annual factor consumption of low-income patients in Shandong Province is significantly below the national average. Consequently, it is imperative to provide additional assistance and care to low-income patients. Early prophylaxis in children is essential to protect the joints.
... 5,6 Emicizumab (Hemlibra®, Roche), a humanized IgG4 bispecific antibody, demonstrates affinity for both the active and inactive forms of factor IX and factor X, effectively mimicking the cofactor activity of FVIII by bridging these two factors. [5][6][7][8] Results from the phase III HAVEN clinical studies have established the safety and efficacy of emicizumab in adult and paediatric HA patients irrespective of the presence of FVIII inhibitors. [9][10][11][12] Subsequently, emicizumab has received approval from the US Food and Drug Administration and the European Medicines Agency for the prophylactic treatment of HA patients, with or without FVIII inhibitors. ...
The hallmark of haemophilia A (HA) therapy is prophylaxis, aimed at spontaneous bleeding prevention. Emicizumab provides a viable alternative to intravenous factor replacement therapy. However, data on its use in infants are limited. This single‐centre open arm prospective study reports on emicizumab prophylaxis in infants. We included severe HA patients under 1 year who started emicizumab prophylaxis since 2018, with longitudinal follow‐up. The study collected data on demographics, clinical and laboratory variables, the occurrence of bleeding events, surgeries and treatment outcomes. Of the 27 enrolled infants, whose median age at prophylaxis initiation was 7 months, 24 primarily choose to start emicizumab therapy (3/27 switched from FVIII prophylaxis due to development of FVIII inhibitors). The median age for prophylaxis initiation decreased to 3 months in 2023. Following emicizumab initiation, the median calculated ABR decreased, and no intracranial haemorrhages were observed. Thrombin generation showed a significant improvement in peak height and endogenous thrombin potential at steady state after a loading period. Our study highlights a shift towards early prophylaxis in the era of non‐replacement therapies. It underscores the need for continuous evaluation and refinement of treatment approaches, emphasizing personalized care and diligent monitoring in the evolving field of paediatric haemophilia care.
... Prophylaxis can, however, significantly reduce the risk of HA. Two prospective, randomized, controlled clinical studies [42,43] have demonstrated an 80-85% reduction in joint bleeds among children receiving primary prophylaxis. ...
Haemophilic arthropathy (HA) is one of the most serious complications of haemophilia. It starts with joint bleeding, leading to synovitis which, in turn, can cause damage to the cartilage and subchondral bone, eventually inducing degenerative joint disease. Despite significant improvements in haemophilia treatment over the past two decades and recent guidelines from ISTH and WFH recommending FVIII trough levels of at least 3 IU/dL during prophylaxis, patients with haemophilia still develop joint disease. The pathophysiology of HA is complex, involving both inflammatory and degenerative components. Early diagnosis is key for proper management. Imaging can detect joint subclinical changes and influence prophylaxis. Magnetic resonance imagining (MRI) and ultrasound are the most frequently used methods in comprehensive haemophilia care centres. Biomarkers of joint health have been proposed to determine osteochondral joint deterioration, but none of these biomarkers has been validated or used in clinical practice. Early prophylaxis is key in all severe haemophilia patients to prevent arthropathy. Treatment is essentially based on prophylaxis intensification and chronic joint pain management. However, there remain significant gaps in the knowledge of the mechanisms responsible for HA and prognosis-influencing factors. Better understanding in this area could produce more effective interventions likely to ultimately prevent or attenuate the development of HA.
... Current treatment for hemophilia B consists of replacing the absent or defective coagulation factor, either when bleeding events occur (on-demand treatment) or by regularly scheduled infusions (prophylactic treatment) with plasma-derived or recombinant FIX concentrates 7 . Based on evidence from clinical trials, primary prophylaxis of bleeding episodes has become the unquestionable standard of care for these patients 8,9 . The emergence of high-quality replacement therapies with recombinant factors and advances in the management of bloodborne viral infections have led to reduced morbidity, improved quality of life (QoL), and patient life expectancy close to that of the general male population 7,10 . ...
... El tratamiento actual de la hemofilia B se basa en reemplazar el factor de coagulación ausente o defectuoso cuando se producen los episodios hemorrágicos (tratamiento a demanda) o a través de infusiones programadas y regularles en el tiempo (tratamiento profiláctico) por concentrados de FIX derivados de plasma o recombinantes 7 . Según la evidencia que arrojan los estudios clínicos, la profilaxis primaria de episodios hemorrágicos se ha convertido en el tratamiento estándar de estos pacientes 8,9 . La aparición de terapias de reemplazo de alta calidad con factores recombinantes sumado a los avances hechos en el manejo de infecciones virales transmitidas por la sangre ha reducido la morbilidad, mejorado la calidad de vida (QoL) y la esperanza de vida de los pacientes hasta cifras parecidas a las de la población general masculina 7,10 . ...
... Early prophylaxis reduces physical impairment from hemophilic arthropathy, maintains joint health throughout life, reduces hospitalization, surgeries, and bleeding episodes [38][39][40][41]. ...
Aim
Hemophilia A (HA) is an inherited bleeding disorder caused by a deficiency of clotting factor VIII in the blood. In resource-limited settings like India, affordability is a significant challenge in managing patients with severe HA. This study aims to assess the cost-effectiveness of intermediate-dose prophylaxis versus on-demand factor therapy in adult and pediatric populations with moderate-to-severe congenital HA without inhibitors in India.
Method
We conducted a prospective cost-effectiveness analysis from a societal perspective, categorizing patients into a base state and a joint disease state (patients with Hemophilia suffering extensive bleeds leading to chronic joint disease). Using targeted literature search and primary market research, we developed a Markov model measuring the total cost of Hemophilia treatment and health outcomes, including life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-utility ratio (ICUR), and incremental cost-effectiveness ratio (ICER). The model extended over a lifetime horizon of 70 years with a one-year cycle length. Sensitivity analyses assessed study robustness.
Results
Low-dose prophylactic therapy was cost-effective for adults (>18 years) and pediatric populations (<18 years), yielding better health outcomes (adults: 0.15 LYs and 2.43 QALYs gained; pediatric: 0.40 LYs and 3.12 QALYs gained). Intermediate-dose prophylaxis showed positive net monetary benefits in terms of Quality-Adjusted Life Years (QALYs) for both adult and pediatric populations, with dominant ICER and ICUR values in both cases.
Conclusion
Using intermediate-dose prophylactic factor VIII therapy is a cost-effective approach that improves clinical outcomes compared to on-demand therapy in the Indian adult and pediatric HA populations without inhibitors.
... both children and adults.3,24 However, dose and frequency of FVIII replacement therapies required to protect from bleed and joint damage vary among individuals and over time.25 Additionally, prophylaxis started early in life prevents musculoskeletal complications from recurrent joint and muscle bleeds.26 Personalized and flexible modalities to suit patients' lifestyles, needs, and preferences toward the maintenance of optimal FVIII levels are needed. ...
Objectives
To assess effectiveness and safety of damoctocog alfa pegol in interim analyses of the ongoing real‐world hemophilia A HEM‐POWR study.
Methods
HEM‐POWR (NCT03932201) is a multinational Phase 4 prospective observational study. The primary objective was annualized bleeding rate (ABR) in previously treated patients (PTPs) with hemophilia A. Secondary objectives included adverse events and number of affected joints.
Results
At data cut‐off (August 17, 2022), the safety analysis set included 268 patients and the full analysis set (FAS) included 161 patients. The most common dosing regimen during observation period was prophylaxis (FAS = 158/161, 98.1%) every 3–4 days (twice weekly; FAS = 78/158, 49.4%) and a median (min, max) infusion dose of 37.5 (10, 72) IU/kg. PTPs receiving prophylactic damoctocog alfa pegol have fewer infusions compared with prior treatment. Median total ABR (Q1, Q3) was 0.0 (0.0, 1.8) and mean total ABR (SD) was 2.4 (8.2). The proportion of patients with no affected joints increased between initial visit and follow‐up. No FVIII inhibitors, treatment‐related adverse events, or deaths were reported.
Conclusions
Damoctocog alfa pegol shows effectiveness and acceptable safety, as well as consistent utilization, in real‐world PTPs with hemophilia A, including in patients with non‐severe hemophilia and those with a history of inhibitors. Please see video for a summary of this study.
... The conventional treatment of haemophilia B patients focuses on replacing the FIX with plasma-derived or recombinant FIX (rFIX) concentrates either on-demand (in the presence of bleeding events) or prophylactically (with regular infusions) [3]. Among these options, primary prophylaxis has become the standard of care for haemophilia patients, demonstrating a reduced morbidity, improved QoL and longer life expectancy [4][5][6]. Despite the advantages of early onset with prophylactic treatment, there are still some unmet needs. ...
Standard FIX prophylaxis for PWHB require frequent injections, which has led to the development of extended half-life products like rIX-FP (albutrepenonacog alfa) that has shown good efficacy in clinical studies. This ambispective study aims to report a real-world experience with rIX-FP in a Spanish centre with PWHB who switched from SHL-FIX or began prophylaxis with rIX-FP. Five PWHB were included in this study, Four PTP switched to rIX-FP with prophylaxis every 7 days whilst one PUP started with an every-14-days regimen. 3 PTPs extended their dosing intervals to every 14 days or every 21 days. In all PTPs, median annualized spontaneous and joint bleeding rates were maintained at 0.00 and median (range) of ABR was 0.92 (0.00–2.77) after switch to rIX-FP. Mean trough level with previous product was 3.68% (SD = 2.06), while it was 7.08% (SD = 3) with all rIX-FP dosing intervals. After switching to rIX-FP, all PTP reduced their annual infusion rate between 50 and 84% and their annual FIX consumption by 61% (59–67%). This is the first reported real-world experience with albutrepenonacog alfa in a small cohort in Spain and demonstrates good bleeding control together with a reduction of the infusion rate, factor consumption and higher through factor level than previous treatment.
... Several studies have shown that adult PwH who receive consistent prophylaxis treatment experience better physical health than those who receive treatment only when necessary. [13][14][15][16] However, factors beyond prophylaxis can also affect the HRQoL of PwH, including limited education, financial resources, and a lack of understanding of the disease. 17 Previous studies have established links between joint health, functional condition, HRQoL, and the clinical and demographic characteristics of PwH. ...
Introduction
Hemophilic arthropathy affects people with hemophilia (PwH) and causes joint dysfunction and disability. Brazil has a unique situation and implemented policies to improve health care for PwH. The aim of this study was to evaluate the Functional Independence Score in Hemophilia (FISH), Hemophilia Joint Health Score (HJHS), and associated factors among adult PwH attending a Hemophilia Comprehensive Care Center in Brazil.
Methods
A post hoc analysis was conducted, including 31 patients who had submitted to a physical evaluation during a previously published cross-sectional study performed from June 2015 to May 2016 at the Brasília Blood Center Foundation, Brazil.
Results
The mean age was 30.8±9.4 years, and 80.6% had severe hemophilia. FISH was 27.0±3.8, and HJHS 18.0±10.8. The ankle was the most often affected joint (25/31, 80.6%). There were significant correlations between FISH and HJHS scores and the Hemophilia Quality of Life Questionnaire for Adults. Patients with severe hemophilia (P = 0.029) and PwH aged ≥ 30 years (P = 0.049) had lower FISH scores. Monthly household income > 2 Brazilian minimum wages was independently associated with improved HJHS (P = 0.033). The factors simultaneously associated with better HJHS and FISH were age < 30 years (P = 0.021) and monthly household income < 2 minimum wages (P = 0.013).
Conclusion
FISH and HJHS showed favorable scores despite being performed in a country with unfavorable socioeconomic conditions. In addition to hemophilia severity and age, monthly household income was independently associated with functional and articular state of PwH. The results highlight the importance of the free provision of coagulation factors in Brazil.
... Prophylaxis with factor (F) VIII has become the gold standard for haemophilia A management, reducing both bleeds and arthropathy. 1,2 Owing to the improvement of treatment over the last decade, patients with haemophilia A are now living longer and, consequently, are subject to many of the comorbidities associated with ageing of the general population, including hypertension, 3,4 obesity, diabetes and cardiovascular diseases, in addition to the typical disease-associated morbidities. 5,6 With older age, in addition to haemophilia-associated morbidities such as chronic and debilitating arthropathy with increased risk of falls and fractures, 3,7 patients face late consequences of underlying concomitant diseases. ...
Background
Advances in treatment have enabled patients with haemophilia A to live longer and therefore may be subjected to comorbidities associated with ageing, in addition to disease-associated morbidities. There have been few reports to date on efficacy and safety of treatment specifically in patients with severe haemophilia A and comorbidities.
Objective
To explore the efficacy and safety of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A aged ⩾40 years with comorbidities of interest.
Design
A post hoc analysis of data from the phase 2/3 PROTECT VIII study and its extension.
Methods
Bleeding and safety outcomes were analysed in a subgroup of patients aged ⩾40 years with ⩾1 comorbidity receiving damoctocog alfa pegol (BAY 94-9027; Jivi®) prophylaxis.
Results
Thirty-four patients with severe haemophilia A were included in this analysis, with a mean age of 49.4 years at time of enrolment. The most prevalent comorbidities were hepatitis C (n = 33; chronic, n = 23), hepatitis B (n = 8) and hypertension (n = 11). Four patients had human immunodeficiency virus. All received damoctocog alfa pegol prophylaxis for the entire study [median (range) time in study = 3.9 (1.0–6.9) years]. During the main study and extension, median total annualised bleeding rates (ABRs) (Q1; Q3) were 2.1 (0.0; 5.8) and 2.2 (0.6; 6.0), respectively; median joint ABRs were 1.9 (0.0; 4.4) and 1.6 (0.0; 4.0), respectively. Mean adherence with prophylaxis schedule was greater than 95% throughout the study. No deaths or thrombotic events were reported.
Conclusion
Efficacy, safety and adherence of damoctocog alfa pegol were confirmed in patients aged ⩾40 years with haemophilia A and one or more comorbidities, with data for up to 7 years supporting its use as a long-term treatment option in this group.
... Prophylaxis consists of IV administration of FVIII concentrate with the main objective of preventing bleeding episodes, hemophilic arthropathy and preserving normal musculoskeletal function. Currently, early long-term prophylaxis is the standard of care to prevent joint bleeding and chronic arthropathy in patients with severe hemophilia [4,6,7]. However, benefits of prophylaxis have been shown even in patients starting this regimen later in life by reducing bleeding frequency and joint deterioration and improving QoL [8,9]. ...
Recently new opportunities are emerging for improving the way patients with Haemophilia A are treated. Among these opportunities, efmoroctocog alfa is a first-in-class recombinant factor VIII-Fc fusion protein (rFVIIIFc) produced by recombinant DNA technology with an extended half-life compared with conventional FVIII preparations. The available evidence coming from an Italian HTA report indicates that efmoroctocog alfa provides an effective alternative to conventional FVIII preparations (including standard rFVIIIs) for the management of Haemophilia A. Moreover, by reducing the frequency of injections required, it has the potential to reduce treatment burden, and hence improve adherence to prophylaxis and patient Quality-of-Life.
... 2,3 Prophylaxis with FVIII replacement is considered the standard of care for management of haemophilia A, as it has been shown to reduce complications from repeated bleeds, particularly joint outcomes. 1,4,5 Octocog alfa (Kovaltry ® [BAY 81-8973]; Bayer) is an unmodified fulllength recombinant blood coagulation factor VIII (rFVIII) product 6,7 indicated for the treatment of haemophilia A. ...
Objectives
To report the final results of the 2‐year TAURUS study, assessing weekly prophylaxis dosing regimens of octocog alfa (Kovaltry®/BAY 81–8973) used in standard clinical practice in patients with moderate‐to‐severe haemophilia A.
Methods
TAURUS (NCT02830477) is a phase 4, multinational, prospective, non‐interventional, single‐arm study in patients of any age with moderate or severe haemophilia A (≤5% factor [F]VIII activity). TAURUS was designed to primarily investigate weekly prophylaxis dosing regimens used in standard clinical practice. Annualised bleeding rates (ABRs), treatment satisfaction and adherence, and safety were also assessed.
Results
Of 302 patients included in the full analysis set, 84.4% (n = 255) maintained their octocog alfa prophylaxis baseline regimen throughout the study, with a majority of patients (76.5%, n = 231) on two times or three times weekly regimens at the end of the observation period (≥1–≤2 years). ABRs, treatment satisfaction, and adherence remained stable during the observation period. Octocog alfa was well tolerated and there were no new or unexpected adverse events.
Conclusions
These data show that a smooth transition is observed when switching to octocog alfa from a previous FVIII treatment, with no safety issues and stable bleeding rates in a real‐world setting of patients with moderate‐to‐severe haemophilia A.
... Low dose protocols are more suitable in developing countries [2]. A landmark study from Italy, Esprit Study published in 2011 showed FVIII prophylaxisis significantly reduces arthropathy [3]. The Current WHO Recommendation states, the first choice of treatment of hemophilia is prophylactic therapy. ...
Important complications of hemophilia are bleeding and joint deformity. Episodic treatment of hemophilia with Factor VIII arrests bleeding but not joint deformity. Thus there is a need to administer Factor VIII prophylactically to prevent bleeding and joint deformity. Apart from high dose prophylaxis practised in developing countries, low dose prophylaxis with 10-15 IU/ kg body weight twice/thrice a week is found to be quite effective in resource limited tropical country like India. Significant reduction in musculo-skeletal, visceral bleeding and joint deformity has been observed from various centres in India. Country wide awareness, including at district level, has happened now in India. Factor VIII is more freely supplied by Govt. agencies n o w.
... FVIII prophylaxis for patient without inhibitors was reported as being 2.4-3.1 higher than on-demand therapy [21]. It is worth mentioning that the aforementioned prices are brute figures that ignore potential financial savings such as fewer hospitalization days, medical leaves, or complication-related costs. ...
We present the case of a 52-year-old male with severe hemophilia A with inhibitors, who was diagnosticated with acute lithiasic cholecystitis that required surgical intervention due to lack of favorable response to conservatory treatment. During surgery, hemostatic support was performed with activated recombinant factor VII (rFVIIa, NovoSeven®). The surgery was performed first laparoscopically with adhesiolysis, followed by subcostal laparotomy and cholecystectomy because of the findings of a pericholecystic plastron with abscess and massive inflammatory anatomical modifications. The patient presented postoperative complications, requiring a second surgical intervention, due to the installation of a hemoperitoneum. Hemostatic treatment with rFVIIa was given for a further 3 weeks postoperatively, and the patient was discharged in safe condition. A surgical intervention increases the risk of bleeding in hemophilic patients, which may have vital complications in the absence of adequate hemostatic support and the support of a multidisciplinary team with experience in hemophilic surgery.
... Furthermore, prophylaxis does not resolve prior joint damage. 9,25,26 As such, the observed lack of effect of emicizumab on participants aged ≥40 years is expected. ...
Introduction:
Emicizumab prophylaxis significantly reduces bleeding events; however, the associated impact on bone/joint health is unknown.
Aim:
To explore the effect of emicizumab prophylaxis on bone/joint health in people with haemophilia A (PwHA) without FVIII inhibitors enrolled in HAVEN 3 (NCT02847637).
Methods:
Haemophilia joint health scores (HJHS; v2.1) were evaluated at baseline and Weeks 49 and 97 in PwHA receiving emicizumab (n = 134), and at baseline and Weeks 49, 73 and 97 in PwHA who switched to emicizumab after 24 weeks of no prophylaxis (n = 17). Bone and joint biomarkers were measured in 117 PwHA at baseline and at Weeks 13, 25, 49 and 73.
Results:
HJHS was lower for PwHA who were previously on FVIII prophylaxis, aged <40 years or had no target joints at baseline compared with PwHA who were receiving no prophylaxis, aged ≥40 years or with target joints. Clinically significant mean (95% confidence interval) improvements from baseline of -2.13 (-3.96, -.29) in HJHS joint-specific domains were observed at Week 49 in PwHA with at least one target joint at study entry (n = 71); these changes were maintained through Week 97. Improvements in HJHS from baseline were also observed for PwHA aged 12-39 years. Biomarkers of bone resorption/formation, cartilage degradation/synthesis, and inflammation did not change significantly during emicizumab prophylaxis.
Conclusions:
Clinically relevant improvements in HJHS were observed in younger PwHA and those with target joints after 48 weeks of emicizumab in HAVEN 3. Biomarkers of bone/joint health did not show significant changes during 72 weeks of emicizumab prophylaxis.
... As the benefits of exercise and sports become apparent for PWH, treating physicians are faced with the dilemma of safely allowing sports participation, while mitigating the potentially increased bleeding risk. In persons with severe or moderate hemophilia, prophylactic administration of factor concentrates prior to sports participation is recommended (21,22). Recently, use of intranasal (IN) desmopressin (Ferring pharmaceuticals, Saint-Prex, Switzerland) prior to sports participation has been proposed in patients with mild hemophilia A (HA) to increase endogenous FVIII activity (FVIII:C) (16). ...
Persons with mild hemophilia A (HA) may use intranasal desmopressin prior to sports participation. Desmopressin is expensive, and can cause vomiting, headache, palpitation and occasionally seizures. Our group has previously documented a 2.3-fold increase in FVIII activity (FVIII:C) in adolescents with mild HA after moderate-intensity aerobic exercise. Herein, we report principal findings of a randomized trial of intranasal desmopressin versus a standardized, moderate-intensity aerobic exercise regimen in adolescents with mild HA. Our primary objective was to compare the change in FVIII:C associated with these two interventions. We also examined changes in hemostatic parameters arising from their sequential administration. The study was conducted simultaneously at the Hospital for Sick Children, Canada and Nationwide Children's Hospital, USA. Thirty-two eligible male adolescents [mean age (±SD): 16.1 (±2.6) years] with mild HA [mean baseline FVIII:C: 27.9 (±18.4)%] were randomized to one of four study arms (desmopressin followed by exercise, desmopressin alone, exercise followed by desmopressin, and exercise alone). Blood work was obtained at baseline, and at three subsequent time-points. Participants randomized to exercise cycled on an ergometer for approximately 12-minutes, with the final 3-minutes at 85% of their predicted maximum heart-rate. Standard weight-based dosing of desmopressin was used. Mean immediate increase in FVIII:C was 1.7-fold with exercise, compared to 1.9-fold with desmopressin (non-inferiority p=0.04). Exercise-induced improvement in hemostatic parameters including FVIII:C was brief, compared to more sustained improvements seen with desmopressin. More than 60% of participants randomized to receive both exercise and desmopressin achieved normal (>50%) FVIII:C, 75- and 135-minutes into the study protocol. Clinicaltrials.gov NCT03379974; NCT03136003
... It has been documented that repeated episodes of joint bleeding would cause arthropathy [8]. Prophylactic FVIII regimens are effective in reducing bleeding frequency and arthropathy in patients with severe hemophilia A [9][10][11]. Standard prophylaxis with 20-40 IU/kg FVIII concentrates every other day or at least three times a week helps in reducing bleeding episodes, decreases hospitalization, and improves long-term joint function [12][13][14]. Despite the effectiveness of standard prophylaxis in reducing bleeding episodes, a subpopulation of patients still experience bleeding, probably because of insufficient plasma FVIII levels during dosing intervals [15,16]. ...
Introduction:
Multiple studies have demonstrated the effectiveness of pharmacokinetic (PK)-guided individualized prophylaxis with human coagulation factor VIII (FVIII) compared with standard prophylaxis, but no studies have evaluated the economics of PK-guided prophylaxis in China. Hence, we conducted this study to assess the cost-effectiveness of PK-guided prophylaxis with recombinant FVIII (rFVIII) versus standard prophylaxis in Chinese adult patients with severe hemophilia A.
Methods:
A discrete event simulation model was developed to simulate 10,000 patients with hemophilia A who received rFVIII treatment over a 1-year time horizon. The standard prophylaxis rFVIII dose was 30 IU/kg by intravenous injection. The PK-guided prophylaxis dosage was adjusted for each patient to maintain FVIII trough level at 1-5 IU/dL. Dosing interval for both approaches was kept fixed at 48 h. The health outcomes included annual joint bleed rate (AJBR) and quality-adjusted life years (QALYs). The model considered the costs of drug. Incremental cost-effectiveness ratio (ICER) was estimated and scenario analysis was performed.
Results:
A total of 94.3% of patients receiving PK-guided individualized prophylaxis achieved the goal of maintaining the trough concentration at 1-5 IU/dL compared with 62.7% on standard prophylaxis. AJBR and QALYs gained in PK-guided and standard prophylaxis were 1.527 vs 1.601, and 0.8384 vs 0.8383, respectively. Costs of drug prophylaxis and costs of treatment for bleeding events in PK-guided prophylaxis (148,641.47 USD; 4546.43 USD) were lower than those in standard prophylaxis (159,620.93 USD; 4753.39 USD). An average saving of USD 11,186.47 was obtained by the PK-guided approach. The prophylaxis treatment scenarios were the most influential factors.
Conclusion:
PK-guided individualized prophylaxis appeared to be a dominant treatment compared with standard prophylaxis, with slightly higher QALYs but lower total costs.
... A further limitation of this study is the small sample size, which is planned to be 30 participants; however, this is similar to the number of participants in other HA clinical trials. 27 Furthermore, recruitment of paediatric participants to clinical trials is difficult due to the requirement for consent from a parent or legal representative, assent from the child, and school attendance and parental availability. 28 ...
Introduction
Persons with haemophilia A (PwHA) commonly experience regular bleeding into joints, which may result in joint damage and complications such as degenerative arthritis. Emicizumab has previously demonstrated efficacy in reducing the occurrence of joint bleeds and target joints, along with having a favourable safety profile; however, data on the long-term effects on joint health are lacking. The AOZORA study will evaluate the long-term safety and joint health of paediatric PwHA without factor (F)VIII inhibitors taking emicizumab; here, we report the details of the study protocol and baseline data.
Methods and analysis
AOZORA is a multicentre, open-label, phase IV clinical study in Japan that aims to enrol approximately 30 PwHA aged <12 years without FVIII inhibitors. The primary endpoints include a long-term safety evaluation of adverse events, laboratory test abnormalities and FVIII inhibitor development; and a long-term joint health assessment using MRI and the Hemophilia Joint Health Score. Exploratory endpoints include characterising participants’ physical activities and the number of activity-related bleeds requiring coagulation factor treatment. Currently, 30 participants have been enrolled, including 20 emicizumab-naïve participants and 10 who transferred from HOHOEMI, a previous study in paediatric PwHA.
Ethics and dissemination
The AOZORA study was approved by the Institutional Review Boards of Nara Medical University and the St Marianna University Group. The study will be conducted in compliance with the Declaration of Helsinki, the standards stipulated in paragraph 3 of Article 14 and Article 80-2 of the Pharmaceuticals, Medical Devices and Other Therapeutic Products Act, the Ministerial Ordinance on Good Clinical Practice and the Ministerial Ordinance on Good Post-marketing Study Practice. Data will be published in peer-reviewed journals and presented at Global congresses.
Trial registration number
JapicCTI-194701.
... 9 The analyses in both 2007 and 2017, found no reported HIV or hepatitis C cases among children with haemophilia, again reflecting the safety of factor concentrates. 9 The morbidity and mortality from haemophilia has also been affected by care outside the hospital including novel therapies, prophylactic therapy, or on-demand treatment. [29][30][31][32] Safety and quality of care have significantly improved with HTCs as reflected by a 40% reduction in mortality and hospitalizations for haemophilia related events. 8,33 Such improvement in outpatient treatment may reduce complications and admissions for haemophilia related complications. ...
Introduction:
Current in-hospital burden and healthcare utilization patterns for persons with haemophilia (PWH) A and B, including both children (ages < 18 years) and adults (ages ≥ 18 years), in the United States (US) are lacking.
Aim:
To evaluate healthcare utilization, the prevalence of comorbidities, and mortality in hospitalized paediatric and adult PWH using a contemporary nationally representative cohort.
Methods:
Hospitalizations of PWH either as the primary reason for admission (principal diagnosis) or one of all listed diagnoses were identified using ICD-10 codes from the 2017 Nationwide Inpatient Sample (NIS), the largest publicly available all-payer inpatient discharge database in the US. Sampling weights were applied to generate nationally representative estimates.
Results:
The contemporary cohort included 10,555 hospitalizations (paediatrics, 18.3%; adults, 81.7%) among PWH as one-of-all listed diagnoses (n = 1465 as principal diagnosis). Median age (interquartile range) was 46 (24-66) years overall; adults, 54 (35-70) years and paediatric, 4 (1-11). The most common comorbidities in adults were hypertension (33.4%), hyperlipidaemia (23.6%), and diabetes (21.1%). In children, hemarthrosis (11.4%), contusions (9.6%), and central line infections (9.3%) were the most common. The overall mortality rate was 2.3%. Median hospital charges per haemophilia admission were $52,616 ($24,303-$135,814) compared to $26,841 ($12,969-$54,568) for all-cause admissions in NIS.
Conclusion:
Bleeding and catheter-related infections are the significant reasons for paediatric haemophilia admissions. Adult haemophilia admissions tend to be associated with age-related comorbidities. Costs for haemophilia-related hospitalizations are higher than the national average for all-cause hospitalizations.
Introduction
Primary prophylaxis is the gold standard in severe haemophilia A (SHA) but time to escalate the prophylaxis regimen varies.
Aim
Assess prophylaxis implementation and long‐term joint health outcomes in SHA with primary prophylaxis.
Methods
Adult male patients born after 1980, with SHA on primary prophylaxis, started before the age of 3 years and second joint bleed, and no history of FVIII inhibitors, were enrolled. Repeated joint‐health examinations were performed with HJHS or HEAD‐US; VERITAS‐PRO assessed adherence.
Results
Thirty patients were enrolled with, at inclusion, median age 33.5 years, annualized bleed rate and joint bleed rate 0, and FVIII consumption 4232 IU/kg/year, respectively. The median age was 1.2 years, at prophylaxis start once weekly with a median FVIII dose of 47.7 IU/kg, and 1.7 years, by the time escalation to a final regimen had occurred, with a median infusion frequency of thrice weekly and FVIII dose 41.7 IU/kg, respectively. Older age correlated with later transition to escalated prophylaxis ( p < .001). Longer time to escalated prophylaxis correlated to more bleeds ( p < .001). Median HJHS increased slowly, reaching 4 at 35–40 years. HJHS at 15–20 years correlated with higher HJHS afterwards. Median total HEAD‐US score was 1 and correlated with HJHS ( p < .001). Median VERITAS‐PRO score was 36, indicating good treatment adherence.
Conclusion
Primary prophylaxis is effective but does not completely prevent the gradual development of arthropathy in SHA. Joint assessments with HJHS should start at an early age, as they correlate with arthropathy in later life. Prophylaxis escalation should proceed expeditiously to prevent bleeds.
Introduction:
Bleeding disorders (BDs) may influence health-related quality of life (HRQoL) in children and caregivers. Measuring HRQoL gives insight into domains requiring support and provides an opportunity to evaluate the effects of novel therapies.
Aim:
To gain insight in the current body of literature on HRQoL in children with BDs in order to identify knowledge gaps for research and further development of this field.
Methods:
Scoping review.
Results:
We included 53 articles, describing studies mainly performed in Europe and North-America (60.4%) and mostly within the last ten years. Only 32% studies included children <4 years. Almost all studies (47/53, 88.7%) were performed in boys with haemophilia, pooling haemophilia A and B (n = 21) and different disease severities (n = 20). Thirteen different generic and five disease-specific HRQoL-questionnaires were applied; all questionnaires were validated for haemophilia specifically. Six (11,3%) combined generic and disease-specific questionnaires. Self-reports were most frequently applied (40/53, 75.5%), sometimes combined with proxy and/or parent-reports (17/53, 32.1%). Eleven studies used a reference group (20.8%). Statistical analyses mostly consisted of mean and SD (77.4%).
Conclusion:
HRQoL-research is mainly performed in school-aged boys with haemophilia, treated in developed countries. Pitfalls encountered are the pooling of various BDs, subtypes and severities, as well as the application of multiple generic questionnaires prohibiting comparison of results. More attention is needed for broader study populations including other BDs, young children, feminine such as young children, feminine bleeding issues and platelet disorders, as well as the use of HRQoL as an effect-measurement tool for medical interventions, and more thorough statistical analysis.
Introduction
Damoctocog alfa pegol (BAY 94‐9027, Jivi ® ) is an approved extended half‐life factor VIII (FVIII) for treatment of previously treated patients with haemophilia A aged ≥12 years. We report the final results of an interventional, post‐marketing study of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A.
Methods
In this open‐label, interventional, post‐marketing, phase 4 trial (NCT04085458), previously FVIII‐treated patients with severe haemophilia A aged ≥18 years received damoctocog alfa pegol for ≥100 exposure days (EDs). Patients initially received 45 IU/kg every 5 days (recommended) or 40 IU/kg twice‐weekly. At Visit 3, patients’ doses could be increased, or treatment frequency adapted. The primary endpoint was FVIII inhibitor development (titter ≥.6 Bethesda units). Secondary endpoints included anti‐polyethylene glycol (PEG) antibody development, treatment‐emergent adverse events (AEs) and annualized bleeding rate (ABR).
Results
Overall, 36 patients were enrolled; 32 patients received treatment, of whom, 27 completed the study. No patients developed FVIII inhibitors; three tested transiently positive for low‐titter anti‐PEG antibodies without clinical relevance. Three patients reported study‐drug‐related AEs of mild or moderate intensity. Two patients discontinued the study due to AEs. No deaths occurred. Most patients (70%) were treated with E5D/E7D regimens. The median (Q1;Q3) total ABR ( N = 30) was 3.0 (.0;9.0) pre‐study and 1.8 (.7;5.9) during the study.
Conclusion
Damoctocog alfa pegol individualized prophylaxis regimens were well‐tolerated with no immunogenicity concerns. ABRs improved following the switch from pre‐study prophylaxis to damoctocog alfa pegol prophylaxis. These results support the favourable safety and efficacy profile of damoctocog alfa pegol prophylaxis.
Background:
Using emicizumab in lieu of immune tolerance induction (ITI) for patients with hemophilia A (HA) and factor (F)VIII inhibitors has been well described. However, decisions regarding ITI initiation, regimen, and preservation of tolerance remain to be elucidated.
Objectives:
To study the course of FVIII inhibitors in patients with HA and a history of FVIII inhibitors receiving emicizumab prophylaxis.
Methods:
Patients with HA, with and without FVIII inhibitors, initiating emicizumab prophylaxis were prospectively followed up in our center. All patients with current or previous inhibitors were included in this analysis. Plasma samples for FVIII inhibitor assays were obtained every 3 to 6 months or following FVIII exposure. Patients documented annual bleeding rate and any FVIII exposure days (EDs).
Results:
Of 162 emicizumab-treated participants, 51 met the inclusion criteria. A decrease in annual bleeding rate was observed in all 51 participants followed up for a median of 3.3 years, with 31 breakthrough bleeding episodes reported in 22 of 51 participants. FVIII inhibitor level transiently increased following FVIII exposures in 5 of 15 failed ITI participants. Eight of 21 participants who did not undergo ITI were exposed to FVIII (1-2 EDs)), and 1 of these 8 participants demonstrated increased FVIII inhibitor levels after head trauma (following 1 ED). Among participants who underwent successful ITI, 8 of 15 patients were exposed to FVIII over a total of 13 EDs (1-2 ED(s) each) for traumatic breakthrough bleeds. In all these participants, inhibitor levels remained zero, indicating successful tolerance maintenance.
Conclusion:
Our longitudinal follow-up of emicizumab-treated patients with HA and FVIII inhibitors shows that occasional exposure to FVIII may induce a transient anamnestic response. Nonetheless, no FVIII inhibitor recurrence was noted following FVIII exposures in patients who underwent successful ITI.
When drugs enter the field of human life, they face problems in the area of delivery, delivery to the destination, and metabolism. These problems can cause reducing drug's therapeutic effect and even increase its side effects. Together, these cases can reduce the patient's compliance with the treatment and complicate the treatment process. Much work has been done to solve or at least reduce these problems. For example, using different forms of a single drug molecule (like Citalopram and Escitalopram); a bit changes in the drug's molecule like Meperidine and α-Prodine, and using carriers (like Tigerase®). PEGylation is a recently presented method that can use for many targets. Poly Ethylene Glycol or PEG is a polymer that can attach to drugs by using different methods and causing sustained release, controlled metabolism, targeted delivery, and other cases. All of them, although they will not necessarily lead to an increase in the effect of the drug, will lead to the improvement of the treatment process in certain ways. In this article, the team of authors has tried to collect and carefully review the best cases based on the PEGylation of drugs that can help the readers of this article.
Recent advances in therapeutics are now providing a wide range of options for adults and children living with hemophilia. Although therapeutic choices are also increasing for the youngest individuals with severe disease, challenges remain about early management decisions, as supporting data are currently limited. Parents and healthcare professionals are tasked with helping children achieve an inclusive quality of life and maintain good joint health into adulthood. Primary prophylaxis is the gold standard to optimize outcomes and is recommended to start before 2 years of age. A range of topics need to be discussed with parents to aid their understanding of the decisions they can make and how these will affect the management of their child/children. For those with a family history of hemophilia, prenatal considerations include the possibility of genetic counseling, prenatal investigations, and planning for delivery, together with monitoring of the mother and neonate, as well as diagnosis of the newborn and treatment of any birth-associated bleeding. Subsequent considerations, which are also applicable to families where infant bleeding has resulted in a new diagnosis of sporadic hemophilia, involve explaining bleed recognition and treatment options, practical aspects of initiating/continuing prophylaxis, dealing with bleeds, and ongoing aspects of treatment, including possible inhibitor development. Over time, optimizing treatment efficacy, in which individualizing therapy around activities can play a role, and long-term considerations, including retaining joint health and tolerance maintenance, become increasingly important. The evolving treatment landscape is creating a need for continually updated guidance. Multidisciplinary teams and peers from patient organizations can help provide relevant information. Easily accessible, multidisciplinary comprehensive care remains a foundation to care. Equipping parents early with the knowledge to facilitate truly informed decision-making will help achieve the best possible longer-term health equity and quality of life for the child and family living with hemophilia.
Plain language summary
Points to be taken into account to help families make decisions to best care for children born with hemophilia
Medical advances are providing a range of treatment options for adults and children with hemophilia. There is, however, relatively limited information about managing newborns with the condition. Doctors and nurses can help parents to understand the choices for infants born with hemophilia. We describe the various points doctors and nurses should ideally discuss with families to enable informed decision-making. We focus on infants who require early treatment to prevent spontaneous or traumatic bleeding (prophylaxis), which is recommended to start before 2 years of age. Families with a history of hemophilia may benefit from discussions before pregnancy, including how an affected child would be treated to protect against bleeds. When mothers are pregnant, doctors can explain investigations that can provide information about their unborn child, plan for the birth, and monitor mother and baby to minimize bleed risks at delivery. Testing will confirm whether the baby is affected by hemophilia. Not all infants with hemophilia will be born to families with a history of the condition. Identification of hemophilia for the first time in a family (which is ‘sporadic hemophilia’) occurs in previously undiagnosed infants who have bleeds requiring medical advice and possibly hospital treatment. Before any mothers and babies with hemophilia are discharged from hospital, doctors and nurses will explain to parents how to recognize bleeding and available treatment options can be discussed. Over time, ongoing discussions will help parents to make informed treatment decisions:
• When and how to start, then continue, prophylaxis.
• How to deal with bleeds (reinforcing previous discussions about bleed recognition and treatment) and other ongoing aspects of treatment.
○ For instance, children may develop neutralizing antibodies (inhibitors) to treatment they are receiving, requiring a change to the planned approach.
• Ensuring treatment remains effective as their child grows, considering the varied needs and activities of their child.
Introduction:
The UK National Haemophilia Database (NHD) collects data from all UK persons with haemophilia A with inhibitors (PwHA-I). It is well-placed to investigate patient selection, clinical outcomes, drug safety and other issues not addressed in clinical trials of emicizumab.
Aims:
To determine safety, bleeding outcomes and early effects on joint health of emicizumab prophylaxis in a large, unselected cohort using national registry and patient reported Haemtrack (HT) data between 01 January 2018 and 30 September 2021.
Methods:
Prospectively collected bleeding outcomes were analysed in people with ≥6 months emicizumab HT data and compared with previous treatment if available. Change in paired Haemophilia Joint Health Scores (HJHS) were analysed in a subgroup. Adverse events (AEs) reports were collected and adjudicated centrally.
Results:
This analysis includes 117 PwHA-I. Mean annualised bleeding rate (ABR) was .32 (95% CI, .18; .39) over a median 42 months treatment with emicizumab. Within-person comparison (n = 74) demonstrated an 89% reduction in ABR after switching to emicizumab and an increase in zero treated bleed rate from 45 to 88% (p < .01). In a subgroup of 37 people, total HJHS improved in 36%, remained stable in 46% and deteriorated in 18%, with a median (IQR) within-person change of -2.0 (-9, 1.5) (p = .04). Three arterial thrombotic events were reported, two possibly drug related. Other AEs were generally non-severe and usually limited to early treatment, included cutaneous reactions (3.6%), headaches (1.4%), nausea (2.8%) and arthralgia (1.4%).
Conclusions:
Emicizumab prophylaxis is associated with sustained low bleeding rates and was generally well-tolerated in people with haemophilia A and inhibitors.
Background:
Safety concerns for an increased risk of thrombotic complications in patients with hemophilia A have been pointed out, particularly during nonreplacement treatment with emicizumab and concomitant bypassing agents. Surveillance with the Roche Global Database reporting adverse events for emicizumab has been discontinued on May 2021.
Objectives:
The objective of this study was to evaluate the reporting rate of hemorrhagic and thrombotic adverse drug reactions (ADRs) associated with nonreplacement (emicizumab) and replacement extended half-life (EHL) factor VIII (FVIII) products as retrieved from the EudraVigilance database.
Methods:
Total ADR reported during treatment with emicizumab or EHL FVIII products from January 1 to December 31, 2021, were collected. The proportional reporting ratio and the reporting odds ratio (ROR) with their 95% CIs were calculated to express the hemorrhagic and thrombotic ADR reporting frequency ratio between emicizumab and EHL FVIII products.
Results:
Overall, 406 and 376 ADRs were reported for emicizumab and for EHL FVIII products, respectively. Hemorrhagic and thrombotic ADRs were 232 and 24 for emicizumab and 275 and 9 for the EHL FVIII products. Approximately 25% of thrombotic ADRs were reported concomitantly with eptacog alfa. ROR of 0.49 (95% CI, 0.36-0.66) for hemorrhagic and of 2.56 (95% CI, 1.18-5.59) for thrombotic ADRs were obtained for emicizumab compared with EHL FVIII products.
Conclusion:
The analysis of 2021 EudraVigilance reports shows a lower reporting rate of hemorrhagic ADR vs a higher reporting rate of thrombotic ADR for emicizumab than for EHL FVIII products. These signals stress the importance of monitoring novel drugs in hemophilia, particularly when administered in association with bypassing agents.
Background:
Chronic arthropathy is a potentially debilitating complication for people with haemophilia - a genetic, X-linked, recessive bleeding disorder, characterised by the absence or deficiency of a clotting factor protein. Staging classifications, such as the Arnold-Hilgartner classification for haemophilic arthropathy of the knee, radiologically reflect the extent of knee joint destruction with underlying chronic synovitis. Management of this highly morbid disease process involves intensive prophylactic measures, and chemical or radioisotope synovectomy in its early stages. However, failure of non-surgical therapy in people with progression of chronic arthropathy often prompts surgical management, including synovectomy, joint debridement, arthrodesis, and arthroplasty, depending on the type of joint and extent of the damage. To date, management of people with mild to moderate chronic arthropathy from haemophilia remains controversial; there is no agreed standard treatment. Thus, the benefits and disadvantages of non-surgical and surgical management of mild to moderate chronic arthropathy in people with haemophilia needs to be systematically reviewed. OBJECTIVES: To assess the efficacy and safety of surgery for mild to moderate chronic arthropathy in people with haemophilia A or B.
Search methods:
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, and two trial registers to August 2022. We also handsearched relevant journals and conference abstract books.
Selection criteria:
Randomized controlled trials (RCTs) and quasi-RCTs comparing surgery and non-surgical interventions, for any joint with chronic arthropathy, in people with haemophilia, who were at least 12 years old.
Data collection and analysis:
The review authors did not identify any trials to include in this review.
Main results:
The review authors did not identify any trials to include in this review.
Authors' conclusions:
The review authors did not identify any trials to include in this review. Due to a lack of research in this particular area, we plan to update the literature search every two years, and will update review if any new evidence is reported. There is a need for a well-designed RCT that assesses the safety and efficacy of surgical versus non-surgical interventions for chronic arthropathy in people with haemophilia.
Hemophilia A, a single gene disorder leading to deficient Factor VIII (FVIII), is a suitable candidate for gene therapy. The aspiration is for single administration of a genetic therapy that would allow production of endogenous FVIII sufficient to restore hemostasis and other biological processes. This would potentially result in reliable protection from bleeding, and its associated physical and emotional impacts. Gene therapy offers the possibility of a clinically relevant improvement in disease phenotype and transformational improvement in quality of life, including an opportunity to engage in physical activities more confidently. Gene therapy products for hemophilia A in advanced clinical development use adeno-associated viral (AAV) vectors and a codon optimized B-domain deleted FVIII transgene. However, the different AAV-based gene therapies have distinct design features such as choice of vector capsid, enhancer and promoter regions, FVIII transgene sequence and manufacturing processes (summarized in the graphic abstract). These, in turn, impact patient eligibility, safety and efficacy. Ideally, gene therapy technology for hemophilia A should offer bleed protection, durable FVIII expression, broad eligibility and limited response variability between patients, and long-term safety. However, several limitations and challenges must be overcome. Here, we introduce the characteristics of the BAY 2599023 (AAVhu37.hFVIIIco, DTX 201) gene therapy product, including the low prevalence in the general population of anti-AAV-hu37 antibodies, as well as other gene therapy AAV products and approaches. We will examine how these can potentially meet the challenges of gene therapy, with the ultimate aim of improving the lives of patients with hemophilia A.
The availability first in the 1970s of plasma-derived and then in the 1990s of recombinant clotting factor concentrates represented a milestone in hemophilia care, enabling not only treatment of episodic bleeding events but also implementation of prophylactic regimens. The treatment of hemophilia has recently reached new landmarks. The traditional clotting factor replacement therapy for hemophilia has been substituted over the last 10 years by novel treatments such as bioengineered factor VIII and IX molecules with extended half-life and non-factor treatments including the bispecific antibody emicizumab. This narrative review is dedicated to these newer therapies, which are contributing significantly to improving the long-term management of prophylaxis in hemophilia patients. Another section is focused on the current state of gene therapy, which is a promising definitive cure for severe hemophilia A and B.
Introduction:
Hemophilia A is a bleeding disorder characterized by a deficiency of a coagulation factor VIII and optimally treated using pharmacokinetics (PK)-guided prophylactic replacement therapy. To decrease patient burden, PK can be estimated from sparse sampling leveraging population PK modeling. However, recommendations for sampling times meant for hemophilia A patients as a group may not be optimal at the individual level.
Objective:
To evaluate a personalized limited sampling approach (Personalized LSA) that suggests a next sampling time point that would provide a more accurate estimation of terminal half-life of FVIII concentrates when using a population PK approach.
Methods:
331 PK studies with rich sampling were extracted from the WAPPS-Hemo database. Two sampling approaches were evaluated and compared: (i) 974 PK studies consisting of 2 samples were built from the rich sampling data including one sample selected using the personalized LSA prediction; (ii) 974 PK studies consisting of 2 samples were built from the rich sampling data including one sample selected randomly. Half-life values were estimated on the sparse data and compared within patients to the estimates obtained on the rich data for assessing the error on half-life values.
Results:
Relative errors between estimates from sparse sampling data using personalized LSA and from rich sampling data were always lower than 20% and significantly lower than the comparative approach that used random sampling (median - 95th percentile were 3.8% - 13.1% vs 7.0% - 23.5 % respectively, p < 10-10 ). Moreover, less than 4% of the samples suggested by the personalized LSA were below the limit of quantification (BLQ).
Conclusions:
Identifying the most informative sampling points for PK assessment using a Personalized LSA approach that accounts for individual differences in PK improves the precision of FVIII terminal half-life estimates in sparse sampling.
Introduction
Extended half-life (EHL) factor VIII (FVIII) products have been designed to allow less frequent infusions and higher bleeding protection than standard half-life (SHL) products. Only few reports analyzed this switch in clinical practice.
Aim
To analyze the differences observed in pharmacokinetics (PK) and clinical outcomes after the switch from SHL to EHL products in severe/moderate haemophilia A (HA) prophylaxis.
Materials and methods
Observational, cross-sectional, multicenter, prospective study comparing PK parameters and clinical variables between SHL FVIII replacement therapy followed by EHL along two consecutive one-year periods. PK estimations were performed through WAPPS-Hemo. FVIII consumption, annual bleeding rate (ABR) and annual joint bleeding rate (AJBR) of each period were compared between both periods.
Results
Seventy-five patients were included (median age 26.0 years). After the switch median reductions of 33.3 % in weekly infusion frequency and 20.4 % in dose/kg/week were observed, avoiding 39.1 infusions/patient/year. Significant improvements were achieved in all PK parameters with EHL, showing mean ratios in half-life and area under the curve (AUC) of 1.5 and 1.9. Significant decreases in median ABR (2.0 vs. 0.0), AJBR (1.0 vs. 0.0) and target joints, and zero total bleeds (27.4 % vs. 54.8 %) and zero joint bleeds (42.5 % vs. 72.6 %) were increased after the switch to EHL. Similar improvements were reported in patients <12 and ≥12 years. No differences were observed in PK parameters between EHL products, but lower AJBR were associated to PEGylated products.
Conclusions
PK-guided switch to EHL FVIII provided significant improvements in PK and lower bleeding rates, treatment burden and consumption compared to SHL products.
Background:
Pharmacokinetic (PK) studies of low-dose prophylaxis (LDP) of coagulation factor VIII (FVIII) in children with severe haemophilia A (SHA) are scarce.
Objective:
This study aims to investigate the PK profile of children with SHA receiving LDP of FVIII.
Methods:
Paediatric patients receiving FVIII infusions (10 IU/kg twice weekly) were included. PK profiles were estimated using the Web Accessible Population Pharmacokinetic Service for Haemophilia (WAPPS-Haemo). The primary outcomes were the terminal half-life (t1/2 ), concentration-time profile, and time to reach an FVIII level of < 1%. The secondary outcome was the suggested dosing interval of FVIII prophylaxis based on the individual PK profile.
Results:
Twenty-five patients were recruited; their mean age was 12.3 ± 3.0 years. The t1/2 differed among patients receiving LDP of FVIII twice weekly, with a median of t1/2 was 14.8 h (IQR 12.6-16). The median time to reach an FVIII level of < 1% was 73.8 h (IQR 58.8-80.3). Most patients could maintain a trough level of FVIII > 1% longer than 48 h. At 72-96 h, patients needed a second dose of FVIII infusion because the FVIII level was < 1%. The suggested dosing interval of FVIII prophylaxis ranged from daily to every 96 h, depending on the individual PK profile.
Conclusion:
Our study identified inter-individual differences in the PK parameters using LDP of FVIII twice weekly. The inter-individual results in different dosing intervals advise the timing of LDP. Estimating individual PK parameters enables the identification of the optimal prophylaxis frequency to prevent bleedings.
Introducción:
El presente artículo resume la guía de práctica clínica (GPC) para diagnóstico y tratamiento de hemofilia en el Seguro Social del Perú (EsSalud).
Objetivo:
Proveer recomendaciones clínicas basadas en evidencia para el diagnóstico y tratamiento de la hemofilia en EsSalud.
Métodos:
Se conformó un grupo elaborador de la guía (GEG) que incluyó médicos especialistas y metodólogos, el cual formuló preguntas clínicas. Se realizaron búsquedas sistemáticas de revisiones sistemáticas y -cuando fue considerado pertinente- estudios primarios en PubMed durante el 2020 y 2021. Se seleccionó la evidencia para responder cada una de las preguntas clínicasformuladas. Se evaluó la certeza de la evidencia usando la metodología Grading of Recommendations Assessment, Development, and Evaluation(GRADE). En reuniones de trabajo periódicas, el GEG usó la metodología GRADE para revisar la evidencia y formular las recomendaciones. La GPC fue revisada por expertos externos previa a su aprobación.
Resultados:
La GPC abordó 09 preguntas clínicas de diagnóstico y tratamiento. En base a dichas preguntas se formularon 05 recomendaciones (01 fuerte y 04 condicionales), 51 puntos de buena práctica clínica, y 02 flujogramas.
Conclusión:
Se emitieron recomendaciones basadas en evidencia para el diagnóstico y tratamiento de personas con hemofilia.
The aim was to evaluate the cost of capecitabine vs conventional combination chemotherapics such as 5-fluorouracil (5-FU) for the treatment of metastatic colorectal cancer (mCRC) in Italy. The study was a multicenter, retrospective longitudinal treatment-cost analysis. Patients older than 18 years, diagnosis of mCRC and at least 3 completed cycles of chemotherapy with oral capecitabine or 5-FU also in association with other chemotherapic agents were enrolled. Direct healthcare resources attributable to mCRC treatment were quantified using 2007 prices and tariffs. The analysis was conducted from the National Health Service perspective with a 6-month time horizon. A total of 231 patients affected by mCRC (55% males; mean age 63.7+/-10.31 yrs) were studied. Total direct costs per patient per month in capecitabine and 5-FU groups were euro1,001.66 +/- euro434.93 and euro3,172.81 +/- euro1,232.37 respectively (p<0.0001). Oral capecitabine therapy cost the health service less than intravenous therapies.
Background The CONSORT statement is intended to improve reporting of randomised controlled trials and focuses on minimising the risk of bias (internal validity). The applicability of a trial’s results (generalisability or external validity) is also important, particularly for pragmatic trials. A pragmatic trial (a term first used in 1967 by Schwartz and Lellouch) can be broadly defined as a randomised controlled trial whose purpose is to inform decisions about practice. This extension of the CONSORT statement is intended to improve the reporting of such trials and focuses on applicability.
Methods At two, two-day meetings held in Toronto in 2005 and 2008, we reviewed the CONSORT statement and its extensions, the literature on pragmatic trials and applicability, and our experiences in conducting pragmatic trials.
Recommendations We recommend extending eight CONSORT checklist items for reporting of pragmatic trials: the background, participants, interventions, outcomes, sample size, blinding, participant flow, and generalisability of the findings. These extensions are presented, along with illustrative examples of reporting, and an explanation of each extension. Adherence to these reporting criteria will make it easier for decision makers to judge how applicable the results of randomised controlled trials are to their own conditions. Empirical studies are needed to ascertain the usefulness and comprehensiveness of these CONSORT checklist item extensions. In the meantime we recommend that those who support, conduct, and report pragmatic trials should use this extension of the CONSORT statement to facilitate the use of trial results in decisions about health care.
To prevent hemophilic arthropathy, prophylactic treatment of children with severe hemophilia should be started before joint damage has occurred. However, treatment is expensive, and the burden of regular venipunctures in young children is high. With the aim of providing information on starting prophylaxis on the basis of individual patient characteristics, the effect of postponing prophylaxis on long-term arthropathy was studied in a cohort of 76 patients with severe hemophilia born between 1965 and 1985. The median age at first joint bleed was 2.2 years (range, 0.2-5.8). Prophylaxis was started at a median age of 6 years (interquartile range [IQR], 4-9), and the median annual clotting factor use on prophylaxis was 1750 IU/kg/y (31 IU/kg/wk). Hemophilic arthropathy was measured by the Pettersson score (maximum, 78 points). At a median age of 19 years, the median Pettersson score was 7 points (IQR, 0-17). After 2 decades of follow-up, the Pettersson score was 8% higher (95% confidence interval, 1%-16%) for every year prophylaxis was postponed after the first joint bleed. This effect was independent of age at Pettersson score, age at first joint bleed, and prophylactic dose used. In conclusion, most patients have their first joint bleed after the age of 2 years. Patients who start prophylaxis soon after the first joint bleed show little arthropathy in adulthood. The longer the start of prophylaxis is postponed after the first joint bleed, the higher the risk of developing arthropathy.
Inhibitor formation occurs at a frequency of 20% to 30% in severe hemophilia A, and 3% in hemophilia B. Today, it represents the major complication in patient care and renders classical substitution therapy ineffective. Genetic factors, such as factor VIII (FVIII) gene mutations and immune response genes, particularly the major histocompatibility complex, have been shown to constitute decisive risk factors for the development of inhibitors. In severe hemophilia A and B, those mutations that result in the absence or severe truncation of the FVIII/factor IX (FIX) proteins are associated with the highest risk for inhibitor formation, indicating that a major driving force in inhibitor development is the presentation of a novel antigen to the patient's immune system. An alternative pathomechanism may underlie inhibitor development in patients with mild hemophilia A. Missense mutations, especially those in the C1/C2 domains, may alter the immunogenicity of the FVIII protein, eliciting an inhibitor response against the mutated epitope. In some patients with hemophilia B, especially those with large deletions to the FIX gene, a severe allergic reaction occurs simultaneously with inhibitor onset. Despite the obviously strong genetic predisposition, discordant inhibitor status in monozygotic hemophilia A twins demonstrates that environmental factors also play a role in the development of inhibitors.
Since the 1970s, mortality in the hemophilia population has been dominated by human immunodeficiency virus (HIV) and few reports have described mortality in uninfected individuals. This study presents mortality in 6018 people with hemophilia A or B in the United Kingdom during 1977 to 1998 who were not infected with HIV, with follow-up until January 1, 2000. Given disease severity and factor inhibitor status, all-cause mortality did not differ significantly between hemophilia A and hemophilia B. In severe hemophilia, all-cause mortality did not change significantly during 1977 to 1999. During this period, it exceeded mortality in the general population by a factor of 2.69 (95% confidence interval [CI]: 2.37-3.05), and median life expectancy in severe hemophilia was 63 years. In moderate/mild hemophilia, all-cause mortality did not change significantly during 1985 to 1999, and median life expectancy was 75 years. Compared with mortality in the general population, mortality from bleeding and its consequences, and from liver diseases and Hodgkin disease, was increased, but for ischemic heart disease it was lower, at only 62% (95% CI: 51%-76%) of general population rates, and for 14 other specific causes it did not differ significantly from general population rates. There was no evidence of any death from variant Creutzfeldt-Jakob disease or from conditions that could be confused with it.
Effective ways to prevent arthropathy in severe hemophilia are unknown.
We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI).
Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.
Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).
There is a growing interest in patient-reported outcomes as measures for evaluating the benefits of new and existing treatments. Health-related quality of life (HRQoL) is one of these patient-reported outcomes and represents the individual experience and perception of illness/health together with the psychosocial response to disease-related and treatment-related symptoms. Generic and disease-specific HRQoL questionnaires enable us to assess and quantify the multi-dimensional perception of well-being, namely the physical components and the psychological (emotional, mental, social and behavioural) components of patient's well-being and functioning. These instruments should be standardized and validated and they should prove to be reliable, valid, specific and sensitive in a similar manner to instruments created for objective parameters. HRQoL assessment can help us to evaluate the benefits of new treatments from the perspective of patient's values and expectations. It can also help to evaluate the quality of care provided, in order to be able to improve it at a local and national level. Moreover, HRQoL assessment can be routinely assessed to monitor improvement and progress or deterioration and decline from the global point of view of each single patient, integrating the otherwise limited angle of objective signs and instrumental or lab parameters.
Haemostasis—a component of the wound defence mechanism—is a process by which vessel wall components and platelets act in concert with procoagulant and anticoagulant proteins to form a plug of cells and cross-linked fibrin. The plug is later remodelled and replaced by new tissue as part of wound healing. These processes are very complex and involve highly controlled pathways of interaction between cells, glycans, and membrane-bound and soluble proteins of coagulation and fibrinolysis, as well as their cognate inhibitors....
To comprehend the results of a randomized, controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through complete transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by using a checklist and flow diagram. The revised CONSORT statement presented in this paper incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Discussion. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting the information is associated with biased estimates of treatment effect or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of a trial (enrollment, intervention allocation, follow-up, and analysis). The diagram explicitly includes the number of participants, for each intervention group, that are included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have performed an intention-to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.
Objective. Arthropathy is the major cause of morbidity in haemophilia. In an attempt to establish optimal therapeutic regimens for persons with haemophilia, we hypothesized that no direct relationship exists between increasing factor dosage and orthopaedic outcomes over time.
Design. A longitudinal uncontrolled 6 year study was carried out. Ankles, knees and elbows of patients were studied using physical and X‐ray examination scores. Bleeding episodes and treatment regimens were determined. The amount of time lost from work and school, as well as days in hospital, was also monitored.
Setting. Twenty‐one international haemophilia centres were used to accrue and follow patients over the 6 year period.
Subject. Severe (< 1 %) factor VIII deficient patients under the age of 25 without inhibitors were recruited into the study.
Intervention. The status of the six major joints of these patients were measured annually for mobility. X‐ray evaluation of these joints was carried out at the beginning and end of the study. Using a World Federation of Haemophilia joint and X‐ray score, stability, progression or regression of arthropathy was evaluated.
Results. Physical and X‐ray examination scores increased significantly with age, and the number of joint bleeds were significant in determining the Δ score . Approximately 10% of patients entered with all six joints normal. Of these, 50% remained so. Year‐long prophylaxis significantly reduced the rate at which joints deteriorate both on physical ( P = 0.02) and X‐ray examination ( P = < 0.001). Patients on prophylaxis had significantly fewer days lost from work or school, as well as fewer days spent in hospital ( P = < 0.01).
Conclusions. Higher doses of factor per se do not necessarily produce improved orthopaedic outcomes. However, full time prophylaxis is likely to produce the best orthopaedic outcome. The most critical factor for a good orthopaedic outcome is the reduction of joint bleeds.
It is the thesis of this paper that most therapeutic trials are inadequately formulated, and this from the earliest stages of their conception. Their inadequacy is basic, in that the trials may be aimed at the solution of one or other of two radically different kinds of problem; the resulting ambiguity affects the definition of the treatments, the assessment of the results, the choice of subjects and the way in which the treatments are compared. It often occurs that one type of approach is ethically less defensible than the other, or may even be ruled out altogether on ethical grounds. We postpone consideration of this aspect of the question until a later section.
In a case of massive bleeding, the possibility of puncturing the joint can be considered to reduce the total load of intra-articular blood, and thus the total load of iron which, in time, can be found in the synovium with devastating long-term effects. Subsequent initiation of prophylaxis, still very early in life, might be more beneficial for the preservation of joints. Thus, it might be argued that the initiation of primary prophylaxis should be based on joint haemorrhage history rather than age and, according to some authors, preferably after the bleed in a single joint. The high cost of recombinant factor VIII may make widespread acceptance of prophylaxis impractical. Thus, beneficial results should be balanced with cost considerations. In this balance of treatment cost and efficacy, it must be taken into account that improperly treated haemophilia patients make great demands on healthcare systems (in terms of costs) because of their need for additional treatments such as expensive joint replacement surgery. However, where resources are limited, it can be argued that prophylaxis may be stopped in adulthood, in a certain proportion of all adult patients, with acceptable consequences for orthopaedic outcome in the long term. By doing so, limited amounts of clotting factor can be used for young patients with optimal cost effectiveness.
In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3-32 years. Treatment is started when the boys are 1-2 years of age, the regimens used being 24-40 IU F VIII kg-1 three times weekly in haemophilia-A cases (i.e. greater than 2000 IU kg-1 annually) and 25-40 IU F IX kg-1 twice weekly in haemophilia-B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.
Arthropathy is the major cause of morbidity in haemophilia. In an attempt to establish optimal therapeutic regimens for persons with haemophilia, we hypothesized that no direct relationship exists between increasing factor dosage and orthopaedic outcomes over time.
A longitudinal uncontrolled 6 year study was carried out. Ankles, knees and elbows of patients were studied using physical and X-ray examination scores. Bleeding episodes and treatment regimens were determined. The amount of time lost from work and school, as well as days in hospital, was also monitored.
Twenty-one international haemophilia centres were used to accrue and follow patients over the 6 year period.
Severe (< 1%) factor VIII deficient patients under the age of 25 without inhibitors were recruited into the study.
The status of the six major joints of these patients were measured annually for mobility. X-ray evaluation of these joints was carried out at the beginning and end of the study. Using a World Federation of Haemophilia joint and X-ray score, stability, progression or regression of arthropathy was evaluated.
Physical and X-ray examination scores increased significantly with age, and the number of joint bleeds were significant in determining the delta score. Approximately 10% of patients entered with all six joints normal. Of these, 50% remained so. Year-long prophylaxis significantly reduced the rate at which joints deteriorate both on physical (P = 0.02) and X-ray examination (P = < 0.001). Patients on prophylaxis had significantly fewer days lost from work or school, as well as fewer days spent in hospital (P = < 0.01).
Higher doses of factor per se do not necessarily produce improved orthopaedic outcomes. However, full time prophylaxis is likely to produce the best orthopaedic outcome. The most critical factor for a good orthopaedic outcome is the reduction of joint bleeds.
To examine the relationship of stress and incidence of bleeding in boys with hemophilia.
We conducted a 6-month longitudinal study of 97 subjects (ages 4 to 16 years) from six hemophilia centers. Diaries recorded bleeding episodes (including site and history of previous trauma) and both child and parent daily stress. Parent and child stressful life event measures were obtained monthly. Socioeconomic data and clotting factor level were determined at enrollment. Logistic regression models examined the influence of recent stress on likelihood of bleeding on each day, controlling for factor level and socioeconomic data. We also determined associations of aggregated previous month's events with bleeding likelihood in the succeeding month.
Fifty-eight percent of study participants had severe hemophilia. The sample population averaged nine bleeding episodes per 6 months; of these; two thirds of bleeding incidents occurred into joints and 44% after injury. Factor level strongly predicted bleeding incidence (p < 0.0001). Increased parent stress was associated with increased bleeding in general (odds ratio = 1.37, p < 0.003) and with injury (odds ratio = 1.65, p < 0.001), but not bleeding into joints. Similar findings followed parent reports of positive life events. Increased parent negative life events in 1 month were associated with increased bleeding in the succeeding month (p < 0.05).
Short- and long-term parental stress may lead to increased bleeding incidence in hemophilia, although factor level much more strongly predicts bleeding.
To assess the incremental cost-effectiveness of prophylactic compared with episodic care in boys with severe hemophilia A.
Eleven U.S. hemophilia treatment centers.
Charge data from a randomly selected cohort of 70 boys receiving episodic infusions for bleeding events and from all 27 boys receiving infusions prophylactically were collected from documents obtained from the hemophilia treatment centers during a period of approximately 2 years. Published and public sources were used for conversion to cost, lifetime earnings, and earnings losses from disability. A model was constructed for a hypothetical patient from ages 3 to 50 years by means of three infusion scenarios.
The cohort receiving prophylactic treatment had fewer bleeding events each year (median, 3 vs 31) but used more concentrate (3323 vs 1015 units/kg per year). Factor VIII concentrate accounted for more than 93% of the cost of both episodic and prophylactic care. Compared with episodic infusion, prophylaxis from ages 3 to 20 years costs $1100 per bleeding event prevented, in comparison with $1380 for prophylaxis from ages 3 to 50 years. The total cost of prophylactic care from ages 3 to 50 years would equal the current total cost of episodic care if the price of the concentrate were decreased by 50%.
Prophylactic care markedly reduces the number of bleeding events and should prevent joint function impairment, but at substantial cost.
The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10. 75 of the patients started before the age of 3, 31 at the age of 3–5 and 15 at the age of 6–9. Each subgroup was evaluated separately. In addition, a regimen of one infusion weekly was compared with that of two (haemophilia B) or three (haemophilia A) infusions weekly in each patient.
A significant decrease in the overall number of joint bleeds per year was found after shortening the infusion interval (P < 0.005), but the individual bleeding pattern varied. In survival analysis of the first pathologic joint score event, those who started prophylaxis before the age of 3 had a better outcome overall than those starting at later ages (P = 0.001). However, in subgroup analysis, no significant difference was seen in the annual number of joint bleeds and the development of arthropathy between those starting with, or shifting to, the more intensive regimen before the age of 3 and those that were put on this regimen at the age of 3–5. Age at start of prophylaxis was found to be an independent predictor for the development of arthropathy (P = 0.0002), whereas dose and infusion interval at start were not.
Our data emphasize the importance of starting replacement therapy during the first years of life. However, it seems that when beginning the regimen it can be individualized and adjusted according to the bleeding pattern. In this way, the need for a venous access system may be assessed on an individual basis.
The European Study on the Clinical Outcomes and Resource Utilization associated with Haemophilia Care was designed to compare various health outcomes associated with on-demand and prophylactic factor substitution methods in European haemophilia patients. While the primary objective of this research is to conduct an economic analysis, an important component of this study is to evaluate quality-of-life differences that may exist between patients who utilize these two styles of therapy. Quality-of-life research has emerged as a primary measure of health outcomes because it allows the augmentation of traditional clinical indicators of health with data gathered from the patient's perspective. A total of 1033 haemophilia patients from 16 European haemophilia treatment centres were enrolled in this study. The SF-36, a multidimensional quality-of-life instrument, was administered to all participants. This instrument measures eight health-related quality-of-life dimensions: physical functioning, physical role limitations, bodily pain, general health, vitality, social functioning, emotional role limitations, and mental health. All haemophilia subjects enrolled in the study scored significantly lower than the population normative means in the three physical dimensions and in the general health dimension. HIV-negative haemophiliac subjects differed significantly by factor substitution type in a multivariate analysis examining all eight health dimensions. Univariate analyses testing each dimension separately indicated that patients treated prophylactically reported significantly less bodily pain, better general health, and scored significantly higher in the physical functioning, mental health, and social functioning dimensions. While these results suggest that health-related quality-of-life may be better for haemophilia patients treated prophylactically, future prospective studies that gather periodic quality-of-life data over time should be conducted.
To comprehend the results of a randomised controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through total transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by use of a checklist and flow diagram. The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Discussion. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect, or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of a trial (enrollment, intervention allocation, follow- up, and analysis). The diagram explicitly shows the number of participants, for each intervention group, included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.
Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.
Patients with severe haemophilia are treated either in case of bleeds only (on demand), or with regular infusions of clotting factor to prevent bleeds (prophylaxis). The introduction of prophylaxis has been hampered by issues of cost and viral safety. In order to compare results and treatment cost of different treatment strategies in adults, three cohorts of patients with severe haemophilia (born 1970–1980) were compared.
106 French patients were treated on demand, 49 Dutch patients were treated with intermediate dose prophylaxis, and 24 Swedish patients were treated with high dose prophylaxis. The annual number of joint bleeds, and the radiological Petterson score were used to compare outcome, annual clotting factor consumption was used to compare costs.
Prophylaxis reduced bleeds and arthropathy: patients treated on demand had a median of 11.5 joint bleeds/year and a median Pettersson score of 16 points, for intermediate dose prophylaxis median bleeds were 2.8 and Pettersson score was 7 points, and for high dose prophylaxis median bleeds were 0.5 joint bleeds and Pettersson score was 4 points. All differences were statistically significant, except the Pettersson scores in both prophylactic regimens. Treatment cost was only increased for high dose prophylaxis: mean clotting factor consumption was 1612 IU kg−1 yr−1 for on demand treatment, 1488 IU kg−1 yr−1 for intermediate dose prophylaxis, and 4012 IU kg−1 yr−1 for high dose prophylaxis.
In young adults, the cost of intermediate dose prophylaxis is similar, but outcome is better than for on demand treatment. The cost of high dose prophylaxis is twofold higher, further improving outcome only slightly.
Infectious and thrombotic complications limit the long-term use of subcutaneous ports as venous accesses for children with haemophilia. This study has evaluated for the first time the safety and feasibility of internal arteriovenous fistulae (AVF) as alternative accesses. During the 3-year study period, 27 severe haemophiliacs, 14 with factor VIII inhibitors (52%), underwent the creation of 31 proximal AVF in the forearm. Mild forearm haematomas were observed after five procedures (16%) in five patients who had or developed inhibitors after surgery. Inadequate AVF maturation was observed after five of 31 procedures (16%) in four children. AVF were first accessed after a median of 42 d and regularly used at home by 26 patients (96%) for a median follow-up period of 29 months. Thrombosis of a venous branch occurred in one AVF (3%) after 9 months of uncomplicated use in a child with inhibitor who spontaneously recovered from the symptoms and still used AVF for nine additional months. Mild symptoms, referable to distal ischaemia, were transiently reported by two children (7%) who needed no remedial intervention. This study demonstrates that the use of AVF in haemophiliacs enabled long-term treatment at home in all patients but one.
To comprehend the results of a randomised controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through total transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by use of a checklist and flow diagram. The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Discussion. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect, or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of a trial (enrolment, intervention allocation, follow-up, and analysis). The diagram explicitly shows the number of participants, for each intervention group, included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have done an intention-to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.
The role of clotting factor concentrate prophylaxis in people with severe hemophilia A or B is unclear Hemophilia A and B are X-linked inherited bleeding disorders, in which recurrent bleeding into joints is the major clinical problem, progressively leading to joint deformity and functional limitation. Current therapy for both treatment and prevention of bleeding includes plasma derived or recombinant clotting factor concentrates. The review included randomized controlled clinical trials that compared the use of clotting factor concentrate as a prophylactic therapy to prevent joint bleeds with their use 'on-demand' or another dose of prophylactic therapy to treat bleeding events.
Prophylactic treatment for severe hemophilia A is likely to be more effective than treatment when bleeding occurs, however, prophylaxis is costly. We studied an inception cohort of 25 boys using a tailored prophylaxis approach to see if clotting factor use could be reduced with acceptable outcomes.
Ten Canadian centers enrolled subjects in this 5-year study. Children were followed every 3 months at a comprehensive care hemophilia clinic. They were initially treated with once-weekly clotting factor; the frequency was escalated in a stepwise fashion if unacceptable bleeding occurred. Bleeding frequency, target joint development, physiotherapy and radiographic outcomes, as well as resource utilization, were determined prospectively.
The median follow-up time was 4.1 years (total 96.9 person-years). The median time to escalate to twice-weekly therapy was 3.42 years (lower 95% confidence limit 2.05 years). Nine subjects developed target joints at a rate of 0.09 per person-year. There was an average of 1.2 joint bleeds per person-year. The cohort consumed on average 3656 IU kg(-1)year(-1) of factor (F) VIII. Ten subjects required central venous catheters (three while on study); no complications of these devices were seen. One subject developed a transient FVIII inhibitor. End-of-study joint examination scores--both clinically and radiographically--were normal or near-normal.
Most boys with severe hemophilia A will probably have little bleeding and good joint function with tailored prophylaxis, while infusing less FVIII than usually required for traditional prophylaxis.
The Haemophilia Utilization Group Study (HUGS) was created 10 years ago to examine the annual utilization and cost of haemophilia-related healthcare services. Retrospective chart reviews for 336 patients with haemophilia A receiving treatment in one of five comprehensive haemophilia treatment centres (HTCs) during 1995 were completed through interview of the provider. This method provided adequate collection of data from patient charts without the abstractor having direct access to patient health information. Utilization data were used to impute the costs of different components of care (e.g. physician visits, factor VIII concentrate, emergency room, hospitalization). The total annual cost of care was 139,102 dollars (SD $304,033). Factor VIII concentrate costs comprised the largest proportion of these costs; mean factor VIII concentrate use was 128,517 units per patient per year. Unbilled physician utilization accounted for 7.8% of the mean total physician costs per annum, while mean allied healthcare costs accounted for 33.5% of the total annual allied healthcare costs per patient. In the ordinary least-squares regression model, higher costs were associated with severe factor VIII deficiency, arthropathy, more comorbid conditions, an inhibitor to factor VIII concentrate, infusing through a port and prophylaxis. Although factor VIII concentrate is the most costly component, the treatment of haemophilia uses many healthcare resources. HUGS has demonstrated that patient clinical characteristics and physician practices predominantly drive the costs of haemophilia care. Specifically, patients with more severe arthropathy had greater healthcare costs. As future funding decisions are made, it is important to provide for all components of care.
A multicentre, international, cross-sectional study was carried out in the frame of field testing of the first haemophilia-specific quality-of-life (QoL) questionnaire (Haemo-QoL). The aim of this paper is to describe health status and health care and their impact on QoL in haemophilic children in Western Europe. Children aged 4-16 years with severe haemophilia without inhibitors were enrolled by 20 centres in France, Germany, Italy, the Netherlands, Spain and the United Kingdom. Clinical information was collected by the physicians with a medical documentation form. Health-related QoL (HRQoL) of children was assessed with Haemo-QoL, available for three age groups. Clinical data were available in 318 patients, 85.5% with haemophilia A. The mean age at first bleeding was 11 months, at first joint bleed 25 months. Functional joint impairments were found in 11.3%. Prophylaxis treatment was given to 66.7% of children in whom breakthrough bleeds occurred 0.4 times a month compared to 1.1 bleeds in children receiving on-demand treatment. A significantly higher factor consumption was found only in the two younger age groups of prophylaxis patients compared to on-demand patients. HRQoL was satisfactory in this cohort: young children were impaired mainly in the dimension 'family' and 'treatment', whereas older children had higher impairments in the so-called 'social' dimensions, such as 'perceived support' and 'friends'. Health care of children in Western Europe is progressively improving with a large diffusion of home treatment and prophylaxis. This provides a high level of health status and HRQoL, being better in haemophilic adolescents on prophylaxis.
In spite of an increased interest in the assessment of quality of life (QoL) in children, so far no instrument for children with haemophilia is available. Because of the low prevalence of the condition, such an instrument should also be cross-culturally applicable. In the study presented, a (QoL) assessment instrument for children with haemophilia (the Haemo-QoL questionnaire) was developed and tested in six countries (France, Germany, Italy, the Netherlands, Spain and the United Kingdom) for psychometric properties in 339 children with haemophilia and their parents. The Haemo-QoL is a self-reported questionnaire for children in the age ranges 4-7 (I: 21 items), 8-12 (II: 64 items), 13-16 years (III: 77 items) as well as for parent rating containing 9-11 subscales (depending on age-group versions). Psychometric testing involved the examination of reliability and validity. The three age-group versions of the Haemo-QoL had acceptable internal consistency and retest reliability values, as well as possessing sufficient discriminant and convergent validity. However, in young children when compared to older children, these indicators were less satisfactory. The Haemo-QoL full version is now available for children of three age groups and their parents and is ready for use in clinical research.
Patients with severe haemophilia A (HA) can either be treated by regular FVIII infusions twice or three times per week (prophylaxis), or only in case of bleeding episodes (on-demand). Whereas prophylaxis reduces the number of bleeding episodes and may therefore prevent the development of haemophilic arthropathy, there is still a lot of controversy surrounding recommendations on age and dose at start of prophylactic regimens. The present database study was performed to investigate the role of primary versus secondary prophylaxis in HA children. The outcome variable was imaging-proven haemophilic joint damage. Forty-two children were initially treated with primary prophylaxis following the first bleeding episode, and were frequency-matched (year of birth, catchment area) to 67 patients receiving "on-demand" therapy with an early switch to "secondary prophylaxis". In multivariate analysis adjusted for the HA mutation type and the presence or absence of thrombophilia, the Pettersson score investigated at a median age of 12.5 years in joints with at least one documented bleeding episode was not significantly different between the two patient groups (p = 0.944), and no statistically significant differences were found in patients with target joints (p = 0.3), nor in children in whom synovitis had occurred (p = 0.77). No conclusion can be drawn from the data presented herein whether primary prophylaxis or an early start of secondary prophylaxis is superior with respect to joint outcome in children with severe HA.
Central venous access devices (CVADs) can facilitate repeated and/or urgent administration of coagulation factors in haemophilic patients. We conducted a systematic review and meta-analysis of complication rates and risk factors for poor outcome. Forty-eight studies with a total of 2704 patients and 2973 CVADs were included. The primary indications for CVADs were immune tolerance therapy (34.9% of patients), difficult venous access (31.8%) and prophylaxis (29.1%). Fully implanted CVADs were employed in 77.4% of cases and external CVADs in 22.6%. A total of 1190 infections were reported, and the pooled incidence of infection was 0.66 per 1000 CVAD days [confidence interval (CI), 0.44-0.97 per 1000 CVAD days]. Among patients developing infection, the pooled time to first infection was 295 days (CI, 181-479 days). Presence of inhibitors was an independent risk factor for infection with an incidence rate ratio (IRR) of 1.67 (CI, 1.15-2.43). Infection was less likely in patients >6 years of age (IRR, 0.46; CI, 0.27-0.79) and recipients of fully implanted CVADs (IRR, 0.31; CI, 0.12-0.86). Available information on thrombosis was limited, with only 55 cases being reported. Eventually, 31.3% of CVADs were removed, and infection was the reason for removal in 69.9% of cases and thrombosis in 4.1%. The pooled time period CVADs remained indwelling prior to removal or the expiration of the study observation period was 578 days per CVAD (CI, 456-733 days per CVAD). CVADs can confer major benefits in patients with haemophilia requiring long-term venous access, and serious complications are rare.
Haemostasis and Thrombosis Centre
- F A Scaraggi
F. A. Scaraggi (Haemostasis and Thrombosis Centre, University Internal Medicine Unit ÔC. FrugoniÕ, Azienda Ospedaliera
Policlinico, Bari, Italy);
Haemophilia and Thrombosis Centre
- A Rocino
A. Rocino (Haemophilia and Thrombosis Centre, Haematology Unit, S. Giovanni Bosco Hospital, Napoli, Italy).
Haemophilia Centre, Haemato-Oncology Department
- E Boeri
E. Boeri (Haemophilia Centre, Haemato-Oncology Department, IRCCS Giannina Gaslini, Genova, Italy).
Paediatric Haemostasis and Thrombosis Centre, Pediatric Clinic
- G Mancuso
G. Mancuso (Paediatric Haemostasis and Thrombosis Centre, Pediatric Clinic, Ospedale dei Bambini, Palermo, Italy).
Haemophilia and Thrombosis Centre
- M Schiavoni
M. Schiavoni (Haemophilia and Thrombosis Centre, Internal Medicine Unit, Presidio Osped. ÔI. Veris delli PontiÕ, Scorrano, LE,
Italy).
Haemophilia Centre, Dipartimento Polispecialistico Medicina 2, Azienda Ospedaliero-Universitaria di Parma
- A Tagliaferri
A. Tagliaferri (Haemophilia Centre, Dipartimento Polispecialistico Medicina 2, Azienda Ospedaliero-Universitaria di Parma,
Parma, Italy).