Short‐term low‐dose secondary prophylaxis for severe/moderate haemophilia A children is beneficial to reduce bleed and improve daily activity,but there are obstacle in its execution: a multi‐centre pilot study in China

We recently showed in a single centre trial that low‐dose secondary prophylaxis in severe/moderate haemophilia patients with arthropathy is feasible and beneficial. However, this regimen has not been validated in a multicentre setting and what obstacles are there to prophylaxis remain unclear. (i) Benefit study: to confirm the benefits of similar prophylaxis protocol in severe/moderate haemophilia A (HA) in a multicentre setting in China. (ii) Follow‐up obstacle study: to investigate obstacles in compliance to prophylaxis treatment. (i) Benefit study: severe/moderate HA children with arthropathy from 15 centres were enrolled to undergo an 8‐week on‐demand treatment, followed by 6 to 12‐week low‐dose secondary prophylaxis. Outcomes compared in the two periods include joint and severe bleeding, daily activities and factor consumption. (ii) Obstacle study: questionnaires to investigators to collect data on patient and centre factors contributing to inability to comply with prophylaxis. We enrolled 191 patients from 15 centres. Sixty‐six (34.6%) from three centres completed the prophylaxis protocol, and they had significantly decreased bleeding (78.8% haemarthrosis and 68.9% severe bleedings) and improved daily activities with no increase in factor consumption over that in the on‐demand therapy period. The remaining 125 patients from 12 centres were not compliant to the prophylaxis protocol; questionnaire data indicated that the major obstacles were inability of patients/parents to accept (41.7%) or to adhere (33.3%) to the prophylaxis protocol, mostly because of failure to understand the benefits and to accept the frequent injections. Non‐availability of a centre comprehensive care team was another important determinant. Short‐term low‐dose secondary prophylactic therapy is beneficial without increasing factors consumption for severe/moderate HA with arthropathy in a multi‐centre setting in China. Obstacles to overcome must include improvement in comprehensive care and in education to patient/parents and healthcare personnel.     

Is on‐demand treatment effective in patients with severe haemophilia?

Summary. On‐demand therapy enables stopping haemorrhages rapidly, reducing joint pain and restoring joint mobility, but does not prevent the beginning and subsequent development of haemophilic arthropathy. The main objective of this study was to identify the clinical and orthopaedic status of severe haemophilic patients with bleeding phenotype receiving on‐demand treatment in Spain. We conducted an epidemiological, observational, retrospective study, recruiting 167 patients from 36 centres (92% of them with haemophilia A), median age at enrolment of 35 years. Forty per cent of the patients received a combination of on‐demand and short‐term prophylaxis regimen; the rest was under on‐demand treatment. One hundred and forty‐five patients (87%) reported at least one bleeding episode and 22 (13%) of the biologically severe patients had no bleeding phenotype. Seventy‐one per cent of the studied population presented established haemophilic arthropathy, reaching 80% if we exclude patients without bleeding phenotype. Forty‐three per cent of these patients had one or two joints affected, 28% of them had three or four affected joints, 20% reported five or six affected joints and 9% more than six injured joints. An increase in established haemophilic arthropathy with age was observed. Forty‐six patients underwent orthopaedic surgery at least once. These data show that on‐demand therapy is not effective in preventing the development of haemophilic arthropathy in severe haemophilic population with bleeding phenotype. Therefore, we suggest that the optimal treatment in these patients should be based on prophylaxis. We recommend analysing the reasons for ending prophylaxis, in case its reinstatement should be necessary.     

Patient‐reported outcomes of 182 adults with severe haemophilia in Germany comparing prophylactic vs. on‐demand replacement therapy

Clotting factor replacement therapy has a major impact on the quality of life in patients with haemophilia. To analyse and compare the outcomes of on‐demand and prophylactic treatment regimens in child‐ and adulthood, a self‐evaluation questionnaire was sent to 182 patients over 30 years of age with severe haemophilia A or B. Analysis of the questionnaire results revealed that most study participants had been treated on‐demand in childhood, but that the majority of these patients subsequently switched to prophylaxis. However, of those patients who began with prophylaxis as children, the vast majority maintained prophylactic treatment as adults. Inhibitor development was reported significantly more frequently by patients who started with on‐demand treatment than by those who started with prophylaxis. In the year prior to completing the questionnaire, adults with severe haemophilia who received prophylactic treatment reported a significantly lower incidence of bleeding as a result of more frequent factor consumption. These results are in close accordance with published prospective data. Although nearly all patients with severe haemophilia had joint pain due to bleeding, those who had always had prophylactic treatment reported superior outcomes in terms of the need for joint replacement, walking speed and distance, participation in school sports and further education. These data clearly underline the superiority of prophylactic treatment for the majority of individuals with severe haemophilia. The worst outcomes were found in those treated on‐demand in childhood who later switched to prophylaxis. In contrast to most studies which have compared treatment regimens on the basis of data from healthcare professionals, this study reflects treatment outcomes from the patient's perspective.     

Prophylaxis for severe haemophilia: clinical and economical issues

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 Pettersson 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.     

Tertiary prophylaxis in adults: is there a rationale?

There is lack of evidence‐based recommendations or clear‐cut consensus regarding the clinical and economic utility of regular prophylaxis started in adulthood, with the aim of keeping the clinical situation from getting worse by prevention of further bleeds contributing to increasing musculo‐skeletal or other morbidity in haemophilia. Such a prophylaxis program has been shown in relatively small cohorts to be effective in reducing bleeding occurrence, with a variable effect on the joint status, but with significantly higher factor consumption and consequently higher costs than on‐demand therapy. There has been no attempt to identify subsets of patients who may benefit from “tertiary” prophylaxis more than others, for example, due to their bleeding phenotype and/or requirements for product issued on‐demand or to identify the dosage that provides the optimal balance of clinical benefit and cost effectiveness. This article reviews the published literature on prophylaxis started beyond the age of 18 years, the barriers to the uptake of prophylaxis programs particularly in adults and highlights areas in need of further research.     

Low dose secondary prophylaxis reduces joint bleeding in severe and moderate haemophilic children: a pilot study in China

Summary. The most common bleeding in haemophilic patients is in joints, and joint disability is the most common complications in these patients receiving inadequate treatment. Limited by economy and inadequate treatment, developing countries face huge challenge to reduce disability and improve quality of life (QoL) of haemophilic children. The aim of this study was to investigate the effect of low dose secondary prophylaxis in China. Children with moderate and severe haemophilia from the Beijing Children Hospital, Beijing, China, and with established joint disease, were followed for a 12‐week observation period followed by a 12‐week low dose secondary prophylaxis‐study period (for haemophilia A, factor VIII concentrate 10 IU kg^?1 twice weekly; for haemophilia B, factor IX concentrate 20 IU kg^?1 weekly). The reduction of joint bleeding, improvement of joint function and QoL during prophylaxis were analysed. In total 34 children (median age 7.8 years) were analyzable. The number of joint bleeds decreased from a total of 337 (individual range 3–24, mean 9.9) during the observation period to 57 (range 0–6, mean 1.7) during the study period with an overall of reduction 83%. Joint function improved in 66.7% of disease joints, with 23.2% of which were considered good to moderate. School attendance improved in all subjects, sports participation and daily activity improved moderately. Low dose secondary prophylaxis significantly reduces frequency of joint bleeding; with moderate improvement in joint function, school attendance, sport participation and daily activities. Low dose secondary prophylaxis is therefore, cost‐effective as applied to developing countries such as China, although there are still unresolved issues.     

Forum on: the role of recombinant factor VIII in children with severe haemophilia A

Summary. The development of recombinant FVIII (rFVIII) products, fuelled by the need for improved safety of treatment arising from the dramatic widespread blood‐borne virus transmission in the 1970–1980s revolutionized the care of children with haemophilia A over the last two decades. The larger availability of perceived safer replacement therapy associated with the introduction of rFVIII products reassured the haemophilia community and there was a strong push in some Western countries to treat haemophilic children only with rFVIII. Moreover, this significantly contributed in the 1990s to the diffusion outside Northern Europe of prophylactic regimens implemented at an early age to prevent bleeding and the resultant joint damage (i.e. primary prophylaxis), together with the possibility of home treatment. These changes led to a substantial improvement of the quality of life of haemophilic children and of their families. The general agreement that primary prophylaxis represents the first‐choice treatment for haemophilic children has been recently supported by two randomized controlled trials carried out with rFVIII products, providing evidence on the efficacy of early prophylaxis over on‐demand treatment in preserving joint health in haemophilic children. However, the intensity and optimal modalities of implementation of prophylaxis in children, in particular with respect to the issue of the venous access, are still debated. A number of studies also supports the role of secondary prophylaxis in children, frequently used in countries in which primary prophylaxis was introduced more recently. With viral safety now less than an issue and with the more widespread use of prophylaxis able to prevent arthropathy, the most challenging complication of replacement therapy for children with haemophilia remains the risk of inhibitor development. Despite conflicting data, there is no evidence that the type of FVIII concentrate significantly influences the complex multifactorial process leading to anti‐FVIII alloantibodies, whereas other treatment‐related factors are likely to increase (early intensive treatments due to surgery or severe bleeds) or reduce (prophylaxis) the risk. Although the optimal regimen is still uncertain, eradication of anti‐FVIII antibodies by immune tolerance induction (ITI), usually with the same product administered at inhibitor detection, should be the first‐choice treatment for all patients with recent onset inhibitors. This issue applies particularly to children, as most patients undergo ITI at an early age, when inhibitors usually appear. The availability of a stable and long‐lasting venous access represents a leading problem also in this setting. These and other topics concerning rFVIII treatment of haemophilic children were discussed in a meeting held in Rome on 27 February 2008 and are summarized in this report.     

Randomized comparison of prophylaxis and on‐demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors

Factor replacement therapy for the treatment of moderate to severe haemophilia A and B can be complicated by the production of inhibitory alloantibodies to factor VIII (FVIII) or factor IX. Treatment with the nanofiltered anti‐inhibitor coagulant complex, Factor Eight Inhibitor Bypassing Activity (FEIBA NF), is a key therapeutic option for controlling acute haemorrhages in patients with high‐titre inhibitors or low‐titre inhibitors refractory to replacement therapy. Given the high risk for morbidity and mortality in haemophilia patients with inhibitors to FVIII or FIX, we conducted this Phase 3 prospective study to evaluate whether prophylaxis with FEIBA NF is a safe and effective treatment option. Over a 1‐year period, 17 subjects were treated prophylactically (85 ± 15 U kg^?1 every other day) while 19 subjects were treated on demand. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 7.9 (8.1), compared to 28.7 (32.3) during on‐demand treatment, which amounts to a 72.5% reduction and a statistically significant difference in ABRs between arms (P = 0.0003). Three (17.6%) subjects (ITT) on prophylaxis experienced no bleeding episodes, whereas none treated on demand were bleeding episode‐free. Total utilization of FEIBA NF for the treatment of bleeding episodes was significantly higher during on‐demand therapy than prophylaxis (P = 0.0067). There were no differences in the rates of related adverse events between arms. This study demonstrates that FEIBA prophylaxis significantly reduces all types of bleeding compared with on‐demand treatment, and the safety of prophylaxis is comparable to that of on‐demand treatment.     

Controlled,cross‐sectional MRI evaluation of joint status in severe haemophilia A patients treated with prophylaxis vs. on demand

In patients with haemophilia A, factor VIII (FVIII) prophylaxis reduces bleeding frequency and joint damage compared with on‐demand therapy. To assess the effect of prophylaxis initiation age, magnetic resonance imaging (MRI) was used to evaluate bone and cartilage damage in patients with severe haemophilia A. In this cross‐sectional, multinational investigation, patients aged 12–35 years were assigned to 1 of 5 groups: primary prophylaxis started at age <2 years (group 1); secondary prophylaxis started at age 2 to <6 years (group 2), 6 to <12 years (group 3), or 12?18 years (group 4); or on‐demand treatment (group 5). Joint status at ankles and knees was assessed using Compatible Additive MRI scoring (maximum and mean ankle; maximum and mean of all 4 joints) and Gilbert scores in the per‐protocol population (n = 118). All prophylaxis groups had better MRI joint scores than the on‐demand group. MRI scores generally increased with current patient age and later start of prophylaxis. Ankles were the most affected joints. In group 1 patients currently aged 27?35 years, the median of maximum ankle scores was 0.0; corresponding values in groups 4 and 5 were 17.0 and 18.0, respectively [medians of mean index joint scores: 0.0 (group 1), 8.1 (group 2) and 13.8 (group 4)]. Gilbert scores revealed outcomes less pronounced than MRI scores. MRI scores identified pathologic joint status with high sensitivity. Prophylaxis groups had lower annualized joint bleeds and MRI scores vs. the on‐demand group. Primary prophylaxis demonstrated protective effects against joint deterioration compared with secondary prophylaxis.     

Resource utilisation in haemophiliacs treated in Europe: Results from the European Study on Socioeconomic Aspects of Haemophilia Care

Summary. The objectives of our study was to answer the following questions: (1) What are the socioeconomic costs and benefits of different haemophilia treatment strategies? (2) Which savings can be achieved through a comprehensive care program? (3) How are haemophiliacs integrated into their social life? (4) What are the annual costs of treating haemophilia from a third party payer perspective? In this cross-sectional study, 840 consecutive haemophiliacs attending 16 haemophiliac treatment centres in 10 European countries at were entered in the study. The following six parameters were analysed: sociodemographic patient data, the type of substitution (on demand or prophylaxis), transfusion-transmitted diseases, the functional joint status, quality of life as well as the total costs of therapy. Three kinds of substitution modalities were distinguished: on demand therapy, pure and modified prophylaxis. The average number of medical visits, the average length of hospital stay, regular drug therapy and the average number of days off work per bleeding joint were recorded from the medical charts as a basis for the subsequent assessment of the costs of therapy. The total study sample comprised of 566 patients. Interestingly, statistically more significant (P= 0.0005) patients were unemployed in the on-demand group (14%) than in the prophylaxis group (3.4%). There was a higher ratio of white collar workers in the on-demand group as compared to the prophylaxis group and vice versa for blue collar workers. The distribution of blue collar workers, clerk, self-employed persons, students and housemen were quite comparable between the patients of the on-demand and prophylactic therapeutic regimen. The labor force participation rate was 55.2% in the patients in the on demand and 59.3% in the patients in the modified prophylactic group. The labor force participation rate across all patients was 56%. Patients on demand therapy used on average 38.3 (median: 12.5) units/kg/week as compared to 68.6 (median: 6) units/kg/ week in the prophylaxis group. The mean usage across all patients was 46.1 (median 19.7) units/kg/week. There were an average of 7.4 (median: 3) joint bleeds per patient across all patients during the 6-month observation period. In the on-demand group 8.8 (median: 5) joint bleeds were recorded versus 3.1 joint bleeds (median: 0) in the prophylactic group. This differences was statistically different (95% CI of difference: 4.33–7.07). Our data suggest that patients receiving prophylactic clotting factor therapy require less additional health care resources, mainly due to the reduction in the number of joint bleeds.     

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B – the impact of prophylactic treatment

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on‐demand‐group, 8% (2/24) children with ICH died and 33% had long‐term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non‐frequent or no prophylaxis.     

Comparing prophylaxis with episodic treatment in haemophilia A: implications for clinical practice

Summary. Recurrent haemarthroses in patients with severe haemophilia A often result in irreversible joint damage. Treatment using routine infusions of factor VIII (FVIII) concentrate, a therapy known as prophylaxis, is currently recommended for the prevention of haemarthroses and arthropathy in persons with severe haemophilia A. However, until recently, the body of evidence supporting prophylaxis in comparison with FVIII infusions given only at the time of haemarthroses was mostly retrospective and anecdotal. Recently, two prospective randomized clinical trials have been conducted to compare prophylaxis with on‐demand FVIII treatment for the prevention of arthropathy and haemarthroses in young children with haemophilia A. A third prospective, non‐randomized trial evaluated a strategy of escalating the dose frequency of prophylaxis. Data from these studies will provide objective evidence for the prevention of haemarthroses and arthropathy in children with severe haemophilia A.     

Prophylaxis for severe hemophilia: experience from Europe and the United States

Since the late 1950s, prophylactic therapy has been used in patients with severe hemophilia in order to convert their phenotype into the phenotype of moderate hemophilia. In the early years, prophylaxis was mostly started after the development of arthropathy. This secondary prophylaxis decreased the number of bleeds but did not halt the development of arthropathy. With the start of primary prophylaxis, however, it was shown that both joint bleeds and arthropathy could be prevented. Although its benefits have been proved, prophylaxis has been used as standard treatment for children in only few countries. There are now favorable results with prophylaxis on bleeding and arthropathy with more than 25 years of follow-up. In general, the strategies used for prophylaxis can be divided into those that are targeted at preinfusion clotting factor levels of > 1% and those that are guided by clinical bleeding patterns of individual patients. In both types of strategies, treatment should be started early, before the start of joint damage. However, clotting factor consumption in the first group of strategies is expected to be higher, whereas bleeding frequencies are expected to be slightly lower. The differences in long-term outcome between both strategies may only become apparent after more than two decades. In addition, some patients may be able to stop taking prophylaxis in adulthood while maintaining a low bleeding frequency. In conclusion, although the optimal prophylactic regimen is still under debate, it is well established that prophylaxis reduces or even prevents joint bleeds and hemophilic arthropathy. Therefore, prophylaxis should be offered to all children with severe hemophilia, at least until adulthood.     

Secondary prophylaxis therapy: what are the benefits,limitations and unknowns?

Summary. Prophylaxis is widely recommended for the management of severe haemophilia A. Adoption of this approach has varied from country to country, and notably in the US prophylaxis is currently administered in fewer than one‐half of severe cases. One implication is that a substantial segment of the severe haemophilia. A population will only be able to reap the potential benefits of prophylaxis if administered in the form of secondary prophylaxis. This therapeutic alternative has been less extensively investigated than primary prophylaxis, but nevertheless sufficient evidence has been reported to allow an assessment of the benefits and limitations of secondary prophylaxis. This evidence addresses the use of secondary prophylaxis in three contexts: (i) early secondary prophylaxis; (ii) delayed secondary prophylaxis and (iii) secondary prophylaxis in adults. In patients receiving early secondary prophylaxis studies in Sweden, the Netherlands, the UK and the US have demonstrated a reduction in the frequency of bleeding episodes and a subsequent low incidence of arthropathy. Additional reported benefits consist of reduced emergency room visits and hospitalizations. However, secondary prophylaxis is associated with an increased risk of the eventual development of arthropathy compared with primary prophylaxis. When delayed until school age or adolescence or until the development of frequent bleeding episodes under on‐demand treatment, secondary prophylaxis generally appears to be unable to reverse all existing or developing joint damage. Nevertheless, multiple studies have shown that this therapy can retard further joint deterioration, reduce the frequency of haemorrhage, hospitalization and missed school days, improve physical function and capacity for self care, lessen restrictions on activities, reduce pain and enhance quality of life. Secondary prophylaxis in adults has been shown effective in reducing bleeding episodes. Adults under secondary prophylaxis can also experience improvements in joint condition, functional capacity and quality of life and a reduction in pain. Irrespective of age at initiation, long‐term secondary prophylaxis appears to reduce the frequency of bleeding episodes even in patients with existing target joints whose bleeding diathesis persists during the early phases of secondary prophylactic therapy. In light of its potential benefits for substantial numbers of patients with severe haemophilia A, secondary prophylaxis should be considered to as a therapeutic option for patients not receiving primary prophylaxis.     

Pattern of bleeding in a large prospective cohort of haemophilia A patients: A three‐year follow‐up of the AHEAD (Advate in HaEmophilia A outcome Database) study

Introduction

Outcome data on treatment of patients with haemophilia A spanning several years of real‐world evidence collection are currently very limited.

Aim and methods

The global prospective long‐term Advate^® Haemophilia A Outcome Database (AHEAD) cohort study collects real‐world data from patients with severe and moderate haemophilia. We report an interim data read‐out after three years of observation.

Results

A total of 522 patients were enrolled from 21 countries: 334 completed year 1 follow‐up, 238 completed year 2 and 136 completed year 3, with an overall follow‐up of 811 patient‐years. Median annual bleeding rates (ABR) were 1.7 in the prophylaxis group and 8.9 in the on‐demand group at year 1 visit, 1.6 and 13.0, respectively, at year 2 visit and 2.2 and 10.3, respectively, at year 3 visit. Moreover, about 42% of patients on prophylaxis vs 12% of patients on on‐demand had zero annual joint bleeding rates (AJBR). Effectiveness of prophylaxis and on‐demand treatment was deemed excellent/good in the majority of cases. Octocog alfa (Advate^®) was well tolerated. The inhibitors that developed in nine patients all disappeared spontaneously. Three patients had been previously exposed to FVIII for ≤50 exposure days (EDs), 3 for >50 EDs and 3 showed a borderline positive inhibitory activity (≤0.6 BU/mL).

Conclusions

These data confirm that the goal of zero bleeds is achievable, although not yet achieved in all patients. Understanding reasons behind the lower response to standard prophylaxis regimens in some patients and personalizing prophylactic treatment may further improve outcome in patients with haemophilia A.     

Clinical outcomes and resource utilization associated with haemophilia care in Europe

We conducted a multicentre, cross- sectional study of 1042 haemophilia subjects across Europe to compare various health outcomes associated with on-demand vs. prophylactic factor-substitution therapy. Demographic, medical history, and healthcare resource utilization data were analysed along with the number of bleeding events over the past 6 months. Treatment-cost data were also examined to provide preliminary information for future economic studies. A logistic regression analysis, controlling for other statistically significant covariates, showed that patients treated on demand were 3.4 times more likely to have had a joint bleed over the previous 6 months than those treated with prophylaxis. Multiple regression analyses further confirmed these findings, because on-demand subjects had, on average, 5.15 more joint bleeds over the reporting period than patients treated with prophylaxis. Notably, these findings were even more dramatic for younger haemophilia patients when our study sample was stratified by age. Due to the high cost of factor replacement, healthcare costs were significantly higher for subjects treated prophylactically. While hospital costs for prophylaxis subjects were, on average, lower, statistically significant cost savings for prophylactic subjects were not noted. These results suggest that clinicians and health policy decision-makers should consider the advantages of prophylactic therapy for haemophilia patients in formulating treatment protocols and allocating health resources.     

Optimizing factor prophylaxis for the haemophilia population: where do we stand?

Summary. The hallmark of severe haemophilia, defined as a circulating level of factor (F) VIII (haemophilia A cases) or FIX (haemophilia B cases) of < 1%, is recurrent bleeding into muscles and joints (haemarthroses) from an early age of life. The inevitable result of such bleeding is progressive joint damage, leading to disabling arthritis that is typically evident within the first 2 decades of life in people with haemophilia who have limited or no access to regular factor replacement therapy, or those in whom factor replacement therapy is ineffective because of the presence of high‐titre inhibitors. For children with severe haemophilia and no evidence of inhibitors, the unwanted musculoskeletal complications of severe haemophilia can be effectively prevented by the early initiation of a programme of long‐term factor prophylaxis. In order to achieve the best outcome (a perfect musculoskeletal status for age) the programme of prophylaxis should be started before the onset of joint damage (primary prophylaxis). The gold standard primary prophylaxis regimen (the Malmö protocol) was pioneered and tested in Sweden and involves the infusion of 20–40 IU of FVIII per kg body weight on alternate days (minimum three times per week) for haemophilia A cases, and 20–40 IU kg^?1 of FIX twice weekly for haemophilia B cases. This protocol is, however, demanding on peripheral veins and very expensive. Modifications of the parent protocol such as starting primary prophylaxis with once‐weekly infusions via peripheral veins with rapid escalation to full‐dose prophylaxis or dose escalation based on frequency of bleeding are increasingly implemented in haemophilia treatment centres in countries that can afford the high cost of such programmes. These modified programmes can be achieved in the majority of young children with severe haemophilia without the need for central venous access devices (e.g. Port‐a‐Caths) and with avoidance of device‐associated complications such as infection and thrombosis. In at least one centre, experience with arteriovenous fistulae as a strategy to ensure reliable venous access is being accumulated. The issues of compliance (adherence) to recommended prophylaxis protocols and when, if ever, to stop a programme of primary prophylaxis once started are real and require ongoing prospective studies. Such studies should incorporate outcome measures such as health‐related quality‐of‐life and economic analyses.     

Prophylaxis with FEIBA in paediatric patients with haemophilia A and inhibitors

The benefits shown with factor VIII (FVIII) prophylaxis relating to joint health and quality of life (QoL) provide the rationale for FEIBA prophylaxis in haemophilia A patients with persistent FVIII inhibitors. FEIBA has previously shown efficacy in preventing bleeds in inhibitor patients who failed to respond to, or were ineligible for immune tolerance induction (ITI). The study examined the outcome of paediatric patients undergoing long‐term FEIBA prophylaxis. A retrospective chart review included severe haemophilia A patients with persistent inhibitors aged ≤13 years at the start of FEIBA prophylaxis. Baseline characteristics captured dose, frequency of prophylaxis, history of inhibitor development, including baseline titre, historical peak titre and history of ITI. Outcome measurements included annual bleed rate before and during FEIBA prophylaxis, joint status and school days missed. Sixteen cases of FEIBA prophylaxis from two centres are presented. The mean age of subjects at prophylaxis initiation was 7.5 ± 3.6 years and median baseline inhibitor titre was 23 (range 3.1–170) BU. Prior to prophylaxis initiation, median annual joint bleeds among all patients was 4 (0–48), which dropped significantly after the first year of prophylaxis, to a median annual joint bleed rate of 1 (0–7; P = 0.0179). Subsequent years (median = 9) of prophylaxis therapy demonstrated similarly low annual joint bleed rates. There were no life‐threatening bleeds, no viral seroconversions or thrombotic events during FEIBA prophylaxis treatment. FEIBA prophylaxis was effective for preventing joint bleeds and subsequent joint damage, delaying arthropathy and improving outcomes in children with haemophilia A and inhibitors to FVIII, who failed or were ineligible for ITI.     

Health‐related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti‐inhibitor complex concentrate: results from the Pro‐FEIBA study

Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health‐related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short‐Form (SF)‐36 Health Survey and the EQ‐5D questionnaire in subjects ≥14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on‐demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on‐demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF‐36 dimensions except for vitality/energy and physical functioning. After prophylaxis, ‘good responders,’ defined as patients experiencing ≥50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role – physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ‐5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on‐demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ‐5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on‐demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on‐demand treatment.     

Secondary prophylaxis treatment versus on‐demand treatment for patients with severe haemophilia A: comparisons of cost and outcomes in Taiwan

Summary. This study compared secondary prophylaxis treatment with on‐demand treatment for severe haemophilia A in Taiwan. Fifty patients from one medical centre were evaluated over a 5‐year period. Differences in annual bleed rates and factor VIII (FVIII) utilization were assessed between patients receiving secondary prophylaxis and patients receiving FVIII concentrates on‐demand. Results were then used as inputs in a pharmacoeconomic model to predict outcomes of future haemophilia therapy strategies in Taiwan. The median annual number of total bleeding episodes was significantly lower in the 13 (26%) patients who received secondary prophylaxis than in the 37 patients who received FVIII on‐demand (7.76 vs. 31.91, P < 0.0001). The between‐group difference in median annual factor VIII utilization was statistically significant (1824.41 IU kg^?1 for the prophylaxis group and 1324.81 IU kg^?1 for the on‐demand group, P < 0.01). It was estimated that approximately $2 million (USD) per year would be added to the cost of treatment by having all severe haemophilia A patients in Taiwan receive secondary prophylaxis instead of on‐demand therapy while 12 566 bleeding will be prevented. It is recommended that National Health Insurance officials utilize these data to evaluate the benefits of enhanced treatment strategies and before making substantial policy changes to haemophilia care in Taiwan.