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.     

Effects of prophylactic treatment regimens in children with severe haemophilia: a comparison of different strategies

Summary.  Both Sweden and the Netherlands have a long experience with primary prophylaxis in children with severe haemophilia. In these countries it has been offered to all children for the last 3–4 decades. In Sweden prophylaxis is generally started at an earlier age with a higher dosage and frequency than in the Netherlands. Patients in the Netherlands receive a more individually tailored regimen, with prophylaxis now started after the first one or two joint bleeds and dosages are increased when breakthrough bleeds occur. The current study evaluated the effect prophylaxis on long-term outcomes and the consumption of clotting factor concentrates in Dutch and Swedish cohorts. Our results show that the orthopaedic outcome in the oldest groups of patients from Sweden and the Dutch cohorts were comparable, although the Swedish patients used twice as much clotting products per year. In the youngest patients, joint status is very good and further follow-up is necessary to demonstrate the benefits of either strategy. In conclusion, more individually tailored regimens aimed at preventing bleeding prevent joint damage in children with severe haemophilia, while clotting factor consumption is about half of that in previously described regimens.     

Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres

Summary. Every other day (qod) factor VIII prophylaxis prevents joint bleeds in children with severe haemophilia A. Although three times weekly or qod prophylaxis is recommended by the National Hemophilia Foundation (NHF), how widely these practices have been adopted is not known. We sought to define current prophylaxis practices at US haemophilia treatment centres (HTCs). An email survey was distributed to US HTCs, utilizing web‐based membership rosters of the Centers for Disease Control (CDC) and the Hemostasis Thrombosis Research Society (HTRS). Of 62 HTCs responding, prophylaxis is initiated on a three times weekly schedule in 29 (46.8%), twice weekly in 13 HTCs (21.0%) and once weekly in 20 HTCs (32.2%). Central venous catheters are used to infuse factor prophylactically at 55 HTCs (88.7%), including in 100% of children initiating prophylaxis at 19 HTCs (30.6%) and in 50% of those at 41 HTCs (66.1%), but avoided altogether at seven HTCs (11.3%). Prophylaxis is initiated after one or more bleeds in 56 HTCs (90.3%), but after the first bleed in only 28 HTCs (25.2%). Among 226 newborns with severe haemophilia A in 62 HTCs, 1.82 births/HTC/year, the median age at first bleed, excluding circumcision, is 7 months. Of the 113 (53.5%) newborns who underwent circumcision, 62 (54.9%) bled. Despite a recommended standard of three times weekly prophylaxis, over half of surveyed HTCs do not follow these guidelines, and nearly one‐third begin prophylaxis on a once weekly schedule to delay or avoid the need for central venous access.     

A global view on prophylaxis: possibilities and consequences

Summary.  Prophylactic infusion therapy, both primary and secondary, has proven of great benefit to patients with haemophilia, specifically those with severe disease or bleeding episodes and patterns that have lead to development of arthropathy. At this time, optimal outcome in patients with severe haemophilia has been proven achievable with primary prophylaxis initiated at an early age in a regimen of three times weekly or every other day for patients with factor VIII deficiency, and twice weekly for those with factor IX deficiency. Despite the demonstrated benefit of primary prophylaxis, this treatment regimen has not been uniformly adopted into clinical practice even in developed countries. In developing countries, where issues of allocation of precious health care resources are of paramount importance, access to adequate treatment for persons with haemophilia on a programme of on-demand therapy is not commonly available; the cost of primary prophylaxis, even with intermediate purity plasma-derived factor concentrates or plasma fractions such as cryoprecipitate, renders this treatment the exception rather than the rule.     

Orthopaedic evaluation in children with severe haemophilia A or B submitted to primary prophylaxis therapy in a coagulopathy treatment centre

Summary. There is a lack of publications concerning the use of primary prophylaxis in developing countries. The aim of this study was to evaluate the effectiveness of primary prophylaxis therapy in preventing the development of arthropathy in children with severe haemophilia A or B. From January 1999 to April 2009, a prospective study was carried out involving 39 patients with severe haemophilia A or B. These haemophilia A and haemophilia B patients received 20–40 UI kg^?1 of factors VIII and IX, three and two times per week, respectively. The patients were followed up by a multidisciplinary team. The analysis was carried out in 23 patients who had been on prophylaxis therapy for at least 12 months. The orthopaedic evaluation was performed according to the recommendations of the Orthopedic Advisory Committee of the World Federation of Hemophilia, by evaluating pain and bleeding, and by conducting physical examination and radiological assessment (Pettersson’s Joint Score and magnetic resonance): 82.6% of patients who had used the factor regularly did not present any clinical or radiographic changes in the studied joints; 17.4% used the factor irregularly at the beginning of the treatment and of those, most patients presented mild changes in the joints; and 4.3% presented transient knee and ankle pain in spite of regular factor use. The preliminary results of primary prophylaxis confirm its effectiveness in preventing haemophilic arthropathy. Socioeconomic factors did not play a significant role.     

Adherence to prophylaxis and quality of life in children and adolescents with severe haemophilia A

Treatment adherence in adolescents with chronic diseases is around 50%, and failure is more common in preventive therapy. In haemophilia, contradictory results are reported by the published studies. The objective of this study was to evaluate adherence with factor VIII (FVIII) prophylaxis in Spanish patients with severe haemophilia A between age 6 and 20 years. Data were collected retrosp‐ectively in the previous 2 years. The primary endpoint was the absolute adherence index (AAI), and the endpoints were related to clinical status, age, prophylaxis regimen, responsibility for factor administration and quality of life (QoL), assessed by the Haemo‐QoL questionnaires. A total of 78 patients from 14 Spanish hospitals were recruited. Adherence ranged between ?64.4 and 66.7 (mean ?3.08). No differences were observed between children and adolescents (7.11 vs. 6.39; P = 0.809). A statistically significant association (P < 0.010) between infra adherent group and target joint was found, as was a statistically significant difference (P < 0.010) between the number of bleeding episodes experienced by the adherent group (mean 1.4) and by infra adherents (mean 4.5). There was no significant difference between AAI and prophylactic regimen (6.35 vs. 6.96, P = 0.848), neither between AAI and the person responsible for factor administration (5.57 vs. 8.79, P = 0.326). The Haemo‐QoL scores (8–12 years) were related to adherence level (P < 0.05). Adherence was approximately ideal and patients perceived a high QoL. Because of the repercussions for compliance, it is essential to work during puberty on emotional and self‐acceptance aspects of the disease, as well as coping, and the patient's family, school and health team relationships.     

Progression of haemophilic arthropathy in children: a Lithuanian – Danish comparative study

Recurrent bleeding into joints initiates a sequence of events leading to a progressive joint damage in people with severe haemophilia. This is a continuous process during childhood and adolescence, therefore joint abnormalities may be minimal on physical examination in very young children – even those receiving on‐demand treatment. The aim of our study was to quantify the burden of arthropathy in Lithuanian patients who had been treated exclusively by on‐demand substitution and compare their physical joint health with age‐matched Danish patients who received prophylaxis from an early age. Boys, aged 4–17 years, with severe haemophilia and no signs of inhibitors were included in the study. Joint outcome based on the Haemophilia Joint Health Score (HJHS) was analysed in two different treatment groups and compared within the matched pairs. In total, 32 (16 in each treatment group) patients were enroled. A total of 192 joints were evaluated. Joint status according to treatment strategy was strikingly different: 27.4 for on‐demand vs. 3.3 for prophylaxis (<0.001) group. Significance of the difference in joint status comparing different treatment strategies was equally strong both in younger (4–9 years) and older (10–17 years) patient groups: 2.2 vs. 12.5 (P = 0.0002) and 3.9 vs. 36.3 (P < 0.0001) respectively. The results further demonstrate the unequivocal effect of prophylaxis on joint status and give an insight into early and late manifestations of joint impairment based on the HJHS in haemophilia patients with treatment on‐demand compared with joint changes that may develop over the time with the preventative treatment.     

Feasibility of prophylaxis and immune tolerance induction regimens in haemophilic children using fully implantable central venous catheters

Venous access represents the major barrier to the feasibility of prophylaxis and immune tolerance induction (ITI) in haemophilic children. Ports improve treatment feasibility, but their duration is limited by infectious complications. This study aimed at evaluating whether or not ports allow haemophilic children to maintain the treatment regimen in the long term. Children were prospectively followed-up and underwent port removal either for complications or transition to peripheral veins. Of 27 ports (17 used for prophylaxis and 10 for ITI), 25 were removed after a median of 3.3 years. Inhibitor children showed a younger age at port insertion (P = 0.02), an earlier occurrence of infections (P = 0.006) at a higher rate (P = 0.00001) and an earlier removal for infection (P = 0.05) than non-inhibitor patients. Daily port use was associated with earlier infections at a higher rate compared to less frequent use (P = 0.02). Port removal after a median of 0.8 years prevented ITI completion in 50% of children, while it hampered the maintenance of prophylaxis in 27% of patients. This study showed that ports improved the feasibility of prophylaxis in the majority of non-inhibitor children, while they were not suitable for inhibitor children who require a prolonged ITI regimen with daily infusions.     

Daily dosing prophylaxis for haemophilia: a randomized crossover pilot study evaluating feasibility and efficacy

Regular replacement therapy (prophylaxis) for haemophilia has been shown to prevent development of disabling arthropathy and to provide a better quality of life compared to treatment on demand; however, at a substantially higher cost. Calculations based on pharmacokinetic principles have shown that shortening dose intervals may reduce cost. The aim of this prospective, randomized, crossover pilot study was to address whether daily dosing is feasible, if it reduces concentrate consumption and is as effective in preventing bleeding as the standard prophylactic dosing regimen. In a 12 + 12 month crossover study, 13 patients were randomized to start either their own previously prescribed standard dose, or daily dosing adjusted to maintain at least the same trough levels as obtained with the standard dose. Ten patients completed the study. A 30% reduction in cost of factor concentrates was achieved with daily prophylaxis. However, the number of bleeding events increased in some patients in the daily dosing arm and patients reported decreased quality of life during daily prophylaxis. Daily treatment had a greater impact on daily life, and the patients found it more stressful.Prophylaxis with daily dosing may be feasible and efficacious in some patients. A substantial reduction of factor consumption and costs can be realized, but larger studies are needed before the introduction of daily prophylaxis into clinical routine can be recommended.     

不同剂量甲强龙治疗小儿重症支原体肺炎临床研究

目的对比静脉使用不同剂量甲强龙对小儿重症支原体肺炎的疗效,探讨更佳的治疗方案。方法将46例重症支原体肺炎患儿随机分为冲击剂量组及常规剂量组。除常规治疗外,冲击剂量组静脉给予甲强龙15~30 mg/(kg·d),常规剂量组静脉给予甲强龙1~2mg/(kg·d),均连续用3 d后改强的松口服。结果冲击剂量组和常规剂量组总有效率分别为95.7%和73.9%,统计学差异显著(P0.05)。冲击剂量组在发热、咳嗽、肺部体征改善时间及胸部X线片恢复时间上明显低于对照组(P0.05)。结论治疗小儿重症支原体肺炎时,冲击剂量甲强龙疗效优于常规剂量。     

Considerations in the evaluation of haemophilia patients for short-term prophylactic therapy: a paediatric and adult case study

The long-term prophylactic administration of clotting factor concentrate in patients with haemophilia reduces bleeding events, slows joint deterioration, and improves quality of life. Prophylaxis can also be effective when used short-term to prevent or reduce bleeding associated with trauma, surgery, and athletic activities. While clinical trials are needed to establish the optimal length of prophylaxis following injury, several weeks and possibly months of treatment may be needed. Discontinuing therapy prematurely can result in rebleeding in the injured area.     

Effects of secondary prophylaxis started in adolescent and adult haemophiliacs

Summary. While primary prophylaxis is a well‐established and recommended method of care delivery for children with severe haemophilia, fewer studies have documented the benefits of secondary prophylaxis started in adolescence or adulthood. To evaluate the role of secondary prophylaxis started in adolescent and adult severe haemophiliacs, a retrospective observational cohort study was conducted in 10 Italian Centres that investigated 84 haemophiliacs who had bled frequently and had thus switched from on‐demand to prophylactic treatment during adolescence (n = 30) or adulthood (n = 54). The consumption of clotting factor concentrates, the orthopaedic and radiological scores, quality of life and disease‐related morbidity were compared before and after starting secondary prophylaxis. Prophylaxis reduced the mean annual number of total and joint bleeds (35.8 vs. 4.2 and 32.4 vs. 3.3; P < 0.01) and of days lost from work/school (34.6 vs. 3.0, P < 0.01). A statistically significant reduction in the orthopaedic score was observed during prophylaxis in adolescents, but not in the whole cohort. Patients used more factor concentrates with corresponding higher costs on prophylaxis, but experienced a better quality of life. With respect to on‐demand treatment, higher factor consumption and cost of secondary prophylaxis were balanced by marked clinical benefits and greater well‐being in this cohort of adolescent/adult haemophiliacs.     

Assessing the effectiveness and cost-effectiveness of prophylaxis against bleeding in patients with severe haemophilia and severe von Willebrand's disease

Abstract . Miners AH, Sabin CA, Tolley KH, Lee CA (Royal Free Hospital School of Medicine, London; University Hospital Queen's Medical Centre, Nottingham; and Royal Free Hampstead NHS Trust, London, UK). Assessing the effectiveness and cost-effectiveness of prophylaxis against bleeding in patients with severe haemophilia and severe von Willebrand's disease. J Intern Med 1998; 244 : 515–22. Objectives To assess the effectiveness and cost-effectiveness of prophylaxis with clotting factor against bleeding in patients with severe haemophilia and von Willebrand's disease (vWD). Design Treatment details that related to 179 patients with severe (< 1 u dL^?1) haemophilia A, B and vWD were retrospectively examined for the period 1980–95. A subgroup of these patients, 25 adults and 22 children, who had previously received treatment on demand and who had switched to treating with prophylaxis, were studied in order to examine the effects of the change. The cost-effectiveness of prophylaxis was also analysed using another subgroup of 38 patients and by adjusting their treatment details by age and method of treatment. Setting Data were obtained on patients who were solely registered at the Royal Free Hospital Haemophilia Centre (RFHHC), London, UK. Outcome measure Bleeds. Results The median annual number of bleeds decreased from 23.5 (range 1–107) in 1980, to 14 (range 0–45) in 1995 (P < 0.0001). Switching from treating on demand to prophylaxis reduced bleeding frequency in 41 out of 47 patients within the period of 1 year. At the base scenario, switching to prophylaxis cost an additional £547 per averted bleed; however, this figure was highly sensitive to certain variables. Conclusion Prophylaxis can reduce bleeding frequency but requires more clotting factor than treatment on demand. More detailed proof of cost-effectiveness is likely to require the use of modelling techniques.