Key messages
– Bleed prevention using clotting factor therapies, compared with treatment for bleeds as they occurred ('as needed'), may reduce annual joint and overall bleeding rates in previously untreated or minimally treated children without joint damage.
– In children with hemophilia who have not received treatment, there is likely no evidence of a difference between the groups in joint damage. They may not improve quality of life compared with treatment as needed, but we are very uncertain about the results.
– Children receiving clotting factor therapies for bleed prevention may have more monthly infusions compared with those receiving treatment as needed, but the evidence is very uncertain. There may be no difference in unwanted effects, such as the development of antibodies that reduce the effect of treatment or infections, between the two groups.
What is hemophilia?
Hemophilia A and B are genetic bleeding disorders in which bleeding into the joints between bones is a major problem. Repeated bleeds can lead to damage in these joints, commonly referred to as 'target joints', causing pain and limiting movement.
How is hemophilia treated?
Currently, bleeding is treated and prevented using clotting factor therapies (medicines), which help the blood to clot. These therapies can be derived from donated blood or created in a laboratory. Recently, new types of treatments that do not use clotting factors have also become available.
What did we want to find out?
We wanted to know whether children who have not been treated for joint bleeding should receive regular treatment with clotting factor therapies to help prevent joint bleeding, joint damage, and improve overall well-being.
What did we do?
We searched for studies that used regular clotting factor therapies or treatment for bleeds as they occurred ('as needed') to prevent bleeding in children up to 10 years of age with hemophilia with no joint damage. We summarized the results of the studies and assessed our confidence in the findings based on study quality and the number of children.
What did we find?
We found three studies with 126 children with severe hemophilia A. The largest study included 65 children, while the smallest study included 21 children. The studies were conducted in three countries: Italy, India, and the USA. One study lasted for 11.5 months, one study lasted for nine years, and one study lasted for 10 years.
Main results
Compared with treatment as needed, bleed prevention with regular clotting factors may reduce the number of joint bleeding episodes in one year and the number of bleeds overall in one year (3 studies, 125 children). There is likely no difference between the groups in joint damage (2 studies, 95 children). Clotting factors may not improve quality of life compared with treatment as needed, but the evidence is very uncertain (2 studies, 105 children). There is likely no difference in joint score assessed by x-ray compared with treatment as needed (2 studies, 61 children). Bleed prevention with regular clotting factors may increase the total number of clotting factor infusions used per child compared with treatment as needed, but the evidence is very uncertain (2 studies, 86 children). There may be no difference in the development of antibodies that reduce the effect of treatment between the two groups (2 studies, 105 children).
What are the limitations of the evidence?
We have moderate to very low confidence in the evidence because the children knew the treatment they were receiving, which could have affected the results. In addition, some of the studies included children who already had joint damage, and the results were not separated from those of children with no joint damage. Even if clinical studies comparing bleed prevention using clotting factor therapies with treatment as needed are no longer ethical, more well-designed studies would be useful to quantify the true effects of clotting factor therapies, and newer therapies (that do not include clotting factors), in preventing joint and overall bleeding in children with hemophilia.
How up to date is this evidence?
The evidence is up to date to 20 November 2024.
Читать полную аннотацию (абстракт)
The hallmark of severe hemophilia is recurrent bleeding into joints and soft tissues with progressive joint damage. The effect of early adoption of prophylactic regimens in children with severe hemophilia, although a promising approach for preventing joint damage, is yet to be systematically reviewed. This review is an update of a previous review, which has now been split to focus on children before the onset of progressive joint damage.
Задачи
To assess the benefits and harms of clotting factor concentrate prophylaxis in the management of previously untreated or minimally treated children with hemophilia A or B with no proven joint damage.
Методы поиска
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, CENTRAL, MEDLINE, Embase, trial registries, and handsearched relevant journals and reference lists of relevant articles.
The last search for the Group's Coagulopathies Trials Register was 20 November 2024.
Критерии отбора
We included randomized controlled trials and quasi-randomized controlled trials evaluating prophylactic use of factor concentrates in children with severe hemophilia A or hemophilia B not yet exposed or minimally exposed to clotting factor concentrates with no proven joint damage. Trials were eligible if they included children aged from birth to six years, and children aged over six years to 10 years if they had not received factor VIII/factor IX or showed no clinical or radiologic signs of arthropathy or target joints.
Сбор и анализ данных
Two review authors independently assessed studies for eligibility, assessed risk of bias, and extracted data. The primary outcomes were annualized joint bleeding rates, joint function protection, and quality of life. The secondary outcomes included annualized overall bleeding rates, radiologic joint score, clotting factor usage, and adverse events. We used the Cochrane RoB 1 tool and a random-effects model in the meta-analyses, and assessed the certainty of the evidence using GRADE.
Основные результаты
We included three studies with 126 assessed children with hemophilia A. The mean age at study entry ranged from 1.6 years to 7.9 years. Each study compared a clotting factor prophylaxis regimen with episodic treatment. No studies compared clotting factor concentrates with placebo or alternative prophylactic regimens.
Clotting factor prophylaxis regimen compared to episodic treatment
For the primary outcome of annualized joint bleeding rates, clotting factor prophylaxis may reduce joint bleeds compared to episodic treatment (mean difference (MD) −4.22, 95% confidence interval (CI) −5.26 to −3.17; 3 trials, 126 participants; low-certainty evidence).
Pooled analysis including two trials during four to seven years of follow-up showed 85.7% of children not having joint damage in the prophylaxis group compared to 58.7% of children in the episodic group. Prophylaxis may not reduce the number of participants with joint damage compared to the episodic group (RR 1.70, 95% CI 0.57 to 5.09; P = 0.34; 2 trials, 95 participants; low-certainty evidence).
Bleed prevention using clotting factor concentrates may not improve quality of life compared to episodic treatment measured using the Haemophilia Quality of Life (Haemo-QoL) over two to 163 months, but the evidence is very uncertain (MD 1.61, 95% CI −4.44 to 7.66; 2 trials, 105 participants; very low-certainty evidence).
For the secondary outcome of annualized overall bleeding events, pooled effect estimates showed that the use of a clotting factor prophylaxis regimen may reduce the number of bleeds per year compared to episodic treatment (MD −9.55, 95% CI −14.92 to −4.17; 3 trials, 126 participants; low-certainty evidence).
There is likely no evidence of a difference between the groups in radiologic joint score measured using the Pettersson scale over a two- to 163-month period (MD −0.48, 95% CI −1.43 to 0.47; 2 trials, 61 participants; moderate-certainty evidence).
Clotting factor prophylaxis may increase the number of infusions per child compared to episodic treatment, but the evidence is very uncertain (MD 7.72 infusions/month, 95% CI 4.36 to 11.07; 2 trials, 86 participants; very low-certainty evidence).
There may be no difference in adverse events, including the development of inhibitors and infections, as well as hospitalizations between groups.
The overarching certainty of the evidence was moderate to very low due to inherent biases, resulting from lack of blinding of study participants, attrition, heterogeneity, and indirectness of population characteristics, which may change our conclusions.
Выводы авторов
There is evidence from randomized controlled trials that prophylaxis confers some protection against joint bleeds and overall bleeds. More conclusive evidence from well-designed studies is needed on the effect of bleed prevention using clotting factors and newer therapies on joint function protection in children with no signs of an onset of joint damage.
