Review question
Should people, who have previously been treated for joint bleeding, be given regular preventative treatment with clotting factor concentrates to manage their condition?
Background
Hemophilia A and B are X-linked inherited bleeding disorders in which bleeding into joints is a major problem. Repeated joint bleeds can lead to affected joints (commonly referred to as 'target joints') becoming damaged and painful, with limited movement. Currently, bleeding is treated and prevented with plasma-derived or recombinant clotting factor concentrates, and more recently non-clotting factor formulations. This review looked at how useful and effective different clotting factor treatment strategies are for preventing joint bleeding and other outcomes in previously treated people with hemophilia A or B.
Search date
Date of last search: 24 February 2021.
Study characteristics
This review includes 10 randomised controlled trials. Eight had treatment arms that compared the regular use of clotting factor concentrates to prevent joint bleeds with different dosing schemes to identify regimens that may be better; four had treatment arms that compared the regular use of factor concentrates to prevent bleeds to their 'on demand' use to treat bleeds once they occur (two trials had multiple arms and were included in both comparisons).
Key results
In people living with hemophilia A or B previously treated for joint bleeding or with existing joint damage, preventive therapy may reduce the number of joint bleeds compared to 'on-demand therapy'. This reduction in bleeds may lead to an improvement in joint function, pain, and quality of life. However, preventive therapy is linked to an increased use of factor concentrates and therefore higher treatment costs. Further studies are needed to establish the best preventive course of treatment in terms of starting time, frequency and dose level.
Certainty of the evidence
Overall, the certainty of the evidence was judged to be low because of different types of bias that could have affected the results. Future research might have an important role in changing our confidence in these results.
There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI.
When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons.
Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.
The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies.
To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries.
Most recent search of Group's Coagulopathies Trials Register: 24 February 2021.
Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia.
Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence.
Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons).
Comparison of two or more prophylactic regimens
For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence).
Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence).
Comparison of prophylactic and on-demand regimens
Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI).
In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence).
Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified.
Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect.