Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously untreated or minimally treated children with hemophilia A or B.

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.