Efficacy, quality of life, and safety of non-clotting factor prophylaxis in Hemophilia A and b: A meta-analysis across inhibitor status

Abstract

Abstract Introduction: Hemophilia A and B are among the most common inherited bleeding disorders in humans with lifelong risk of spontaneous and recurrent bleeding. While prophylaxis with clotting factors has improved outcomes, challenges like inhibitor development and treatment burden persist. In this study, we aim to synthesize randomized evidence to support the superiority of non-clotting factor prophylactic therapy over on-demand therapy in hemophilia patients regardless of inhibitor status. In addition, the study also explores for differences across individual non-factor agents to inform clinical decision-making. Methods: Following the PRISMA guidelines, we systematically searched CENTRAL (Cochrane Central Register of Controlled Trials), PubMed, and ClinicalTrials.gov for studies published up to May 30th, 2025, using keywords and MeSH terms related to ‘hemophilia A and B’, ‘non-clotting factor prophylaxis’, and ‘on-demand therapy’. Eligible studies included double-arm randomized controlled trials (RCTs) comparing non-clotting factor prophylaxis (emicizumab, fitusiran, or concizumab) with on-demand treatment in patients with hemophilia A or B, regardless of inhibitor status. Data on annualized bleeding rate (ABR), spontaneous and joint bleeds, patient-reported outcomes (Haem-A-QoL), bleeding burden thresholds (≤3 treated bleeds), and adverse events were extracted. The risk of bias was assessed using the Cochrane Risk of Bias 2.0 (RoB 2.0) tool. Meta-analyses were conducted in RStudio (v5.4.1) using a random-effects model, and results were reported as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CIs). Results: The review includes 7 randomized controlled trials involving 531 patients with congenital hemophilia (A/B) and 3 therapeutic regimens, including Emicizumab, Concizumab and Fitusiran. The age of the patients ranged from 12-75 years old. Participants in the included studies had congenital hemophilia A or B, with or without the presence of factor VIII or IX inhibitors. The number of White patients was (n = 137/336, 40.8%) across 4 studies, while Asian patients were (n = 157/336 , 46.7%) across the same studies. Hispanic or Latino patients were (n = 7/183, 3.8%) and Non-Hispanic/Latino patients were (n = 169/183, 92.3%), both reported in 2 studies. The number of bleeding events in the past 6 months before screening ranged from 7 to 25, as reported in three studies. Non-clotting factor prophylaxis significantly reduced the annualized bleeding rate (ABR) for all treated bleeds (RR = 0.14; 95% CI: 0.09–0.20; I² = 61.2%, p = 0.0117, n = 531), spontaneous bleeds (RR = 0.10; 95% CI: 0.06–0.17; I² = 59.3%, p = 0.0310, n = 468) and joint bleeds (RR = 0.12; 95% CI: 0.06–0.22; I² = 67.6%, p = 0.0086, n = 468). Haem-A-QoL total score improved with prophylaxis (MD = –9.07; 95% CI: –13.70 to –4.44; I² = 71.3%, p = 0.0151, n = 362). Prophylaxis increased the likelihood of achieving zero treated bleeds (RR = 3.94; 95% CI: 1.66–9.34; I² = 90.4%, p < 0.0001, n = 531) and of having ≤3 treated bleeds (RR = 5.83; 95% CI: 2.07–16.41; I² = 89.2%, p < 0.0001, n = 306). There was no statistically significant difference seen in the risk of any treatment-emergent adverse events (RR = 1.81; 95% CI: 1.39–2.38; I² = 0%, p = 0.5577, n = 415) or serious adverse events (RR = 0.96; 95% CI: 0.48–1.92; I² = 0%, p = 0.5154, n = 415). A network meta-analysis comparing fitusiran, emicizumab, and concizumab reported superiority over on-demand therapy but no statistically significant difference over each other in the primary outcomes with a p-value greater than 0.05 (ABR for all treated bleeds and Haem-A-QoL total score). However, the estimated annual treatment costs varied, with emicizumab ($564,000–$669,000/year) and fitusiran ($642,000/year) priced comparably; cost data for concizumab remains pending. Conclusion: Compared to on-demand therapy, non-factor prophylactic therapies significantly reduce bleeding episodes, improve quality of life, and increase the likelihood of zero bleeds in patients with hemophilia. Although associated with a higher rate of adverse events, the therapies themselves did not increase the risk of serious adverse events. While efficacy outcomes were similar across agents, cost differences may influence treatment selection.These findings support the clinical utilization of non-factor prophylaxis in managing hemophilia A and B, regardless of inhibitor status.