Comparative Efficacy and Safety of Non-Clotting Factor Prophylaxis Versus. on-Demand Therapy in Hemophilia: A Meta-Analysis of Randomized Controlled Trials

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. We aim for a comparative effectiveness between these agents and traditional therapy with this study. Methods A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. Studies were identified through PubMed, Cochrane Central, and ClinicalTrials.gov up to May 30th, 2025. Eligible studies were double-arm RCTs comparing non-clotting factor prophylaxis (emicizumab, fitusiran, concizumab) and on-demand therapy in patients with hemophilia A or B. Results Non-clotting factor prophylaxis significantly reduced the annualized bleeding rate (ABR) for all treated bleeds [ n = 399, (RR = 0.13; 95% CI: 0.09–0.19), I 2 = 63.8%, p = 0.0107], spontaneous bleeds [RR = 0.08; 95% CI: (0.06, 0.11), I 2 = 0.0%, p = 0.5933)] and joint bleeds [RR = 0.09; 95% CI: (0.06, 0.14), : I 2 = 26.2%, p = 0.2468 ]. Haem-A-QoL total score improved with prophylaxis [MD = −11.08 [−16.34, −5.83], I 2 = 57.5%, p = 0.0949]. Prophylaxis increased the likelihood of achieving zero treated bleeds [RR = 4.11; 95% CI: (1.48%, 11.45%), I 2 = 88.5%, p < 0.0001]. An exploratory network meta-analysis comparing fitusiran, emicizumab, and concizumab reported no statistically significant difference in the ABR for all treated bleeds. 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.