Comparison of Drugs Used for Prophylaxis in Hemophilia a or B with Inhibitors: A Systematic Review and Frequentist Network Meta-Analysis of Randomized Clinical Trials
Authors: Ali Muhammad Ashar , Aiman Wajeeha , Bajwa Shammas , Anwer Faiz 
Published: December 2024

Background:
Frequent infusions with hemostatic agents in hemophilia patients can lead to the formation of anti-drug antibodies that can bind with clotting factors and inhibit their function. Inhibitor formation leads to worsening of hemophilia symptoms and is difficult to treat with clotting factor concentrates and is categorized as hemophilia with inhibitors. This network meta-analysis (NMA) aims to assess the efficacy of different prophylactic drugs for hemophilia A and B with inhibitors and provide a comparison among these drugs.
Methods:
Cochrane and PRISMA guidelines were followed to conduct this NMA. A comprehensive literature search was performed in PubMed and Embase with keywords for “hemophilia” AND “drug therapy” from the inception of data till April 2024. We screened a total of 1052 articles and 6 randomized clinical trials (RCTs, N=457) were included in this NMA.The estimation of parameters across different models was accomplished using the graph theoretical approach, which entails constructing a Moore-Penrose pseudoinverse matrix with the Netmeta package in R (version 4.3.1). NMA was registered on PROSPERO CRD42024532136.
Results:
In 6 RCTs (N=457), 38 patients were treated with fitusiran prophylaxis, 114 patients with concizumab prophylaxis, 147 patients with emicizumab prophylaxis, 17 patients with FEIBA NF prophylaxis, 26 patients with AICC prophylaxis, and 115 patients were only treated on demand without prophylaxis. Patients' ages ranged from 7 to 75 years. 389 (85%) patients had hemophilia A while 68 (15%) patients had hemophilia B. Emicizumab was only used in prophylaxis of patients with hemophilia A with inhibitors.
The ratios of means treated annualized rate of bleeding (ARB) ranged from 0.09 (95% CI= 0.05 to 0.16, emicizumab) to 0.38 (95% CI=0.26 to 0.56, anti-inhibitor complex concentrate, AICC) for prophylaxis as compared to on-demand treatment. Emicizumab and fitusiran were significantly better than AICC prophylaxis for the ratio of mean ARB (4.22 [2.16 to 8.25] and 4.06 [1.75 to 9.45], respectively).
The ratio of mean joint ARB ranged from 0.06 (95% CI= 0.03 to 0.15, emicizumab) to 0.39 (95% CI=0.25 to 0.59, AICC) for prophylaxis as compared to on-demand treatment. Emicizumab and fitusiran were significantly better than AICC prophylaxis for the ratio of mean ARB (6.41 [2.40 to 17.12] and 4.13 [1.65 to 10.33], respectively). Emicizumab and fitusiran were also significantly better than FEIBA-NF (4.3 [1.56 to 12.5] and 2.78 [1.07 to 7.20], respectively).
The odds ratio of zero bleeding events ranged from 34.62 (95% CI= 4.15 to 289, fitusiran) to 7.93 (95% CI= 0.37 to 171). The odds of achieving zero bleeding events were significantly better with fitusiran, emicizumab, and concizumab as compared to on-demand treatment.
Conclusion:
Emicizumab, concizumab, and fitusiran were effective as prophylactic agents and were significantly better than on-demand treatment in patients with hemophilia with inhibitors. Emicizumab and fitusiran had higher efficacy as compared to other prophylactic agents in hemophilia. More large-scale randomized head-to-head comparisons are needed to confirm these results.