Abstract
Introduction: Hereditary Angioedema (HAE) is a rare genetic disorder characterized by recurrent and potentially life-threatening episodes of swelling, necessitating effective prophylactic treatments to prevent attacks and improve patient outcomes. This network meta-analysis aims to compare the efficacy and safety of FDA-approved prophylactic therapies for HAE, including the recently approved garadacimab (July 2025), Haegarda, Lanadelumab, and Berotralstat.
Methods: A systematic search was conducted across five databases to identify relevant RCTs, with study screening performed using Covidence. Network meta-analysis was carried out using the Netmeta package in R, and visualizations, including forest plots, were generated using Stata 18.0. The quality and risk of bias of the included studies were assessed using the ROB 2.0 tool.
Result: A total of 1,749 records were screened, with 15 studies meeting the inclusion criteria, involving 1,128 patients (720 in the treatment group and 543 in the control group). The patient distribution included 148 in the Berotralstat group, 335 in the Haegarda group, 79 in the Garadacimab group, and 158 in the Lanadelumab group. Garadacimab demonstrated the greatest risk reduction in HAE episodes (RR 0.783, 95% CI [0.459; 1.21]), followed by Haegarda (RR 0.857, 95% CI [0.621; 1.12]), Lanadelumab (RR 0.930, 95% CI [0.563; 1.40]), and Berotralstat (RR 1.06, 95% CI [0.736; 1.57]). The SUCRA ranking confirmed Garadacimab as the most effective treatment, followed by Haegarda, Lanadelumab, and Berotralstat as the least effective. In terms of attack characteristics, the overall time taken for the first attack was 127.4 ± 86 days in the treatment group compared to 38 ± 45.6 days in the control group. The duration of an HAE attack was 3.06 ± 1.97 hours in the treatment group, compared to 7.38 ± 4.6 hours in the control group. The total number of days free from HAE was 151 ± 173 in the treatment group versus 63 ± 71 in the control group. The safety profile of the treatments was assessed with the following results: Injection site reactions (RR -0.11, 95% CI [-0.72; 0.50]), gastrointestinal adverse events (RR 0.25, 95% CI [-0.25; 0.75]), and neurological adverse events (RR -0.64, 95% CI [-0.64; -0.01]). Additionally, the overall quality of life, as assessed by the AE-QOL questionnaire, improved by -5.5 ± 14.6 in the treatment group.
Conclusion: This network meta-analysis offers a detailed comparison of the efficacy and safety profiles of FDA-approved prophylactic treatments for HAE. Garadacimab emerged as the most effective treatment, followed by Haegarda, Lanadelumab, and Berotralstat. These findings emphasize the importance of evaluating both efficacy and safety when selecting the optimal treatment for HAE patients, with significant improvements in quality of life observed in the treatment group. The risk of bias in the included studies was low, strengthening the reliability of the findings.
