Efficacy and safety of the antithrombin siRNA fitusiran as prophylaxis in haemophilia a and B: A systematic review and meta-analysis

Abstract Introduction: The management of bleeding in individuals with Haemophilia A and B has proven to be challenging. Conventional treatments that involve the infusion of clotting factors are both intensive and cost-prohibitive for many patients. Fitusiran, a novel investigational agent, presents a promising alternative by regulating the coagulation pathway through a different mechanism of action. This systematic review and meta-analysis aim to evaluate the efficacy and safety of fitusiran as a prophylactic treatment in patients with Haemophilia A and B. Methods: A systematic review was conducted under the PRISMA guidelines. An extensive literature search from PubMed, EMBASE, and MEDLINE for randomised controlled trials (RCTs), non-randomised controlled trials, and observational studies to find 6 RCTs having 438 participants on fitusiran for Haemophilia A and B. The primary outcomes included annualised bleeding rate (ABR), annualised joint bleeding rate (AJBR), and annualised spontaneous bleeding rate (ASBR). Secondary outcomes included Haemophilia Quality of Life (Haem-A-QoL) Physical Health Score, Haemophilia Quality of Life (Haem-A-QoL) Total Score and Safety outcomes. Three reviewers independently reviewed the data. The data was analysed using Stata. The effect measure was the pooled mean with corresponding 95% confidence intervals (95% CI) for annualised bleeding rate (ABR) and Haemophilia Quality of Life Index score (Haem-A-QoL) and annualised bleeding rates. Adverse effects rates were pooled using the Freeman-Tukey transformation, with the results being presented as proportions with 95% CI. Results: Six randomised controlled trials assessing fitusiran's effectiveness and safety as a preventive treatment for individuals with Haemophilia A and B were included in this meta-analysis. Fitusiran demonstrated significant efficacy in reducing bleeding episodes across multiple endpoints. The pooled analysis revealed a significant reduction in ABR (mean difference [MD] = -3.45; 95% CI: -4.12 to -2.78; p < 0.0001; I² = 56%), AJBR (MD = -2.19; 95% CI: -3.12 to -2.14; p < 0.0001; I² = 32%), and ASBR (MD = -2.19; 95% CI: -2.71 to -1.68; p < 0.0001; I² = 48%). Improvements in quality of life were also observed, with significant changes in the Haem-A-QoL total score (standardised mean difference [SMD] = -0.65; 95% CI: -0.82 to -0.48; I² = 28%) and physical health domain (SMD = -0.54; 95% CI: -0.70 to -0.38; I² = 21%). With non-significant Egger's test results (p > 0.10), the evaluation of publication bias using funnel plots revealed a symmetrical distribution across all key endpoints. This suggested a low risk of publication bias. Safety outcomes showed no statistically significant increase in adverse events or thromboembolic complications associated with fitusiran use (relative risk [RR] = 1.03; 95% CI: 0.87 to 1.22; p = 0.72). Conclusions: Fitusiran's effectiveness and safety as a preventive treatment for Haemophilia A and B are strongly corroborated by this systematic review and meta-analysis. Fitusiran significantly reduces bleeding rates and improves quality of life without a corresponding increase in adverse events, including thromboembolic complications. These findings underscore the therapeutic potential of fitusiran as a transformative treatment option in haemophilia care and warrant further integration into clinical practice guidelines and long-term safety surveillance.