Efficacy and safety of human fibrinogen concentrate (BT524) in patients with major haemorrhage undergoing major orthopaedic or abdominal surgery (AdFIrst): a randomised, active-controlled, multicentre, partially blinded, phase 3 non-inferiority trial.

Background: Major haemorrhage is associated with considerable morbidity and mortality, but the optimal treatment remains disputed. This trial aimed to compare the efficacy and safety of human fibrinogen concentrate (FC) vs. either fresh frozen plasma (FFP) or cryoprecipitate (Cryo) as first-line treatment in patients with major bleeding during major orthopaedic or abdominal surgery, respectively. Methods: AdFIrst was a randomised, active-controlled, partially blinded, non-inferiority phase 3 trial conducted at 15 hospitals in Europe. Eligible patients (≥18 years), undergoing major spinal surgery or cytoreductive surgery for pseudomyxoma peritonei, with clinically relevant intraoperative blood loss were randomised by an interactive web response system (1:1) to receive intravenous FC (2-4 g) compared to FFP (15 mL/kg body weight) or Cryo (10 units); doses were repeated as needed. The primary endpoint was intraoperative blood loss from the time of decision to treat until the end of surgery with a non-inferiority margin of 150 mL, assessed in the per-protocol analysis set (PPS). Safety was assessed in all patients who received at least one dose of trial drug. The trial is complete (ClinicalTrials.gov: NCT03444324). Findings: Between February 12, 2018, and November 21, 2023, 222 patients (131 [59%] female; 91 [41%] male; 97% white) were enrolled and randomly assigned to receive either FC (n = 110) or FFP/Cryo (n = 112). The PPS included 201 patients (FC: n = 103; FFP/Cryo: n = 98). The primary endpoint was met; the least squares mean (LSM: adjusted mean estimated using ANOVA) intraoperative blood loss was 1381 mL (95% confidence interval [CI] 1187-1574) in the FC group and 1660 mL (95% CI 1461-1860) in the FFP/Cryo group. The LSM difference was -279 mL (95% CI -552 to -6; p < 0·0001), indicating a notable treatment difference beyond non-inferiority. In a post-hoc analysis, FC showed superiority to reduce intraoperative blood loss over FFP/Cryo in the PPS (p = 0·0087). Serious adverse events were reported in 28/110 patients (25%) in the FC and 41/112 patients (37%) in the FFP/Cryo group. Thromboembolic events occurred in 17 patients (FC: 4 (4%) and FFP/Cryo: 13 (12%). There were no treatment-related deaths. Interpretation: In patients undergoing major spinal or cytoreductive surgery for pseudomyxoma peritonei (PMP), FC was non-inferior to FFP/Cryo for the management of clinically relevant intraoperative bleeding. The efficacy and safety advantages observed in this trial support the emerging adoption of first-line use of FC in treatment guidelines. Funding: Biotest AG, Germany.