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Objectives: In a multicentre, randomized-controlled, phase III trial in complex cardiovascular surgery (Randomized Evaluation of Fibrinogen vs Placebo in Complex Cardiovascular Surgery: REPLACE), single-dose human fibrinogen concentrate (FCH) was associated with the transfusion of increased allogeneic blood products (ABPs) versus placebo. Post hoc analyses were performed to identify possible reasons for this result., Methods: We stratified REPLACE results by adherence to the transfusion algorithm, pretreatment fibrinogen level (≤2 g/l vs >2 g/l) and whether patients were among the first 3 treated at their centre., Results: Patients whose treatment was adherent with the transfusion algorithm [FCH, n = 47 (60.3%); placebo, n = 57 (77.0%); P = 0.036] received smaller quantities of ABPs than those with non-adherent treatment (P < 0.001). Among treatment-adherent patients with pretreatment plasma fibrinogen ≤2 g/l, greater reduction in 5-min bleeding mass was seen with FCH versus placebo (median -22.5 g vs -15.5 g; P = 0.071). Considering patients with the above conditions and not among the first 3 treated at their centre (FCH, n = 15; placebo, n = 22), FCH was associated with trends towards reduced transfusion of ABPs (median 2.0 vs 4.0 units; P = 0.573) and greater reduction in 5-min bleeding mass (median -21.0 g vs -9.5 g; P = 0.173). Differences from a preceding single-centre phase II study with positive outcomes included more patients with pretreatment fibrinogen >2 g/l and fewer patients undergoing thoracoabdominal aortic aneurysm repair., Conclusions: None of the patient stratifications provided a clear explanation for the lack of efficacy seen for FCH in the REPLACE trial versus the positive phase II outcomes. However, together, the 3 factors demonstrated trends favouring FCH. Less familiarity with the protocol and procedures and unavoidable differences in the study populations may explain the differences seen between the phase II study and REPLACE., Clinical Trial Registration: NCT01475669 https://clinicaltrials.gov/ct2/show/NCT01475669; EudraCT trial no: 2011-002685-20., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Single-dose human fibrinogen concentrate (FCH) might have haemostatic benefits in complex cardiovascular surgery., Methods: Patients undergoing elective aortic surgery requiring cardiopulmonary bypass were randomly assigned to receive FCH or placebo. Study medication was administered to patients with a 5 min bleeding mass of 60-250 g after separation from bypass and surgical haemostasis. A standardized algorithm for allogeneic blood product transfusion was followed if bleeding continued after study medication., Results: 519 patients from 34 centres were randomized, of whom 152 (29%) met inclusion criteria for study medication. Median (IQR) pretreatment 5 min bleeding mass was 107 (76-138) and 91 (71-112) g in the FCH and placebo groups, respectively (P=0.13). More allogeneic blood product units were administered during the first 24 h after FCH, 5.0 (2.0-11.0), when compared with placebo, 3.0 (0.0-7.0), P=0.026. Fewer patients avoided transfusion in the FCH group (15.4%) compared with placebo (28.4%), P=0.047. The FCH immediately increased plasma fibrinogen concentration and fibrin-based clot strength. Adverse event rates were comparable in each group., Conclusions: Human fibrinogen concentrate was associated with increased allogeneic blood product transfusion, an unexpected finding contrary to previous studies. Human fibrinogen concentrate may not be effective in this setting when administered according to 5-minute bleeding mass. Low bleeding rates and normal-range plasma fibrinogen concentrations before study medication, and variability in adherence to the complex transfusion algorithm, may have contributed to these results., Clinical Trial Registration: ClinicalTrials.gov identifier no. NCT01475669; EudraCT trial no. 2011-002685-20., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)