Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE) a double blind phase III study of haemostatic therapy.
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.
British journal of anaesthesia