Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy

Abstract

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.

Keywords: blood, coagulation; fibrinogen; haemorrhage; surgery, cardiovascular.

Fig 1

Patient disposition. CTA, completer of transfusion algorithm (i.e. patients in whom the standardized treatment algorithm was adhered to); FCH, human fibrinogen concentrate; ITT, intention to treat.

Fig 2

First and second bleeding mass (median, interquartile range and range; a) and the timings of these assessments [mean (sd); b]. BM, bleeding mass; CPB, cardiopulmonary bypass; FCH, human fibrinogen concentrate.

Fig 3

Transfusion of allogeneic blood products within 24 h of administering study medication. (a) Median, interquartile range and range. (b) Variability by pooled centre. *Austria, Denmark, Finland, Germany, Italy, and Poland. FCH, human fibrinogen concentrate.

Fig 4

Changes through time in plasma fibrinogen concentration (measured by the Clauss assay; a) and FIBTEM MCF (b). Error bars represent interquartile ranges. CPB, cardiopulmonary bypass; FCH, human fibrinogen concentrate; MCF, maximum clot firmness.