Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of haemostatic therapy.
Single-dose human fibrinogen concentrate (FCH) might have haemostatic benefits in complex cardiovascular surgery.



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.



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.



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.



ClinicalTrials.gov identifier no. NCT01475669; EudraCT trial no. 2011-002685-20.
Clinic for Anesthesiology and Intensive Care Medicine, Franziskus Hospital, Kiskerstraße 26, D-33615 Bielefeld, Germany niels.rahe-meyer@franziskus.de.
N
N
Rahe-Meyer
Duke University School of Medicine, Durham, NC, USA.
J H
JH
Levy
St Michael's Hospital University of Toronto, Toronto, ON, Canada.
C D
CD
Mazer
Helsinki University Hospital, Helsinki, Finland.
A
A
Schramko
Papworth Hospital, Cambridge, UK.
A A
AA
Klein
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
R
R
Brat
Kobe University Hospital, Kobe, Japan.
Y
Y
Okita
Nagoya University Graduate School of Medicine, Nagoya, Japan.
Y
Y
Ueda
CSL Behring, Marburg, Germany.
D S
DS
Schmidt
CSL Behring, King of Prussia, PA, USA.
R
R
Ranganath
University Hospital of Southampton, Southampton, UK.
R
R
Gill
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001803:Blood Transfusion / Q000706:statistics & numerical data; D002315:Cardiopulmonary Bypass; D013504:Cardiovascular Surgical Procedures; D004311:Double-Blind Method; D005260:Female; D005340:Fibrinogen / Q000627:therapeutic use*; D006470:Hemorrhage / Q000188:drug therapy*; D006488:Hemostasis, Surgical; D006490:Hemostatics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D006490:Hemostatics; D005340:Fibrinogen
blood, coagulation; fibrinogen; haemorrhage; surgery, cardiovascular