Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial
A J Wikkelsø, H M Edwards, A Afshari, J Stensballe, J Langhoff-Roos, C Albrechtsen, K Ekelund, G Hanke, E L Secher, H F Sharif, L M Pedersen, A Troelstrup, J Lauenborg, A U Mitchell, L Fuhrmann, J Svare, M G Madsen, B Bødker, A M Møller, FIB-PPH trial group, Anne Wikkelsø, Hellen Edwards, Arash Afshari, Jakob Stensballe, Jens Langhoff-Roos, Ann Merete Møller, Charlotte Albrechtsen, Kim Ekelund, Gabriele Hanke, Heidi F Sharif, Erik L Secher, Marina Christensen, Benedicte Utke Ramsing, Peter Jensen-Gadegaard, Anna Engskov, Camilla Wulff, Marianne Berntsen, Kristian J Andersen, Volker Classen, Pernille Opstrup, Lars H Lundstrøm, Marianne S Flindt, Jens Lunde, Lars Møller Pedersen, Ane Troelstrup, Jeannet Lauenborg, Birgit Lassen, Mette Andersson, Marie Winther-Olsen, Sine Hougaard, Christine Andersen, Maria Petersen, Anja Mitchell, Lone Fuhrmann, Jens Svare, Christian Viggo Nielsen, Michelé Lefort Sønderskov, Rasmus Winkel, Mathias Johansen, Marie Søgaard, Mette G Madsen, Birgit Bødker, Casper Okkels, Rasmus Berthelsen, Karen Elisabeth Linnet, Line Stendall, Iben Darfeld, Mikkel Madsen, Louise Pedersen, A J Wikkelsø, H M Edwards, A Afshari, J Stensballe, J Langhoff-Roos, C Albrechtsen, K Ekelund, G Hanke, E L Secher, H F Sharif, L M Pedersen, A Troelstrup, J Lauenborg, A U Mitchell, L Fuhrmann, J Svare, M G Madsen, B Bødker, A M Møller, FIB-PPH trial group, Anne Wikkelsø, Hellen Edwards, Arash Afshari, Jakob Stensballe, Jens Langhoff-Roos, Ann Merete Møller, Charlotte Albrechtsen, Kim Ekelund, Gabriele Hanke, Heidi F Sharif, Erik L Secher, Marina Christensen, Benedicte Utke Ramsing, Peter Jensen-Gadegaard, Anna Engskov, Camilla Wulff, Marianne Berntsen, Kristian J Andersen, Volker Classen, Pernille Opstrup, Lars H Lundstrøm, Marianne S Flindt, Jens Lunde, Lars Møller Pedersen, Ane Troelstrup, Jeannet Lauenborg, Birgit Lassen, Mette Andersson, Marie Winther-Olsen, Sine Hougaard, Christine Andersen, Maria Petersen, Anja Mitchell, Lone Fuhrmann, Jens Svare, Christian Viggo Nielsen, Michelé Lefort Sønderskov, Rasmus Winkel, Mathias Johansen, Marie Søgaard, Mette G Madsen, Birgit Bødker, Casper Okkels, Rasmus Berthelsen, Karen Elisabeth Linnet, Line Stendall, Iben Darfeld, Mikkel Madsen, Louise Pedersen
Abstract
Background: In early postpartum haemorrhage (PPH), a low concentration of fibrinogen is associated with excessive subsequent bleeding and blood transfusion. We hypothesized that pre-emptive treatment with fibrinogen concentrate reduces the need for red blood cell (RBC) transfusion in patients with PPH.
Methods: In this investigator-initiated, multicentre, double-blinded, parallel randomized controlled trial, we assigned subjects with severe PPH to a single dose of fibrinogen concentrate or placebo (saline). A dose of 2 g or equivalent was given to all subjects independent of body weight and the fibrinogen concentration at inclusion. The primary outcome was RBC transfusion up to 6 weeks postpartum. Secondary outcomes were total blood loss, total amount of blood transfused, occurrence of rebleeding, haemoglobin <58 g litre(-1), RBC transfusion within 4 h, 24 h, and 7 days, and as a composite outcome of 'severe PPH', defined as a decrease in haemoglobin of >40 g litre(-1), transfusion of at least 4 units of RBCs, haemostatic intervention (angiographic embolization, surgical arterial ligation, or hysterectomy), or maternal death.
Results: Of the 249 randomized subjects, 123 of 124 in the fibrinogen group and 121 of 125 in the placebo group were included in the intention-to-treat analysis. At inclusion the subjects had severe PPH, with a mean blood loss of 1459 (sd 476) ml and a mean fibrinogen concentration of 4.5 (sd 1.2) g litre(-1). The intervention group received a mean dose of 26 mg kg(-1) fibrinogen concentrate, thereby significantly increasing fibrinogen concentration compared with placebo by 0.40 g litre(-1) (95% confidence interval, 0.15-0.65; P=0.002). Postpartum blood transfusion occurred in 25 (20%) of the fibrinogen group and 26 (22%) of the placebo group (relative risk, 0.95; 95% confidence interval, 0.58-1.54; P=0.88). We found no difference in any predefined secondary outcomes, per-protocol analyses, or adjusted analyses. No thromboembolic events were detected.
Conclusions: We found no evidence for the use of 2 g fibrinogen concentrate as pre-emptive treatment for severe PPH in patients with normofibrinogenaemia.
Clinical trial registration: ClinicalTrials.gov: https://ichgcp.net/clinical-trials-registry/NCT01359878. Published protocol: http://www.trialsjournal.com/content/pdf/1745-6215-13-110.pdf.
Keywords: blood coagulation; erythrocyte transfusion; fibrinogen; postpartum haemorrhage.
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Source: PubMed