1.
Early and Systematic Administration of Fibrinogen Concentrate in Postpartum Haemorrhage Following Vaginal Delivery: The FIDEL Randomized Controlled Trial
Ducloy Bouthors AS, Mercier FJ, Grouin JM, Bayoumeu F, Corouge J, Le Gouez A, Rackelboom T, Broisin F, Vial F, Luzi A, et al
BJOG : an international journal of obstetrics and gynaecology. 2021
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Editor's Choice
Abstract
OBJECTIVE To assess the benefits and safety of early human fibrinogen concentrate in postpartum haemorrhage (PPH) management. DESIGN Multicentre, double-blind, randomized placebo-controlled trial. SETTING 30 French hospitals. POPULATION patients with persistent PPH after vaginal delivery requiring a switch from oxytocin to prostaglandins. METHODS Within 30 min after introduction of prostaglandins, patients received either 3 g fibrinogen concentrate or placebo. MAIN OUTCOME MEASURES Failure as composite primary efficacy endpoint: at least 4 g/dL of haemoglobin decrease and/or transfusion of at least 2 units of packed red blood cells within 48h following investigational medicinal product administration. Secondary endpoints: PPH evolution, need for haemostatic procedures, and maternal morbidity-mortality within 6±2 weeks after delivery. RESULTS 437 patients were included : 224 received FC and 213 placebo. At inclusion, blood loss (877 ± 346mL) and plasma fibrinogen (4.1 ± 0.9g/L) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the Fibrinogen and placebo groups, respectively (OR=0.99) after adjustment for centre and baseline plasma fibrinogen; (95%CI: [0.66;1.47]; p=0.96). No significant differences in secondary efficacy outcomes were observed. The mean plasma FG was unchanged in the Fibrinogen group and decreased by 0.56 g/L in the placebo group. No thromboembolic or other relevant adverse effects were reported in the Fibrinogen group, versus two in the placebo group. CONCLUSIONS As previous placebo-controlled studies findings, early and systematic administration of 3 g fibrinogen concentrate did not reduce blood loss, transfusion needs, and postpartum anaemia, but prevented plasma fibrinogen decrease without any subsequent thromboembolic events.
PICO Summary
Population
Patients with persistent post-partum haemorrhage after vaginal delivery enrolled in the FIDEL trial (n= 437).
Intervention
Fibrinogen concentrate (n= 224).
Comparison
Placebo (n = 213).
Outcome
At inclusion, blood loss (877 ± 346mL) and plasma fibrinogen (4.1 ± 0.9g/L) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the fibrinogen and placebo groups, respectively after adjustment for centre and baseline plasma fibrinogen. No significant differences in secondary efficacy outcomes were observed. The mean plasma fibrinogen was unchanged in the fibrinogen group and decreased by 0.56 g/L in the placebo group. No thromboembolic or other relevant adverse effects were reported in the fibrinogen group, versus two in the placebo group.
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Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial
Collins PW, Cannings-John R, Bruynseels D, Mallaiah S, Dick J, Elton C, Weeks AD, Sanders J, Aawar N, Townson J, et al
British Journal of Anaesthesia. 2017;119((3)):411-421.
Abstract
Background: Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed size. Methods: Women with PPH 1000-1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused. Results: Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3-1.7), P =0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th-75th centile) of 1 (0-4.5) unit of allogeneic blood products and had an additional 300 (100-350) ml blood loss whereas those who received placebo also received 3 (0-6) units of allogeneic blood products and had 700 (200-1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group. Conclusions: Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre -1 , but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis. Trial registration: ISRCTN46295339 ( http://www.isrctn.com/ISRCTN46295339 , last accessed 5 July 2017), EudraCT 2012-005511-11 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-005511-11 , last accessed 5 July 2017).
3.
Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial
Wikkelso AJ, Edwards HM, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, Ekelund K, Hanke G, Secher EL, Sharif HF, et al
British Journal of Anaesthesia. 2015;114((4):):623-33.
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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: http://clinicaltrials.gov/show/NCT01359878. Published protocol: http://www.trialsjournal.com/content/pdf/1745-6215-13-110.pdf.Copyri ght The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Clinical Commentary
Dr Akshay Shah, Adult Intensive Care Unit, John Radcliffe Hospital, Oxford
What is known?
Post-partum haemorrhage (PPH) is a leading cause of maternal morbidity and mortality worldwide. Fibrinogen is an essential component of haemostasis and fibrinogen levels of <2 g.L-1, in patients with PPH, have been shown to predict further severe bleeding and requirement for blood and blood products. Current guidelines recommend using fibrinogen concentrate to correct acquired hypofibrinogenaemia although high quality evidence for this is lacking. A recent Cochrane review demonstrated weak evidence for fibrinogen concentrate in reducing transfusion requirements in bleeding patients undergoing elective cardiac surgery.
What did this paper set out to examine?
This was a multicentre randomised placebo-controlled study aimed to assess the efficacy of pre-emptive treatment with fibrinogen concentrate early in PPH without any laboratory evidence of hypofibrinogenaemia. This is different to previous studies that have examined the use of fibrinogen concentrate once coagulopathy and a fibrinogen deficit have been established. Patients aged >18 years with a PPH, defined as bleeding from the uterus and/or birth canal with 24 hours of delivery were randomised to receive a fixed dose of 2g of fibrinogen concentrate or placebo (isotonic saline). The primary outcome was red blood cell (RBC) transfusion during a 6-week follow-up period postpartum.
What did they show?
Data from 244 patients were available for final analysis; 123 in the fibrinogen group and 121 in the placebo group. There was no difference in the primary outcome RBC transfusion was given to 25 patient (20.3%) in the fibrinogen group and 26 patients (21.5%) in the placebo group. There was also no difference in clinically important secondary outcomes such as estimated blood loss, adverse effects and progression to severe PPH between both groups. An important limitation of this study is that patients who may stand to benefit the most from fibrinogen therapy were either under-represented or not included only 2.2% of patients had a critical fibrinogen level of <2 g.L-1 and 46 patients 15% of the bleeding population in this study, could not be randomised because they were bleeding too heavily and therefore informed consent could not be obtained. Furthermore, the difference in fibrinogen concentrate between the treated and placebo group was only 0.4 g.L-1 which suggests that a larger dose may be required.
What are the implications for practice and for future work?
This study highlights the lack of benefit of fibrinogen concentrate in patients with early PPH and a normal fibrinogen level, which may help, limits it use. Future research should be directed towards developing fast and accurate tests for measuring fibrinogen levels and developing 'goal-directed’ therapy towards patients who may benefit the most such as those with severe PPH and/or acquired hypofibrinogenaemia.
4.
The FIB-PPH trial: fibrinogen concentrate as initial treatment for postpartum haemorrhage: study protocol for a randomised controlled trial
Wikkelsoe AJ, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, Ekelund K, Hanke G, Sharif HF, Mitchell AU, Svare J, et al
Trials. 2012;13:110.
Abstract
BACKGROUND Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality worldwide. In Denmark 2% of parturients receive blood transfusion. During the course of bleeding fibrinogen (coagulation factor I) may be depleted and fall to critically low levels, impairing haemostasis and thus worsening the ongoing bleeding. A plasma level of fibrinogen below 2 g/L in the early phase of postpartum haemorrhage is associated with subsequent development of severe haemorrhage. Use of fibrinogen concentrate allows high-dose substitution without the need for blood type crossmatch. So far no publications of randomised controlled trials involving acutely bleeding patients in the obstetrical setting have been published. This trial aims to investigate if early treatment with fibrinogen concentrate reduces the need for blood transfusion in women suffering severe PPH. METHODS/DESIGN In this randomised placebo-controlled double-blind multicentre trial, parturients with primary PPH are eligible following vaginal delivery in case of: manual removal of placenta (blood loss ? 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss ? 1000 ml). Caesarean sections are also eligible in case of perioperative blood loss ? 1000 ml. The exclusion criteria are known inherited haemostatic deficiencies, prepartum treatment with antithrombotics, pre-pregnancy weight <45 kg or refusal to receive blood transfusion. Following informed consent, patients are randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo). Haemostatic monitoring with standard laboratory coagulation tests and thromboelastography (TEG, functional fibrinogen and Rapid TEG) is performed during the initial 24 hours.Primary outcome is the need for blood transfusion. To investigate a 33% reduction in the need for blood transfusion, a total of 245 patients will be included. Four university-affiliated public tertiary care hospitals will include patients during a two-year period. Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) good clinical practice (GCP). DISCUSSION A widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use. The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH. TRIAL REGISTRATION ClincialTrials.gov NCT01359878.