1.
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.
2.
Fibrinogen concentrate for bleeding - a systematic review
Lunde J, Stensballe J, Wikkelso A, Johansen M, Afshari A
Acta Anaesthesiologica Scandinavica. 2014;58((9):):1061-74.
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Abstract
Fibrinogen concentrate as part of treatment protocols increasingly draws attention. Fibrinogen substitution in cases of hypofibrinogenaemia has the potential to reduce bleeding, transfusion requirement and subsequently reduce morbidity and mortality. A systematic search for randomised controlled trials (RCTs) and non-randomised studies investigating fibrinogen concentrate in bleeding patients was conducted up to November 2013. We included 30 studies of 3480 identified (7 RCTs and 23 non-randomised). Seven RCTs included a total of 268 patients (165 adults and 103 paediatric), and all were determined to be of high risk of bias and none reported a significant effect on mortality. Two RCTs found a significant reduction in bleeding and five RCTs found a significant reduction in transfusion requirements. The 23 non-randomised studies included a total of 2825 patients, but only 11 of 23 studies included a control group. Three out of 11 found a reduction in transfusion requirements while mortality was reduced in two and bleeding in one. In the available RCTs, which all have substantial shortcomings, we found a significant reduction in bleeding and transfusions requirements. However, data on mortality were lacking. Weak evidence from RCTs supports the use of fibrinogen concentrate in bleeding patients, primarily in elective cardiac surgery, but a general use of fibrinogen across all settings is only supported by non-randomised studies with serious methodological shortcomings. It seems pre-mature to conclude whether fibrinogen concentrate has a routine role in the management of bleeding and coagulopathic patients. More RCTs are urgently warranted. 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
Clinical Commentary
What is known?
Fibrinogen is a coagulation protein that is vital for the formation of a stable clot. Fibrinogen levels have been reported to be one of the first to fall during major haemorrhage, often before many of the other haemostatic factors. Knowing this, it has been hypothesised that fibrinogen replacement (i.e. fibrinogen concentrate, cryoprecipitate or FFP) may be beneficial as a treatment for major haemorrhage. Proposed benefits include: reversal/attenuation of the acquired coagulopathy which commonly accompanies major haemorrhage (of which hypofibrinogenaemia is a significant part), reduction of blood loss, reduction in the overall need for allogeneic transfusion and possibly reduction in mortality. For these reasons the treatment of major bleeding using fibrinogen replacement has become a focus for research, particularly in the settings of trauma, surgery and obstetrics.
What did this paper set out to examine?
This systematic review set out to evaluate the published evidence around the use of fibrinogen concentrate (FgC) for the treatment of bleeding, with the specific aims of examining whether FgC was efficacious (as defined by: reduction in blood loss or reduction in transfusion need) and if there were any clear benefits (e.g. mortality reduction) or harmful effects (e.g. thromboembolic disease). The authors reviewed RCTs, as well as large non-randomised prospective and retrospective studies. Studies were limited to humans and included all studies that used FgC for treatment of bleeding. Exclusions included: inherited fibrinogen disorders and case reports.
What did they show?
This paper included 7 RCTs and 23 observational studies. 12 on-going RCTs were identified. Many of the observational studies did not have a control arm (n = 12). Four clinical settings were evaluated: surgery (cardiac surgery and non-cardiac surgery), trauma and obstetrics. The FgC dose ranged from 2-8g across the studies. All 7 RCTs were in the elective surgery setting (5 cardiac). All had a high risk of bias and all were small (63 or fewer participants) and 1 was in abstract form only. Overall these studies showed no mortality benefit of FgC, however 6 out of the 7 reported either a significant reduction in transfusion use or a significant reduction in blood loss. Meta-analysis quantified the reduction of allogeneic transfusion into a relative risk of: 0.53 (0.32, 0.89) in participants given FgC. ICU stay was also significantly shorter in FgC treated participants (by 10.9 h (-21.38, -0.38)). (It should be noted that there was marked study heterogeneity (I2 = 79%)). 6 of the 7 studies were partly or fully funded by industry partners. No RCT reported thromboembolic event data. Of the 23 observational studies, 3 found a reduction in transfusion use (1 surgery study, 2 trauma studies); 2 found a reduction in mortality (both retrospective trauma studies) and 1 found a significant reduction in bleeding (surgery study). Only one retrospective study reported thromboembolic data (obstetric) and found no increase in thrombotic events. The paper described the effect of FgC on blood fibrinogen levels and similar results were seen in both RCT and observational study settings. On average 1 g FgC infused to RCT participants raised the blood level by 0.24 g/L and in the observational setting raised the blood level by 0.28 g/L. The authors commented that there was marked heterogeneity between studies, in many areas, including: (1) whether FgC was administered alone or with other pro-haemostatic agents (i.e. PCC, FFP); (2) how decisions were made to give the FgC in some studies viscoelastic testing was used to guide FgC doses and in others set doses were administered; (3) the timing of FgC administration pre or post operatively; (4) the use of different controls ranging from none to placebo controlled. This limited the pooling of data and the ability to make firm conclusions. The authors did conclude that even though there continues to be increasing use of FgC in clinical settings of major haemorrhage, the evidence to support this practice is weak.
What are the implications for practice and for future work?
This systematic review highlights the limited evidence that is available to support the use of FgC in the treatment of bleeding. The RCT data showed that FgC reduced bleeding and transfusion need in one setting only - elective surgery i.e. within a controlled clinical environment. It is unclear how applicable these data are for other clinical settings, such as trauma, where up to 30% of patients with haemorrhage have an accompanying coagulopathy and where fibrinolysis is an important part of the bleeding phenotype. FgC or fibrinogen replacement needs to be evaluated in each clinical setting, since although no study has directly compared the coagulation profiles of different patient groups with major bleeding, it is probable that different groups will have differing needs. For example, normally mothers at full term have a fibrinogen level of between 4-7 g/L, a level that would be deemed abnormally high in non-pregnant populations. Future work needs to address the differences between patients in order to move towards a more individualised treatment approach. Study heterogeneity limited the ability of the authors to pool data. Consensus about how best to collect outcomes and report data in major bleeding trials would go a long way towards reducing this variation.
3.
Fibrinogen concentrate in bleeding patients
Wikkelso A, Lunde J, Johansen M, Stensballe J, Wetterslev J, Moller AM, Afshari A
Cochrane Database of Systematic Reviews. 2013;8:CD008864.
Abstract
BACKGROUND Hypofibrinogenaemia is associated with increased morbidity and mortality, but the optimal treatment level, the use of preemptive treatment and the preferred source of fibrinogen remain disputed. Fibrinogen concentrate is increasingly used and recommended for bleeding with acquired haemostatic deficiencies in several countries, but evidence is lacking regarding indications, dosing, efficacy and safety. OBJECTIVES We assessed the benefits and harms of fibrinogen concentrate compared with placebo or usual treatment for bleeding patients. SEARCH METHODS We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8); MEDLINE (1950 to 9 August 2013); EMBASE (1980 to 9 August 2013); International Web of Science (1964 to 9 August 2013); CINAHL (1980 to 9 August 2013); LILACS (1982 to 9 August 2013); and the Chinese Biomedical Literature Database (up to 10 November 2011), together with databases of ongoing trials. We contacted trial authors, authors of previous reviews and manufacturers in the field. SELECTION CRITERIA We included all randomized controlled trials (RCTs), irrespective of blinding or language, that compared fibrinogen concentrate with placebo/other treatment or no treatment in bleeding patients, excluding neonates and patients with hereditary bleeding disorders. DATA COLLECTION AND ANALYSIS Three review authors independently abstracted data; we resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effects of fibrinogen concentrate in adults and children in terms of various clinical and physiological outcomes. We presented pooled estimates of the effects of intervention on dichotomous outcomes as risk ratios (RRs) and on continuous outcomes as mean differences, with 95% confidence intervals (CIs). We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis. MAIN RESULTS We included six RCTs with a total of 248 participants; none of the trials were determined to have overall low risk of bias. We found 12 ongoing trials, from which we were unable to retrieve any data. Only two trials provided data on mortality, and one was a zero event study; thus the meta-analysis showed no statistically significant effect on overall mortality (2.6% vs 9.5%, RR 0.28, 95% CI 0.03 to 2.33). Our analyses on blood transfusion data suggest a beneficial effect of fibrinogen concentrate in reducing the incidence of allogenic transfusions (RR 0.47, 95% CI 0.31 to 0.72) but show no effect on other predefined outcomes, including adverse events such as thrombotic episodes. AUTHORS' CONCLUSIONS In the six available RCTs of elective surgery, fibrinogen concentrate appears to reduce transfusion requirements, but the included trials are of low quality with high risk of bias and are underpowered to detect mortality, benefit or harm. Furthermore, data on mortality are lacking, heterogeneity is high and acute or severe bleeding in a non-elective surgical setting remains unexplored. Currently, weak evidence supports the use of fibrinogen concentrate in bleeding patients, as tested here in primarily elective cardiac surgery. More research is urgently needed.
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.