Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre, randomised, double blind, placebo-controlled pilot trial

Abstract

BackgroundThere is increasing interest in the timely administration of concentrated sources of fibrinogen to patients with major traumatic bleeding. Following evaluation of early cryoprecipitate in the CRYOSTAT 1 trial, we explored the use of fibrinogen concentrate, which may have advantages of more rapid administration in acute haemorrhage. The aims of this pragmatic study were to assess the feasibility of fibrinogen concentrate administration within 45 minutes of hospital admission and to quantify efficacy in maintaining fibrinogen levels ≥ 2 g/L during active haemorrhage.MethodsWe conducted a blinded, randomised, placebo-controlled trial at five UK major trauma centres with adult trauma patients with active bleeding who required activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy plus 6 g of fibrinogen concentrate or placebo.ResultsTwenty-seven of 39 participants (69%; 95% CI, 52–83%) across both arms received the study intervention within 45 minutes of admission. There was some evidence of a difference in the proportion of participants with fibrinogen levels ≥ 2 g/L between arms (p = 0.10). Fibrinogen levels in the fibrinogen concentrate (FgC) arm rose by a mean of 0.9 g/L (SD, 0.5) compared with a reduction of 0.2 g/L (SD, 0.5) in the placebo arm and were significantly higher in the FgC arm (p < 0.0001) at 2 hours. Fibrinogen levels were not different at day 7. Transfusion use and thromboembolic events were similar between arms. All-cause mortality at 28 days was 35.5% (95% CI, 23.8–50.8%) overall, with no difference between arms.ConclusionsIn this trial, early delivery of fibrinogen concentrate within 45 minutes of admission was not feasible. Although evidence points to a key role for fibrinogen in the treatment of major bleeding, researchers need to recognise the challenges of timely delivery in the emergency setting. Future studies must explore barriers to rapid fibrinogen therapy, focusing on methods to reduce time to randomisation, using ‘off-the-shelf’ fibrinogen therapies (such as extended shelf-life cryoprecipitate held in the emergency department or fibrinogen concentrates with very rapid reconstitution times) and limiting the need for coagulation test-based transfusion triggers.Trial registrationISRCTN67540073. Registered on 5 August 2015.

Defining trauma‐induced coagulopathy with respect to future implications for patient management: Communication from the SSC of the ISTH

“…Depletion is associated with poor outcomes, an effect which can be reversed with supplementation . Low fibrinogen concentrations correlate with increased transfusions, ventilator days, and increased early and late mortality . Fibrinogen supplementation improves clot initiation and stability, and may decrease mortality in this group .…”

Viscoelastic haemostatic assays and fibrinogen in paediatric acute traumatic coagulopathy: A comprehensive review

“…While there is no evidence proving a difference in efficacy between cryoprecipitate and FC, there are practical factors that may allow more rapid administration in clinical practice. A number of studies have investigated the time to administration of fibrinogen replacement and have compared FC to cryoprecipitate but as yet there have been no large studies powered for patient‐centred outcomes or reduction in blood product usage . Systems that achieve early and rapid fibrinogen replacement generally involve empiric delivery of FC to patients presenting with clinical indications of severe bleeding, not those exclusively with a low fibrinogen level .…”

The use of coagulation factor concentrates for perioperative bleeding management – a global perspective

“…First, only two trials have been performed to determine the most effective dosing strategy (e.g., fixed dose vs. weight based vs. targeted to a postinfusion fibrinogen level): an RCT in postpartum hemorrhage found no impact of 2 g of fibrinogen, suggesting the minimum required dose is more than 2 g, and a trial in major pediatric surgery found earlier dosing of fibrinogen concentrate (at a higher FIBTEM maximum clot firmness threshold) was more effective in reducing transfusion requirements . Second, the preemptive use of fibrinogen concentrate before or early in the course of hemorrhage has been tested in only several small pilot trials, and a large definitive trial in severe traumatic hemorrhage is under way with cryoprecipitate (CRYOSTAT‐2/ISRCTN14998314). Overall, the preemptive use of fibrinogen before hemorrhage occurs has not been successful .…”