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

Uncontrolled bleeding is the most common preventable cause of death in major trauma [1]; it affects up to 40% of patients with severe injury. Trauma haemorrhage is exacerbated by a complex interplay of clotting abnormalities and may result in a trauma-induced coagulopathy (TIC). Activation of protein C is central to TIC [2] and associated with increased fibrinolysis [3] and loss of fibrinogen [4]. Hypofibrinogenaemia occurs early after injury and is an independent predictor of death [5]. Augmentation of blood fibrinogen levels necessitates the use of a concentrated form of fibrinogen supplementation (e.g., cryoprecipitate or fibrinogen concentrate [FgC]) because fresh frozen plasma (FFP) alone is ineffective [4, 6].

There is continued debate about the comparative effectiveness of the two concentrated fibrinogen treatments [7, 8], despite two recent feasibility randomised controlled trials (RCTs) in trauma haemorrhage (CRYOSTAT 1 [9] and FiiRST [10]). The aim of this paper is to report the findings of a second feasibility study in adult trauma haemorrhage using FgC. The primary objectives of the E-FIT 1 study were to determine whether it was possible to deliver FgC therapy early (within 45 minutes) to adult trauma patients and the proportion of participants whose fibrinogen levels were maintained ≥ 2 g/L during active haemorrhage.

This is the second RCT evaluating administration of FgC in trauma. Despite median administration times approximating 40 minutes, the range varied widely (10 to 82 minutes), and only 69% of participants received 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). However, the FgC group had a fibrinogen level of 1.6 g/L on admission (0.7 g/L lower than the placebo arm), which likely reflects the trends towards higher injury severity and greater degree of shock in the intervention arm. Importantly, the fibrinogen level in the 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 average fibrinogen level at 2 hours from admission was significantly higher in the FgC arm (p < 0.0001). Fibrinogen levels did not remain elevated by 7 days, a finding also shown in the two other feasibility RCTs [9, 10], suggesting no long-term effect of fibrinogen replacement.

Transfusion requirements were not different between arms; however, it was notable that there was a trend towards increased cryoprecipitate use in the FgC arm. Transfusion needs were greater for all blood components in the FgC arm, again a difference likely reflecting the higher injury burden and shock, the empiric nature of transfusion administration, and the lower admission level of fibrinogen. The proportion of patients achieving haemostasis at 3 hours, however, was identical in both arms, suggesting that duration of bleeding does not fully explain the need for greater cryoprecipitate use in the FgC arm (data not shown).

No safety signal for thrombotic events was detected in this study. Venous thromboembolism was reported only in the FgC arm and was under 10%, a rate similar to that in a recent FgC trauma study in which researchers also used 6 g of FgC as their intervention [10]. More deaths were recorded in the FgC arm (n = 8 vs. n = 3), with no difference in deaths resulting from bleeding between arms, although the study was not powered for mortality. Differences in death rates may represent the variability in baseline characteristics between groups (i.e., higher injury severity and worse organ failure in the FgC arm).

Rapid reconstitution is often cited as an important benefit of FgC. Our study, and that of Nascimento et al. [10], reported similar median FgC reconstitution times: 23 minutes (SD, 9) (E-FIT1) and 26 minutes (SD, 5) (FiiRST). In a non-RCT setting, dissolution of fibrinogen for in vitro testing has been reported within 30 seconds [20], although it most commonly takes 10 minutes [21]. The longer reconstitution times in our study were due to the need to dissolve the fibrinogen whilst maintaining allocation concealment. The study vials were kept in cardboard tamper-proof boxes, meaning that dissolution of fibrinogen powder (or placebo) could not be visually assessed and that each vial needed to ‘rest’ for 3 minutes prior to being drawn into a syringe [14]. In an unblinded RCT, time to factor concentrate administration was shorter at 10 minutes (IQR, 10–16) [22]. A future alternative source of concentrated fibrinogen may be extended shelf-life cryoprecipitate [23], which could be pre-thawed and held in the ED, avoiding reconstitution times, but this has yet to be tested in an RCT setting.

The inclusion criteria for this trial did not use fibrinogen level. Goal-directed transfusion therapy using viscoelastic haemostatic assays (VHAs) (thromboelastography or rotational thromboelastometry [ROTEM]) is standard practice in many trauma centres in Europe and the United States [22, 24, 25], and it is advocated for guiding transfusion therapy. In a retrospective European study, VHA-guided therapy has led to a 50% reduction in the incidence of massive transfusions for trauma compared with that predicted by the trauma-associated severe haemorrhage score, with an associated reduction in mortality from 33% to 22% [26]. However, delays to first results are incurred (on average, 15–20 min [21, 22]), and empiric, immediate transfusion therapy for patients with uncontrolled haemorrhage is a standard of care [27]. To date, in trauma haemorrhage, there are no evidence-based thresholds to guide fibrinogen treatment, only expert consensus [28]. A small RCT, which was terminated early, used dual ROTEM measures to guide transfusion (FIBTEM A10 > 8 mm, EXTEM CT < 78 seconds), and these data may support the use of ROTEM to direct transfusion therapy [22] but need validation in a larger study. A large European study is due to be completed in 2018 (iTACTIC; ClinicalTrials.gov, NCT02593877) which will compare the efficacy of VHA and standard clotting tests for transfusion in trauma.

Our study was designed to include participants with the clinical phenotype of severe bleeding, not those exclusively with a low fibrinogen level. We did not use VHA or Clauss fibrinogen for two reasons: (1) to minimise delay to randomisation (VHA testing incurs 10–15-min delays) when speed of delivery of transfusion is known to be important [27, 29, 30] and (2) to include participants with the broader clinical entity of bleeding. The recent RETIC trial used FIBTEM A10 for eligibility, and randomisation took approximately 35–38 minutes, compared with 15–16 minutes in our study [22].

This is one of the first published multi-centre UK trauma transfusion studies, and it provides evidence that the delivery and conduct of RCTs in the challenging environment of the ED is possible. Prior to study start it was predicted that the recruitment would take 18 months. Recruitment was completed within 10 months, facilitated both by the research infrastructure and by the ability of research teams to recruit outside core hours. Rapid recruitment has recently been seen in another transfusion trauma study (FEISTY; ClinicalTrials.gov, NCT02745041) showing an encouraging appetite for the collection of high-quality collaborative study data.

This study has several limitations. It is a small feasibility study, and large differences were seen between treatment groups, in particular shock parameters and fibrinogen levels, which will alter treatment effects. Treatments for trauma haemorrhage are more effective when given earlier in the time course of major bleeding, as demonstrated by the CRASH-2 data [29], and it is possible that a time delay incurred in the delivery of FgC in this study may have attenuated potential clinical benefits. This study was designed to test the ability of the research teams to administer FgC rapidly, and secondary endpoints should be viewed cautiously because the study was not powered for evaluation of clinical outcomes.

E-FIT 1 shows that it was not feasible to administer the study intervention within 45 minutes of admission consistently, and the pre-defined target of 90% participants was not met. Although the proportion of participants with fibrinogen levels above 2 g/L was not statistically different between arms, the rise in fibrinogen levels was greater in the active arm. There was no safety signal for thrombotic events in this study. This trial has highlighted the need for future studies to focus on the barriers to rapid delivery of concentrated fibrinogen therapies by examining each step in the trial process, including times taken to confirm eligibility and subsequent randomisation, as well as the specifics of speed of drug reconstitution and delivery.