Research in context
Evidence before this study
The literature relevant for protocol creation and discussion of present results is largely summarised in several published guidelines on the management of trauma-related and perioperative bleeding. In addition, we searched PubMed using the search terms “PCC vs FFP and trauma”, “fibrinogen concentrate vs FFP and trauma”, and “fibrinogen concentrate for bleeding a systematic review” to identify articles comparing coagulation factor therapy and transfusion of FFP in trauma patients, published before Nov 30, 2016. Neither in 2011 nor now were we able to identify any published prospective randomised trial directly comparing FFP and a CFC-based concept in patients with trauma.
Although the clinical effectiveness of FFP is largely unproven, most cited guidelines—except that of the Austrian Society and the European Society of Anaesthesiology guideline on the management of severe perioperative bleeding—recommend the use of FFP as first-line therapy for correction of coagulopathy. As an alternative to transfusion of FFP, CFC have been licensed for use for the past two decades in many European countries for treatment of congenital but also acquired deficiency. The last published meta-analysis on the efficacy and safety of fibrinogen concentrate in surgical adult and paediatric patients included 14 randomised trials (1035 patients) and reported significant reduction in bleeding, transfusion requirements and probably decreased mortality, but criticised a high-to-moderate risk of bias and the fact that the evidence primarily came from cardiac surgery.
Uncertainty on the optimal management of trauma-induced coagulopathy still exists. The updated European guidelines on the management of bleeding trauma patients published in 2016 recommend that suspected or detected plasmatic coagulopathy should be corrected by transfusion of FFP or CFC, or both. In 2011, we published results of a large cohort study demonstrating low fibrinogen and fibrin polymerisation and low clot firmness as the predominant pathologies in trauma, and we also found that these pathologies were associated with mortality and transfusion requirements. In addition, we had knowledge that the exclusive use of CFC might reduce transfusion requirements. To provide robust results, we designed a randomised clinical trial comparing first-line FFP transfusion and first-line CFC administration in major trauma.
Added value of this study
This randomised trial is the first to our knowledge to compare first-line use of FFP and CFC for treatment of coagulopathy and associated bleeding in major blunt trauma. The trial was terminated early after randomisation of 100 patients, as the a-priori planned interim analysis showed an unfavourable risk–benefit balance for patients randomised to the FFP arm. However, the available sample size appears sufficient to make some conclusions that first-line CFC is superior to FFP. In our study, there was an increased risk for development of multiple organ failure with first-line use of FFP. We observed that first-line transfusion of FFP is frequently ineffective for correction of outcome-related pathologies of bleeding, hypofibrinogenaemia, low fibrin polymerisation, and poor clot strength. Use of FFP was associated with enduring coagulopathic bleeding, increased transfusion requirements, and also need for massive transfusion.
Implication of all the available evidence
Considering all the published literature on the treatment of trauma-induced coagulopathy using FFP, CFC, or both, our findings confirm results of earlier non-randomised studies reporting poor correction of coagulopathy with use of first-line FFP transfusion. By contrast, the early and effective fibrinogen supplementation, as feasible when using fibrinogen concentrate, restores clot strength quickly, shortens the phase of ongoing bleeding, limits transfusion requirements, and reduces the need for massive transfusion. Results also indicate that early effective fibrinogen supplementation translates into improved clinical outcome.
FFP=fresh frozen plasma. CFC=coagulation factor concentrates.