Elsevier

The Lancet Haematology

Volume 4, Issue 6, June 2017, Pages e258-e271
The Lancet Haematology

Articles
Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial

https://doi.org/10.1016/S2352-3026(17)30077-7Get rights and content

Summary

Background

Effective treatment of trauma-induced coagulopathy is important; however, the optimal therapy is still not known. We aimed to compare the efficacy of first-line therapy using fresh frozen plasma (FFP) or coagulation factor concentrates (CFC) for the reversal of trauma-induced coagulopathy, the arising transfusion requirements, and consequently the development of multiple organ failure.

Methods

This single-centre, parallel-group, open-label, randomised trial was done at the Level 1 Trauma Center in Innsbruck Medical University Hospital (Innsbruck, Austria). Patients with trauma aged 18–80 years, with an Injury Severity Score (ISS) greater than 15, bleeding signs, and plasmatic coagulopathy identified by abnormal fibrin polymerisation or prolonged coagulation time using rotational thromboelastometry (ROTEM) were eligible. Patients with injuries that were judged incompatible with survival, cardiopulmonary resuscitation on the scene, isolated brain injury, burn injury, avalanche injury, or prehospital coagulation therapy other than tranexamic acid were excluded. We used a computer-generated randomisation list, stratification for brain injury and ISS, and closed opaque envelopes to randomly allocate patients to treatment with FFP (15 mL/kg of bodyweight) or CFC (primarily fibrinogen concentrate [50 mg/kg of bodyweight]). Bleeding management began immediately after randomisation and continued until 24 h after admission to the intensive care unit. The primary clinical endpoint was multiple organ failure in the modified intention-to-treat population (excluding patients who discontinued treatment). Reversal of coagulopathy and need for massive transfusions were important secondary efficacy endpoints that were the reason for deciding the continuation or termination of the trial. This trial is registered with ClinicalTrials.gov, number NCT01545635.

Findings

Between March 3, 2012, and Feb 20, 2016, 100 out of 292 screened patients were included and randomly allocated to FFP (n=48) and CFC (n=52). Six patients (four in the FFP group and two in the CFC group) discontinued treatment because of overlooked exclusion criteria or a major protocol deviation with loss of follow-up. 44 patients in the FFP group and 50 patients in the CFC group were included in the final interim analysis. The study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy compared with those in the CFC group (23 [52%] in the FFP group vs two [4%] in the CFC group; odds ratio [OR] 25·34 [95% CI 5·47–240·03], p<0·0001) and increased needed for massive transfusion (13 [30%] in the FFP group vs six [12%] in the CFC group; OR 3·04 [0·95–10·87], p=0·042) in the FFP group. Multiple organ failure occurred in 29 (66%) patients in the FFP group and in 25 (50%) patients in the CFC group (OR 1·92 [95% CI 0·78–4·86], p=0·15).

Interpretation

Our results underline the importance of early and effective fibrinogen supplementation for severe clotting failure in multiple trauma. The available sample size in our study appears sufficient to make some conclusions that first-line CFC is superior to FFP.

Funding

None.

Introduction

Presence of trauma-induced coagulopathy reflects severity of injury and correlates with mortality. Trauma-induced coagulopathy results from blood loss, dilution, consumption, and increased fibrinolytic activity. In addition, hypoperfusion-induced activation of the protein C system, endothelial and platelet dysfunction, anaemia, acidosis, hypothermia, and hypocalcaemia contribute to the development of trauma-induced coagulopathy.1, 2 Thus, effective treatment of trauma-induced coagulopathy is important and might affect early mortality of trauma patients by decreasing avoidable death from haemorrhage. Treatment might also avoid late morbidity or mortality by minimising blood loss and exposure to allogeneic blood transfusions, which should translate into decreased risk for multiple organ failure. However, besides the recommendation for use of transfusion algorithms, great uncertainty exists on whether a fresh frozen plasma (FFP)-based or coagulation factor concentrate (CFC)-based therapy, or even a combination of the two, should be used for correction of trauma-induced coagulopathy.2

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.

Previous studies3, 4 have shown that decreased fibrin polymerisation and low clot firmness are the predominant and outcome-related pathologies in patients with polytrauma. Observational studies have suggested that the exclusive use of coagulation factors decreases transfusion requirements and might improve outcome.5, 6, 7, 8, 9 We therefore designed a randomised clinical trial comparing the administration of FFP and CFC, guided by viscoelastic measurements. We hypothesised that use of CFC would raise coagulation factor levels effectively and rapidly, because high concentrations of clotting factors can be applied quickly and at low volumes. We also hypothesised that prothrombin complex concentrate (PCC) would rarely be needed, because thrombin generation is usually maintained or even increased in major trauma.10 Furthermore, bleeding cessation primarily depends on the ability to form stable clots, and thus on fibrinogen and platelets, rather than on the speed of coagulation initiation.3, 4, 11, 12 We further hypothesised that timely correction of trauma-induced coagulopathy would shorten the bleeding phase, thus limiting haemodynamic instability and reducing transfusion requirements, which should decrease the rate of multiple organ failure.2, 13, 14, 15, 16 The aim of the study was to compare the efficacy of FFP and CFC for reversal of coagulopathy, blood loss-associated transfusion requirements, and the development of multiple organ failure as an overall clinical outcome parameter.

Section snippets

Study design and participants

The RETIC study was a prospective, single-centre, parallel-group, open-label, randomised study done at the Level 1 Trauma Center in Innsbruck Medical University Hospital (Innsbruck, Austria) to investigate treatment of trauma-induced coagulopathy in major blunt trauma. Adult patients (aged 18–80 years) admitted to the trauma centre with trauma exhibiting an Injury Severity Score (ISS) greater than 15 and clinical signs or risk of substantial haemorrhage were screened for trauma-induced

Results

Between March 3, 2012, and Feb 20, 2016, 292 trauma patients with an expected ISS greater than 15 were screened for eligibility, of whom 192 were found ineligible (figure 1). 100 patients were enrolled and randomly assigned to receive either FFP (n=48) or CFC (n=52). Six patients dropped out soon after randomisation (figure 1), meaning 94 patients (50 patients CFC, 44 patients FFP) were included in the modified intention-to-treat analysis. Post-hoc subgroup analysis in the per-protocol

Discussion

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 study aimed to compare the efficacy of haemostatic treatment in correcting trauma-induced coagulopathy, consequently arising blood loss-associated transfusion requirements, and clinical outcome. The trial was terminated early after randomisation of 100 patients, as the a-priori planned interim analysis showed an

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