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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
Innerhofer P, Fries D, Mittermayr M, Innerhofer N, von Langen D, Hell T, Gruber G, Schmid S, Friesenecker B, Lorenz IH, et al
The Lancet. Haematology. 2017;4((6):):e258-e271.. e258
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Abstract
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.
Clinical Commentary
What is known?
The management of major trauma haemorrhage has changed significantly over the last two decades, and the use of haemostatic resuscitation (the transfusion of red cells and FFP early and in high ratio to mitigate/treat clotting abnormalities that arise from severe trauma haemorrhage) is now standard practice. There are attendant risks from the transfusion of blood components (TRALI, TACO, increased rates of multiple organ failure (MOF) in trauma) and the potential to use clotting factor concentrates (CFCs) such as prothrombin complex concentrate, factor XIII and fibrinogen in place of FFP may confer advantages.
What did this paper set out to examine?
The RETIC study was a single centre, open-label, RCT evaluating the effects of FFP vs. coagulation factor concentrates (CFCs) as treatment for major bleeding after injury in adult trauma patients (age 18 80). The primary endpoint was the development of MOF during ICU stay, as defined by the SOFA score. Secondary endpoints were numerous and included transfusion use, changes to clotting parameters, thromboembolic complications and mortality. The study was designed to detect a difference in MOF between groups notably the publication did not specify the difference expected and 292 patients were required for 80% power.
What did they show?
The study recruited 100 patients (48 FFP and 52 CFC) between March 2012 Feb 2016. Six patients were later excluded. 44FFP and 50 CFC patients were analysed. The baseline characteristics in each arm were balanced. The study was terminated early for safety 52% patients in FFP arm required rescue therapy (double dose therapy followed by switching to the other treatment to stop the bleeding) compared to 4% CFC group (OR: 25.34 [95% CI 5.47 240.03], p < 0.0001). Additionally more FFP patients received massive transfusion; OR 3.04 [0.95 10.87], p = 0.042.
Primary endpoint results were provided using a modified ITT population (patients randomised but did not complete therapy were removed). The study showed no significant difference in MOF between arms: 66% FFP arm vs. 50% CFC arm; OR 1.92 [95%CI 0.78 4.86], p = 0.15. Post-hoc logistic regression analysis showed a significant difference in MOF development in the FFP arm for patients who had higher injury severity and worse brain injury; OR 3.13 [1.19-8.88], p = 0.025. The CFC patients were more likely to have coagulopathy reversed OR 25.34 [5.47-240.03], p <0.0001. (Defined by: FIBTEM A10 >8mm, EXTEM CT < 78 secs and no clinical bleeding). Seven patients died 5 CFC and 2 FFP, most due to severe brain injury and no patient died from exsanguination.
What are the implications for practice and for future work?
Overall, given these limitations, there will be debate about the implications of this trial for practice. The findings regarding reversal of coagulopathy are intriging there is a clear agreement between reversal of coagulopathy i.e. a FIBTEM A10 >8mm, and an EXTEM CT < 78 secs and reduced bleeding. This is the first time, in an RCT setting, that improved ROTEM parameters have been linked to clinical reduction of bleeding and these findings are important. One particular area for further research might be to validate whether the ROTEM parameters are effective thresholds for bleeding treatment and importantly linking the thresholds with hard clinical outcomes such as mortality or significant reduction in transfusion therapy.
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Transfusion of fresh-frozen plasma in critically ill patients with a coagulopathy before invasive procedures: a randomized clinical trial (CME)
Muller MC, Arbous MS, Spoelstra-de Man AM, Vink R, Karakus A, Straat M, Binnekade JM, de Jonge E, Vroom MB, Juffermans NP
Transfusion. 2015;55((1):):26-35.
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Abstract
BACKGROUND Prophylactic use of fresh-frozen plasma (FFP) is common practice in patients with a coagulopathy undergoing an invasive procedure. Evidence that FFP prevents bleeding is lacking, while risks of transfusion-related morbidity after FFP have been well demonstrated. We aimed to assess whether omitting prophylactic FFP transfusion in nonbleeding critically ill patients with a coagulopathy who undergo an intervention is noninferior to a prophylactic transfusion of FFP. STUDY DESIGN AND METHODS A multicenter randomized open-label trial with blinded endpoint evaluation was performed in critically ill patients with a prolonged international normalized ratio (INR; 1.5-3.0). Patients undergoing placement of a central venous catheter, percutaneous tracheostomy, chest tube, or abscess drainage were eligible. Patients with clinically overt bleeding, thrombocytopenia, or therapeutic use of anticoagulants were excluded. Patients were randomly assigned to omitting or administering a prophylactic transfusion of FFP (12mL/kg). Outcomes were occurrence of postprocedural bleeding complications, INR correction, and occurrence of lung injury. RESULTS Due to slow inclusion, the trial was stopped before the predefined target enrollment was reached. Eighty-one patients were randomly assigned, 40 to FFP and 41 to no FFP transfusion. Incidence of bleeding did not differ between groups, with a total of one major and 13 minor bleedings (p=0.08 for noninferiority). FFP transfusion resulted in a reduction of INR to less than 1.5 in 54% of transfused patients. No differences in lung injury scores were observed. CONCLUSION In critically ill patients undergoing an invasive procedure, no difference in bleeding complications was found regardless whether FFP was prophylactically administered or not.Copyright 2014 AABB.
Clinical Commentary
Dr Simon Stanworth, NHS Blood & Transplant, Oxford, UK
What is known?
Audits continue to document that a common reason for transfusion of plasma is to non-bleeding critically ill patients with laboratory measures of abnormal coagulopathy and prior to invasive procedures. Although the broader observational literature argues against benefit for this practice, evidence from randomized controlled trials is very limited.
What did this paper set out to examine?
This paper describes a multi-centred randomized open-label trial in adult critically ill patients to determine whether FFP transfusion could be safely omitted prior to invasive procedures. The patients admitted to critical care were prospectively screened between 2010 and 2013 for prolongation of the INR. Patients fulfilling the inclusion criteria were randomly assigned to receive or not to receive a single dose of 12mg of FFP prior to defined invasive procedures which included insertion of a central venous catheter, for thoracocentesis, percutaneous tracheostomy, drainage of abscess or fluid collection. The primary outcome of the study was procedure related bleeding occurring within 24 hours after the procedure. Bleeding was assessed using a tool previously validated and published in the critically ill population. For this tool, major bleeding was defined if bleeding accompanied by any of the following; a decrease in Hb by more that 2g/dL in the absence of another course of bleeding, transfusion of two or more units of red cells without an increase in Hb, a decrease in systolic blood pressure by more that 20mmHg, an increase in heart rate or wound related bleeding requiring specific intervention.
What did they show?
Due to slow patient accrual the trial was stopped before the predefined target enrolment was reached which was indicated to be a sample size in each arm of 198 patients. 81 patients were randomly assigned, 42 FFP and 41 to no FFP transfusion. The incidence of bleeding did not differ between the two study group arms. One major bleed was reported but although this event rate was consistent with the prediction of the researchers, the lower event rate was considered too small to complete a planned inferiority analysis. There were 13 minor bleeds recorded but there is some uncertainty about these numbers given that the clinical significance of these events is unclear. It was also noted that transfusion resulted in a reduction of INR to less than 1.5 in 54% of the transfused patients. No differences were reported in lung injuries scores between the arms.
What are the implications for practice and for future work?
The researchers are to be commended for attempting to address a clinical important research question: that of the role of plasma transfusion prior to invasive procedures in critically ill patients. Unfortunately the trial failed to recruit to target and the findings are not able to provide the level of evidence required to refute a clinical role for plasma in this setting. There is a need for research to address the best diagnostic tests as well as the optimal role of plasma or other pro-haemostatic coagulation factors. Arguably another lesson from this trial is the value of pilot trials ahead of a larger trial which might, for example, identify issues with recruitment.
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Transfusion requirements in surgical oncology patients: a prospective, randomized controlled trial
Pinheiro de Almeida J, Vincent JL, Barbosa Gomes Galas FR, Pinto Marinho de Almeida E, Fukushima JT, Osawa EA, Bergamin F, Lee Park C, Nakamura RE, Fonseca SM, et al
Anesthesiology. 2015;122((1):):29-38.
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Abstract
BACKGROUND Several studies have indicated that a restrictive erythrocyte transfusion strategy is as safe as a liberal one in critically ill patients, but there is no clear evidence to support the superiority of any perioperative transfusion strategy in patients with cancer. METHODS In a randomized, controlled, parallel-group, double-blind (patients and outcome assessors) superiority trial in the intensive care unit of a tertiary oncology hospital, the authors evaluated whether a restrictive strategy of erythrocyte transfusion (transfusion when hemoglobin concentration <7 g/dl) was superior to a liberal one (transfusion when hemoglobin concentration <9 g/dl) for reducing mortality and severe clinical complications among patients having major cancer surgery. All adult patients with cancer having major abdominal surgery who required postoperative intensive care were included and randomly allocated to treatment with the liberal or the restrictive erythrocyte transfusion strategy. The primary outcome was a composite endpoint of mortality and morbidity. RESULTS A total of 198 patients were included as follows: 101 in the restrictive group and 97 in the liberal group. The primary composite endpoint occurred in 19.6% (95% CI, 12.9 to 28.6%) of patients in the liberal-strategy group and in 35.6% (27.0 to 45.4%) of patients in the restrictive-strategy group (P = 0.012). Compared with the restrictive strategy, the liberal transfusion strategy was associated with an absolute risk reduction for the composite outcome of 16% (3.8 to 28.2%) and a number needed to treat of 6.2 (3.5 to 26.5). CONCLUSION A liberal erythrocyte transfusion strategy with a hemoglobin trigger of 9 g/dl was associated with fewer major postoperative complications in patients having major cancer surgery compared with a restrictive strategy.
Clinical Commentary
What is known?
Thresholds for red cell transfusion are currently under much scrutiny with a growing number of randomised controlled trials (RCTs) supporting the safety of restrictive transfusion practices in specified patient groups e.g. patients treated on the intensive care unit (TRICC) [1], following hip (FOCUS) [2] and cardiac surgery (TRACS) [3, 4], and patients with acute upper gastrointestinal bleeding [5] and sepsis (TRISS) [6]. Patients with cancer who are anaemic have poorer outcomes than those who are not [7] but there are no previous RCTs examining risks and benefits of transfusion in surgical patients with malignancy.
What did this paper set out to examine?
This paper describes 198 critically ill patients following surgery for abdominal malignancy randomised to restrictive (threshold 7 g/dl) and liberal (9 g/dl) transfusion strategies [8]. The primary outcome was a composite 30-day endpoint of all-cause mortality, cardiovascular complications, acute respiratory distress syndrome, acute kidney injury requiring renal replacement therapy, septic shock and reoperation.
What did they show?
This is the first RCT to demonstrate a worse outcome for patients assigned a restrictive threshold. There is an almost two-fold increase in the composite 30-day endpoint in the restrictive group (35.6% versus 19.6%, p=0.012). Thirty day mortality was 8.2% (liberal) versus 22.8% (restrictive), p= 0.005. The most common causes of death were septic shock and multisystem organ failure. Cardiovascular events and intra-abdominal sepsis were more frequent in the restrictive group.
The extent of the worse outcomes in the restrictive group is unexpected following larger RCTs supporting the safety of restrictive transfusion practice. The least supportive of this strategy was the recently published cardiac surgery RCT which concluded that a restrictive threshold was not superior to a liberal threshold [4]; they showed no difference in the primary outcome (serious infection or ischaemic event at 3 months). However, there was an increased mortality in the restrictive group (4.2% versus 2.6%, p=0.045).
There are significant differences in outcomes between the 2 groups in Almeida’s study and so we must consider whether these are attributable to differences in transfusion practice. Importantly, 57.7% of those even in the liberal group (79.2% in the restrictive group) were not transfused during the randomisation period. The reported difference in haemoglobin between the groups relates to the pre-transfusion haemoglobin and therefore does not include haemoglobins of those not transfused (68.9% of total study population).
Although the target thresholds were 7.0 and 9.0 g/dl, patients were transfused on average at 6.8 g/dl (restrictive group) and 7.9 g/dl (liberal). Compared to the preceding large RCTs there is a lack of separation in haemoglobin levels between groups [2, 6]. All 13 protocol deviations in the liberal group occurred when patients with haemoglobin <9.0 g/dl were not transfused; all 7 deviations in the restrictive group were for transfusions given with haemoglobin >7.0 g/dl.
The median duration for which patients remained randomised (i.e. length of ICU stay) was 4 days, compared to 11 days in the TRICC trial and until discharge or death in the Villanueva and FOCUS trials. In this study the small difference in haemoglobin between the groups only emerges at 4 days.
These factors together call into doubt whether the differences in outcomes can be attributed to differences in transfusion alone, and so an alternative explanation for the differences in outcomes must be sought. One possible reason is the small excess in major operations (oesophagectomy, gastroduodenopancreatectomy) as compared to cystectomy and hysterectomy in the restrictive group; this may also explain the excess of abdominal sepsis. There was a small, non-significant, excess of patients with diabetes, chronic obstructive pulmonary disease and congestive heart failure in the restrictive group.
The question addressed in the study is important and there are positive aspects to the trial which should be highlighted. This is the first randomised study specifically assessing post-operative patients with malignancy; the FOCUS study is the only other large RCT to include significant numbers of cancer patients (18.0 and 18.8% in the two arms) but the types, stage or remission status are not given. In the current study there were attempts to blind patients and investigators and the clinical practice described is deliverable on most ICUs. There were small numbers of protocol deviations and follow-up to the primary endpoint was complete.
What are the implications for practice and for future work?
It is important to consider the limitations of this study if its findings are to be used to inform practice. In the presence of multiple other RCT data supportive of restrictive transfusion practice we would caution against changing practice based on this research. Despite its unexpected findings, this study questions the safety of restrictive transfusion practice and it is important that future trials continue to address the safety this approach among different patient groups.
References
1. Hébert PC, et al., A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med, 1999. 340(6): 409-17.