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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
    The Lancet. Haematology. 2017

    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.
  • Efficacy and safety of fibrinogen concentrate in surgical patients: a meta-analysis of randomized controlled trials
    Journal of Cardiothoracic and Vascular Anesthesia. 2016

    Abstract

    OBJECTIVES To investigate the efficacy and safety of fibrinogen concentrate (FC) in surgical patients. DESIGN Meta-analysis of randomized controlled studies (RCTs). SETTING Perioperative. PARTICIPANTS Adult and pediatric surgical patients. INTERVENTIONS A search of PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, Transfusion Evidence Library, Google Scholar, and the proceedings from major international anesthesiology meetings up to February 1, 2016 for RCTs that compared FC with placebo or other comparators. MEASUREMENTS AND MAIN RESULTS The primary outcome was all-cause mortality. Pooled risk ratios and mean differences (MDs) were computed with either fixed-effects or random-effects models. The study included 14 RCTs comprising 1,035 patients; the majority of patients underwent cardiac surgery. All-cause mortality was lower in the fibrinogen group (4/432 [0.9%] v 15/430 [3.5%]; risk ratio 0.26; 95% confidence interval [CI] 0.09-0.78; p = 0.02; heterogeneity statistic (l2) = 0%). The use of FC was associated with reduced bleeding (MD -127 mL; 95% CI -207 to -47; p = 0.002; I2= 54%) and a lower number of red blood cells units transfused versus comparator (MD -0.9; 95% CI -1.3 to -0.5; p<0.001; I2 = 42%). There were no differences in the rates of thrombotic events and myocardial infarction. CONCLUSIONS In surgical patients, FC was associated with reduced bleeding and a lower number of red blood cell units transfused, and it also might reduce mortality. However, none of the analyzed trials was powered for estimation of survival and adverse events with FC use. Half of the included studies were of high or moderate risk of bias. The evidence primarily came from cardiac surgery settings.

    Clinical Commentary

    Dr. MJR Desborough, Haematology/Transfusion Medicine, NHS Blood and Transplant, Oxford, UK.

    What is known?

    Bleeding is an important and potentially preventable adverse event associated with surgery. Prevention, or treatment, of bleeding must be balanced against the risk of arterial or venous thrombotic events. Fibrin, which is formed from fibrinogen, is a key part of blood clot formation. In situations where a patient’s fibrinogen concentration is low, fibrinogen concentrate (or another source of fibrinogen such as cryoprecipitate) is often administered. However it is less clear whether fibrinogen concentrate is effective and safe for patients with a normal baseline fibrinogen level.

    An alternate, or adjuvant approach, is the use of anti-fibrinolytic agents (which prevent fibrin from being broken down) such as tranexamic acid and epsilon aminocaproic acid. These drugs are increasingly used to prevent peri-operative blood loss and do not appear to be associated with significant adverse events.

    A systematic review and meta-analysis published in 2013 on fibrinogen concentrate in surgical patients found no difference in mortality but found a significant reduction in the incidence of red cell transfusion (Wikkelsø et al. Cochrane Database Syst Rev 2013;8:CD008864).

    What did this paper set out to examine?

    The authors set out to compare efficacy and safety of fibrinogen concentrate in surgical patients in a systematic review and meta-analysis. Randomised controlled trials including adult or paediatric surgery were included. Trials were included if they compared fibrinogen concentrate to placebo or another haemostatic therapy (fresh frozen plasma, platelets, cryoprecipitate or coagulation factor concentrates). The only exclusion was congenital (inherited) fibrinogen deficiency.

    The primary outcome was all-cause mortality. Secondary outcomes were blood loss; proportion of patients who received a red cell transfusion; number of red cell units used; surgical revisions for bleeding; and thrombotic complications.

    What did they show?

    The authors identified 14 randomised controlled trials with 1035 patients. The majority of trials were in the setting of cardiac surgery. There was a high level of variation in the comparators that were used, the trigger for infusion of fibrinogen concentrate; prophylactic or therapeutic use; the timing of administration; and the dose of fibrinogen concentrate. The authors reported that half of the included studies were at high or moderate risk of bias.

    The risk of all-cause mortality was significantly lower in the group treated with fibrinogen concentrate. The event rate for mortality was very low with the majority of trials having no deaths in either arm. The meta-analysis included an unpublished paper and exclusion of this paper form the meta-analysis resulted in a non-significant difference in mortality (Mengoli et al. J Cardiothorac Vasc Anesth 2017;31:e33-5).

    Blood loss; number of red cell units transfused; and proportion of patients who received a red cell transfusion were significantly lower for those treated with fibrinogen concentrate. No difference was found in the risk of surgical revisions for bleeding or thrombotic complications.

    What are the implications for practice and for future work?

    This meta-analysis suggests that fibrinogen concentrate may reduce peri-operative mortality, bleeding and transfusion requirements. However the considerable variation in triggers, comparators and settings suggests that further randomised controlled trial data will be necessary to demonstrate efficacy in this setting. It is unclear whether anti-fibrinolytic drugs such as tranexamic acid or epsilon aminocaproic acid were used in the trials included in this meta-analysis. Now that these agents have been widely adopted into clinical guidelines, the efficacy and risk profile of fibrinogen concentrate may differ and this should be taken into account in future randomised controlled trials.
  • Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials
    Bjog : an International Journal of Obstetrics and Gynaecology. 2016

    Abstract

    BACKGROUND Postpartum haemorrhage is the leading cause of maternal mortality. Tranexamic acid (TXA) reduces surgical haemorrhage and the risk of death in bleeding trauma patients. OBJECTIVES To assess the effects of TXA on risk of postpartum haemorrhage and other clinically relevant outcomes. SEARCH STRATEGY We searched the MEDLINE, CENTRAL, EMBASE, PubMed, ClinicalTrials.gov and WHO ICTRP electronic databases to May 2015. SELECTION CRITERIA Randomised controlled trials comparing TXA with no TXA or placebo in women giving birth vaginally or by caesarean section. DATA COLLECTION AND ANALYSIS Two authors extracted data and assessed the risk of bias for each trial. Because of data concerns we did not conduct a meta-analysis. MAIN RESULTS We found 26 trials including a total of 4191 women. Examination of the trial reports raised concerns about the quality of the data. Eight trial reports contained identical or similar text and there were important data inconsistencies in several trials. Two trials did not have ethics committee approval. Meta-analysis of baseline variables suggested that randomisation was inadequate in many trials. CONCLUSIONS There is no reliable evidence that TXA prevents postpartum haemorrhage during childbirth. Many of the trials conducted to date are small, low quality and contain serious flaws. TWEETABLE ABSTRACT No evidence that TXA prevents postpartum haemorrhage. Existing trials are unreliable, with serious flaws.

    Clinical Commentary

    What is known?

    Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide with about 50,000 deaths each year. In those women who survive PPH, hysterectomy is sometimes necessary to stop the haemorrhage, depriving many women of their ability to bear additional children. Tranexamic acid (TXA) reduces bleeding by inhibiting fibrinolysis. TXA is an inexpensive, widely available drug that has been proven to reduce bleeding in surgery and reduce the risk of death in bleeding trauma patients. TXA given at delivery could potentially prevent severe postpartum bleeding.

    What did this paper set out to examine?

    The authors conducted a systematic review of randomised controlled trials (RCTs) to assess the effects of TXA on the risk of PPH as well as other clinically relevant outcomes. They searched MEDLINE, CENTRAL, EMBASE, PubMed, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform electronic databases for reviews published as of May 2015. Selection criteria included RCTs comparing TXA with no TXA or placebo in women giving birth vaginally or by caesarean section (CS).

    What did they show?

    The authors found 31 reports describing 26 trials involving 4191 women published between 2001 and 2015. Eight reports contained identical or similar data and there were important clinical inconsistencies in several trials. Two trials did not have ethics committee approval and meta-analysis showed that randomization was inadequate in many trials. The median sample size was 120 patients (74-740). All but one were single centre trials. Trials were conducted in China (3), Egypt (2), India (9), Iran (5), Malaysia (1), Pakistan (2), Turkey (3) and Ukraine (1). Twenty-two trials focused on the effects of TXA on women giving birth by CS and four in women delivering vaginally.

    TXA was given within 30 minutes prior to incision in all of the CS trials except one (given at delivery of anterior shoulder). TXA was given at delivery of anterior shoulder in 3 and at delivery of placenta in the remaining vaginal births. The TXA dose ranged from 0.5 g to 1 g. Women receiving TXA were compared to those given placebo in 13 reports and with those in a no-TXA group in the remaining 13 trials.

    The number of patients assigned to each group was not reported in one trial, rendering the data unusable. Frequency of PPH was reported in 13 of the trials (50%), blood loss in 24 (92%), thromboembolic events in 16 (62%), death in six (23%), surgical intervention in five (19%) and transfusion of blood products in 10 (38%). No trial reported on maternal well-being or quality of life. A major problem when comparing these studies is that even the definition of what constitutes PPH varied; four trials classified PPH as blood loss = 1000 mL after CS and = 500 mL after vaginal delivery. The remaining trials used other, lower thresholds such as = 500 mL after CS and = 400 mL after vaginal delivery.

    Because of the authors’ concerns about the quality of the trials and data reliability, they chose not to perform a meta-analysis. They instead calculated effect estimates and 95% CI’s were presented as Forest plots. They concluded that, in all trials, fewer women in the TXA group developed PPH than in the control group. Additionally, from the data of the trials where blood loss was evaluated, the effect estimates were consistent with less blood loss in the TXA group; the difference was statistically significant in all but one trial. In the trials detailing blood product transfusion data, where products were transfused (7), fewer women in the TXA group received a blood transfusion than in the control group. In studies reporting adverse outcomes, there were no deaths, surgical interventions, myocardial infarctions, strokes or pulmonary embolisms.

    What are the implications for practice and for future work?

    This publication provided valuable data in its description of the scale and nature of deficiencies in the studies evaluating the effect of TXA in preventing PPH. Unless the problems with these studies are brought to the attention of the maternal fetal medicine and transfusion medicine leaders, treatment decisions may be based on unsound evidence putting women at risk. The information provided by the authors should serve to guide future trial developers such that conclusions are based on the highest quality research possible.

    Based on the studies reviewed by the authors, it is clear that large, multicentre randomized control trials with clinically relevant endpoints must be developed before widespread clinical guidelines endorsing TXA in preventing PPH are implemented. It should be noted that the data from the WOMAN trial was not available at the time of this study.

  • Transfusion-related adverse events in the Platelet Dose study
    Transfusion. 2015;55(1):144-53

    Abstract

    BACKGROUND How platelet (PLT) product characteristics such as dose, source (whole blood derived [WBD] vs. apheresis), storage duration, and ABO matching status affect the risks of transfusion-related adverse events (TRAEs) is unclear. Similarly, more information is needed to define how recipient characteristics affect the frequency of TRAEs after PLT transfusion. STUDY DESIGN AND METHODS In the multicenter Platelet Dose ("PLADO") study, pediatric and adult hematology-oncology patients with hypoproliferative thrombocytopenia were randomized to receive low-dose (LD), medium-dose (MD), or high-dose (HD) PLT prophylaxis for a pretransfusion PLT count of not more than 10x10(9) /L. All PLT units (apheresis or WBD) were leukoreduced. Post hoc analyses of PLADO data were performed using multipredictor models. RESULTS A total of 5034 PLT transfusions to 1102 patients were analyzed. A TRAE occurred with 501 PLT transfusions (10.0%). The most common TRAEs were fever (6.6% of transfusions), allergic or hypersensitivity reactions (1.9%), and sinus tachycardia (1.8%). Patients assigned HD PLTs were more likely than LD or MD patients to experience any TRAE (odds ratio for HD vs. MD, 1.50; 95% confidence interval, 1.10-2.05; three-group comparison p=0.02). PLT source and ABO matching status were not significantly related to overall TRAE risk. Compared to a patient's first PLT transfusion, subsequent PLT transfusions were less likely to have a TRAE reported, primarily due to a lower risk of allergic or hypersensitivity reactions. CONCLUSION The most important PLT unit characteristic associated with TRAEs was PLT dose per transfusion. HD PLTs may increase the risk of TRAEs, and LD PLTs may reduce the risk.Copyright 2014 AABB.

    Clinical Commentary

    What is known?

    Patients with severe thrombocytopenia (very low platelet count) due to a hypoproliferative bone marrow (markedly reduced platelet production) receive prophylactic (given to prevent bleeding) platelet transfusions. This usually occurs when the platelet count drops below a certain threshold (the current standard is a platelet count of 10 x 109/l). Platelet transfusions are known to be associated with risks. Mild to moderate reactions to platelet transfusions include rigors (severe shivering accompanied by a feeling of coldness), fever, and urticaria (hives). These reactions are not life-threatening but can be extremely distressing for the patient. Rarer, but more serious side effects include: transfusion-transmitted infections (bacterial and viral infections) and transfusion-related acute lung injury (TRALI).

    What did this paper set out to examine?

    This is a secondary analysis of the PLADO Study (Slichter et al, 2010). The authors set out to show whether the characteristics of the patient receiving the platelet transfusion (patient’s age, sex, type of treatment, number of previous platelet transfusions) or of the platelet component itself (whether the platelets were ABO matched with the patient, how the platelet component had been produced, number of platelets within the transfusion, number of days the platelets had been stored for) affected the frequency of transfusion-related adverse events (TRAEs) after platelet transfusions. In this study TRAEs were any event that occurred within 4 hours of the platelet transfusion irrespective of whether medical staff at the time thought the event was related to the transfusion. TRAEs consisted of at least one of the following: allergic or hypersensitivity reaction; slow or fast heart rate; high or low blood pressure; shortness of breath; low oxygen levels; wheezing; cough; rigors or chills, fever, infection, or haemolysis (breakdown of red blood cells). The severity of TRAEs were graded. Multivariable analyses were carried out that compared any TRAE versus none, any TRAE of Grade 2 or above versus none, and any TRAE of Grade 3 or above versus none. As well as analyses of specific TRAEs that occurred in at least 50 (1%) of transfusions in the analysis.

    What did they show?

    Fever (6.6%) and allergic reactions (1.9%) were the most common TRAEs. A multipredictor logistic regression model for any TRAE versus no TRAE, which adjusted for all other variables in the model and for within-person correlation. This study found that a high number of platelets within the component increased the risk of a TRAE (odds ratio for high platelet number vs. intermediate platelet number, 1.50; 95% confidence interval, 1.10-2.05). This effect was no longer seen when only grade 2 or above TRAEs were considered, however this may be due to the small number of episodes observed. Compared to a patient’s first platelet transfusion, participants who had more than five platelet transfusions were less likely to have a TRAE reported during subsequent transfusions. This was primarily due to a lower risk of allergic or hypersensitivity reactions.

    What are the implications for practice and for future work?

    The primary publication of the PLADO study showed that a large number of platelets within a transfusion does not decrease the risk of WHO grade 2 or above bleeding, and does not reduce the number of transfusion episodes compared to an intermediate number of platelets within a component. This study now shows that platelet components that contain a large number of platelets may put patients at a higher risk of developing a TRAE. This study provides an additional reason why platelet components that contain a high number of platelets should not be used routinely.
  • Transfusion of fresh-frozen plasma in critically ill patients with a coagulopathy before invasive procedures: a randomized clinical trial (CME)
    Transfusion. 2015;55(1):26-35

    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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