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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-related adverse events in the Platelet Dose study
Kaufman RM, Assmann SF, Triulzi DJ, Strauss RG, Ness P, Granger S, Slichter SJ
Transfusion. 2015;55((1):):144-53.
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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.
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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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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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Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial
Hourlier H, Reina N, Fennema P
Archives of Orthopaedic & Trauma Surgery. 2015;135((4):):465-71.
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INTRODUCTION A randomised, double-blind clinical trial was conducted comparing the efficacy of tranexamic acid (TXA) as a single intravenous bolus or a continuous infusion to patients undergoing total knee arthroplasty (TKA). Study hypothesis was that a second dose of TXA would not offer any clinical benefits over the single infusion. MATERIALS AND METHODS One hundred and six patients were randomised to a single intraoperative dose of 30 mg/kg tranexamic acid (OS group, n = 54), or to a loading dose of 10 mg/kg tranexamic acid followed 2 h later by a continuous 2 mg/kg/h infusion for 20 h (OD group, n = 52). The primary outcome was blood loss calculated from haematological values and perioperative transfusions. Secondary outcomes included the occurrence of major complications within the first postoperative year. RESULTS All patients completed tranexamic acid therapy without adverse events. The mean blood loss was 1,148 +/- 585 ml in group OS and 1,196 +/- 614 ml in group OD (p = 0.68). No patients received a transfusion. There were no occurrences of major complications up to 6-weeks follow-up. CONCLUSIONS The study demonstrated that a single bolus of tranexamic acid 30 mg/kg is as effective as a continuous infusion in patients undergoing tranexamic acid. The single application of tranexamic acid as part of routine care is recommended.
Clinical Commentary
Dr Antony Palmer, University of Oxford.
Tranexamic Acid for Reducing Blood Loss and Transfusion Rates in Total Knee Arthroplasty - commentary on 3 papers: 1) Hourlier H, Reina N, Fennema P. Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 465-71; 2) Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 573-88; 3) Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. European Journal of Orthopaedic Surgery & Traumatologie 2015, 25(3): 525-41.
What is known?
Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, studies often reach conflicting conclusions as to the safety and efficacy of this agent. In addition, the optimal dosing strategy and route of delivery for TKA remains unknown.
What did this paper set out to examine?
These three publications include two meta-analyses of randomised controlled trials that compare tranexamic acid treatment to no treatment or placebo in patients undergoing unilateral TKA. Each meta-analysis includes data from over 30 trials. Outcomes include total blood loss, transfusion rate, and the incidence of vascular occlusive events. The authors also compare outcomes of intravenous and intraarticular tranexamic acid delivery. The third publication is a randomised controlled trial comparing the efficacy of a single intravenous bolus of tranexamic acid versus a continuous infusion in 106 patients undergoing unilateral TKA.
What did they show?
The meta-analyses conclude that tranexamic acid reduces total blood loss associated with TKA when given intravenously or intraarticularly. The effect is considered clinically relevant given there is also a reduction in blood transfusion rates (relative risk <0.5), although the authors did identity a high level of statistical heterogeneity between studies. There was no apparent increase in the risk of DVT (deep vein thrombosis) or PE (pulmonary embolism) in patients receiving tranexamic acid. When comparing intravenous and intraarticular delivery, there was no significant difference in outcomes. Results from the randomised controlled trial suggest that a single intraoperative bolus of tranexamic acid is as effective as a continuous infusion. There were no adverse events and no patient required a blood transfusion.
What are the implications for practice and for future work?
Tranexamic acid administration at the time of TKA appears safe and effective at reducing blood loss and the need for transfusion. An increasing body of evidence now supports its use in clinical practice, however, the optimal dose and route of administration remains unclear. Although outcomes do not appear to differ between intravenous and intraarticular delivery, intraarticular tranexamic acid may overcome systemic contraindications such as renal insufficiency. The finding that a single intravenous bolus is as effective as a continuous infusion warrants further investigation. Future research would benefit from a standardised protocol for tranexamic acid administration as a comparator for novel dosing regimes. Sources of heterogeneity that must be taken into consideration include surgical and anaesthetic technique, concurrent use of other pharmaceutical agents, transfusion thresholds, and the method of diagnosing adverse events. In addition, it is important that studies address patient reported outcome measures pertaining to joint function and quality of life.
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Topical and intravenous tranexamic acid reduce blood loss compared to routine hemostasis in total knee arthroplasty: a multicenter, randomized, controlled trial
Aguilera X, Martinez-Zapata MJ, Hinarejos P, Jordan M, Leal J, Gonzalez JC, Monllau JC, Celaya F, Rodriguez-Arias A, Fernandez JA, et al
Archives of Orthopaedic & Trauma Surgery. 2015;135((7)):1017-25.
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INTRODUCTION Tranexamic acid (TXA) is becoming widely used in orthopedic surgery to reduce blood loss and transfusion requirements, but consensus is lacking regarding the optimal route and dose of administration. The aim of this study was to compare the efficacy and safety of topical and intravenous routes of TXA with routine hemostasis in patients undergoing primary total knee arthroplasty (TKA). MATERIALS AND METHODS We performed a randomized, multicenter, parallel, open-label clinical trial in adult patients undergoing primary TKA. Patients were divided into three groups of 50 patients each: Group 1 received 1 g topical TXA, Group 2 received 2 g intravenous TXA, and Group 3 (control group) had routine hemostasis. The primary outcome was total blood loss. Secondary outcomes were hidden blood loss, blood collected in drains, transfusion rate, number of blood units transfused, adverse events, and mortality. RESULTS One hundred and fifty patients were included. Total blood loss was 1021.57 (481.09) mL in Group 1, 817.54 (324.82) mL in Group 2 and 1415.72 (595.11) mL in Group 3 (control group). Differences in total blood loss between the TXA groups and the control group were clinically and statistically significant (p < 0.001). In an exploratory analysis differences between the two TXA groups were not statistically significant (p = 0.073) Seventeen patients were transfused. Transfusion requirements were significantly higher in Group 3 (p = 0.005). No significant differences were found between groups regarding adverse events. CONCLUSION We found that 1 g of topical TXA and 2 g of intravenous TXA were both safe strategies and more effective than routine hemostasis to reduce blood loss and transfusion requirements after primary TKA. LEVEL OF EVIDENCE I.
Clinical Commentary
Dr. Antony Palmer, University of Oxford
What is known?
Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, the optimal dosing strategy and route of delivery for TKA remains unknown. The vast majority of studies comparing intravenous and intraarticular delivery have not demonstrated a difference in efficacy or adverse event profile, however, the dose and mode of administration vary significantly between studies.
What did this paper set out to examine?
This manuscript presents the results of an open-label randomised controlled study comparing blood loss in patients receiving routine haemostasis (50 patients: control group) or routine haemostasis and tranexamic acid (100 patients: treatment group) at the time of primary total knee arthroplasty. Patients receiving tranexamic acid were divided into two groups: Group 1 received 1g of tranexamic acid applied topically across the surgical field after prosthesis cementation. Group 2 received 1g of tranexamic acid intravenously 15-30 minutes prior to tourniquet inflation and again once the tourniquet was deflated.
What did they show?
The primary outcome measure was total blood loss, and this was significantly lower in the intravenous and topical tranexamic acid groups compared with the control group. There was no statistically significant difference between intravenous and topical administration. The authors considered a 200ml reduction in blood loss within drains to be clinically significant, and this was demonstrated in both tranexamic groups compared with the control group, but again there was no difference between routes of administration. The frequency and nature of adverse events was comparable across groups.
What are the implications for practice and for future work?
The results from this study suggest that 1g of tranexamic acid administered topically to the surgical field after implant cementation, or 1g of tranexamic acid delivered intravenously prior to tourniquet inflation and on tourniquet deflation, are both safe and effective means of achieving a clinically-significant reduction in total blood loss associated with primary total knee arthroplasty surgery. As with the majority of previous studies, no difference was detected between the different routes of administration and the study may have lacked power for this analysis. The optimal dose and timing of tranexamic acid administration remains unknown and the regimes adopted in this study may be suboptimal. A recent meta-analysis suggested that the efficacy of topical tranexamic acid might be greater when doses exceeding 2g are administered. The role of intraarticular administration warrants further investigation given this route may overcome systemic contraindications. There are a number of benefits from reducing the blood loss associated with total knee arthroplasty surgery. These have not yet been demonstrated in terms of functional recovery or length of hospital stay and this represents a further area for future research.
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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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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.
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Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial
Wikkelso AJ, Edwards HM, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, Ekelund K, Hanke G, Secher EL, Sharif HF, et al
British Journal of Anaesthesia. 2015;114((4):):623-33.
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BACKGROUND In early postpartum haemorrhage (PPH), a low concentration of fibrinogen is associated with excessive subsequent bleeding and blood transfusion. We hypothesized that pre-emptive treatment with fibrinogen concentrate reduces the need for red blood cell (RBC) transfusion in patients with PPH. METHODS In this investigator-initiated, multicentre, double-blinded, parallel randomized controlled trial, we assigned subjects with severe PPH to a single dose of fibrinogen concentrate or placebo (saline). A dose of 2 g or equivalent was given to all subjects independent of body weight and the fibrinogen concentration at inclusion. The primary outcome was RBC transfusion up to 6 weeks postpartum. Secondary outcomes were total blood loss, total amount of blood transfused, occurrence of rebleeding, haemoglobin <58 g litre(-1), RBC transfusion within 4 h, 24 h, and 7 days, and as a composite outcome of 'severe PPH', defined as a decrease in haemoglobin of >40 g litre(-1), transfusion of at least 4 units of RBCs, haemostatic intervention (angiographic embolization, surgical arterial ligation, or hysterectomy), or maternal death. RESULTS Of the 249 randomized subjects, 123 of 124 in the fibrinogen group and 121 of 125 in the placebo group were included in the intention-to-treat analysis. At inclusion the subjects had severe PPH, with a mean blood loss of 1459 (sd 476) ml and a mean fibrinogen concentration of 4.5 (sd 1.2) g litre(-1). The intervention group received a mean dose of 26 mg kg(-1) fibrinogen concentrate, thereby significantly increasing fibrinogen concentration compared with placebo by 0.40 g litre(-1) (95% confidence interval, 0.15-0.65; P=0.002). Postpartum blood transfusion occurred in 25 (20%) of the fibrinogen group and 26 (22%) of the placebo group (relative risk, 0.95; 95% confidence interval, 0.58-1.54; P=0.88). We found no difference in any predefined secondary outcomes, per-protocol analyses, or adjusted analyses. No thromboembolic events were detected. CONCLUSIONS We found no evidence for the use of 2 g fibrinogen concentrate as pre-emptive treatment for severe PPH in patients with normofibrinogenaemia. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov: http://clinicaltrials.gov/show/NCT01359878. Published protocol: http://www.trialsjournal.com/content/pdf/1745-6215-13-110.pdf.Copyri ght The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Clinical Commentary
Dr Akshay Shah, Adult Intensive Care Unit, John Radcliffe Hospital, Oxford
What is known?
Post-partum haemorrhage (PPH) is a leading cause of maternal morbidity and mortality worldwide. Fibrinogen is an essential component of haemostasis and fibrinogen levels of <2 g.L-1, in patients with PPH, have been shown to predict further severe bleeding and requirement for blood and blood products. Current guidelines recommend using fibrinogen concentrate to correct acquired hypofibrinogenaemia although high quality evidence for this is lacking. A recent Cochrane review demonstrated weak evidence for fibrinogen concentrate in reducing transfusion requirements in bleeding patients undergoing elective cardiac surgery.
What did this paper set out to examine?
This was a multicentre randomised placebo-controlled study aimed to assess the efficacy of pre-emptive treatment with fibrinogen concentrate early in PPH without any laboratory evidence of hypofibrinogenaemia. This is different to previous studies that have examined the use of fibrinogen concentrate once coagulopathy and a fibrinogen deficit have been established. Patients aged >18 years with a PPH, defined as bleeding from the uterus and/or birth canal with 24 hours of delivery were randomised to receive a fixed dose of 2g of fibrinogen concentrate or placebo (isotonic saline). The primary outcome was red blood cell (RBC) transfusion during a 6-week follow-up period postpartum.
What did they show?
Data from 244 patients were available for final analysis; 123 in the fibrinogen group and 121 in the placebo group. There was no difference in the primary outcome RBC transfusion was given to 25 patient (20.3%) in the fibrinogen group and 26 patients (21.5%) in the placebo group. There was also no difference in clinically important secondary outcomes such as estimated blood loss, adverse effects and progression to severe PPH between both groups. An important limitation of this study is that patients who may stand to benefit the most from fibrinogen therapy were either under-represented or not included only 2.2% of patients had a critical fibrinogen level of <2 g.L-1 and 46 patients 15% of the bleeding population in this study, could not be randomised because they were bleeding too heavily and therefore informed consent could not be obtained. Furthermore, the difference in fibrinogen concentrate between the treated and placebo group was only 0.4 g.L-1 which suggests that a larger dose may be required.
What are the implications for practice and for future work?
This study highlights the lack of benefit of fibrinogen concentrate in patients with early PPH and a normal fibrinogen level, which may help, limits it use. Future research should be directed towards developing fast and accurate tests for measuring fibrinogen levels and developing 'goal-directed’ therapy towards patients who may benefit the most such as those with severe PPH and/or acquired hypofibrinogenaemia.
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Promoting the return of lapsed blood donors: A seven-arm randomized controlled trial of the question-behavior effect
Godin G, Germain M, Conner M, Delage G, Sheeran P
Health Psychology. 2014;33((7):):646-55.
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Objective: This study tested key variations in the question-behavior effect against a control condition or an implementation intention condition on returning to give blood among lapsed donors (individuals who had not given blood in the past 2 years). Design: At baseline, 7,000 lapsed donors were randomized to 1 of 6 experimental conditions or to a control condition. Participants in the experimental conditions were asked to complete a 6-item postal questionnaire assessing intentions only, interrogative intention, moral norm plus intention, anticipated regret plus intention, positive self-image plus intention, or implementation intentions. Objective measures of behavior were obtained 6 and 15 months later. The frequency of registrations to give blood over the next 6 and 15 months was measured. Results: Intention-to-treat analysis of the frequency of registrations (GENMOD procedure, Poisson distribution) indicated main effects for condition (experimental vs. control) at both 6 months, chi2(1) = 4.64, p < .05, and 15 months, chi2(1) = 5.88, p < .05. Positive self-image and implementation intention interventions outperformed the control condition at 6 months. At 15 months, standard intention, interrogative intention, and regret plus intention conditions showed more frequent registrations compared with control and were just as effective as implementation intention formation. Moderation analysis showed that the moral norm and positive self-image conditions were significant for first-time (1 previous donation) but not repeat (2 or more previous donations) donors. Conclusion: The question-behavior effect can be used to reinvigorate blood donation among lapsed donors, and can be as effective as forming implementation intentions. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
Clinical Commentary
Prof. Barbara Masser - University of Queensland, St Lucia, Australia.
What is known?
The question-behaviour effect (QBE) defined as the increased probability of engaging in a behaviour as a result of simply measuring intentions to engage in that behaviour has been observed for many health behaviours. It has previously been observed in blood donation, but the results as to the efficacy of this as an intervention for blood donation are somewhat mixed. The efficacy of the QBE as a method of re-activating lapsed donors has not been previously explored.
What did this paper set out to examine?
The authors conducted a randomized controlled trial with 7,000 lapsed donors (donors who had not registered to give blood in the last 2 years). The aim was to explore whether the QBE could be enhanced by i) measuring intentions in an interrogative (‘Do I have the intention..’) rather than declarative (‘I intend..’) form; ii) whether assessing additional constructs such as anticipated regret at not donating in the future, moral norm/obligation to donate or positive self-image as a function of donating prior to declarative intention would enhance the QBE in comparison to the intention only conditions and in comparison to an established behavioural change intervention (implementation intentions); iii) whether these effects would vary as a function of donors’ age, gender, first time vs. repeat donor status and whether they returned a completed questionnaire or not.
Participants were randomly assigned to one of the six intervention conditions (declarative or interrogative intention, moral norm, anticipated regret, positive self-image each paired with declarative intention or implementation intentions) or the control (business as usual) condition. The outcome variables were registrations at blood drives during a 6 and 15-month period.
What did they show?
Intention to treat analyses showed that while implementation intentions increased registrations to donate in comparison to the control condition at both 6 and 15 months, the effects of the QBE interventions were less consistent. At 6 months, those allocated to the positive self-image condition registered at a significantly higher rate than donors in the control condition. At 15 months, donors in the anticipated regret, interrogative intention and declarative intention conditions registered at a significantly higher rate than those in the control condition. These effects did not differ by donor gender or age. However, only first-time (and not repeat) donors in the moral norm and positive self -image conditions registered at a significantly higher rate than donors in the control condition at 6 and 15 months. Donors in all the intervention conditions who returned the questionnaires registered at significantly higher rates than those who did not and at a rate significantly greater than those in the control condition at both time points.
Although response rates were uniformly low and thus these are analyses somewhat statistically underpowered, donors in the implementation intention condition who returned their questionnaire registered at a significantly higher rate than responders in all other conditions at 15 months, and at a significantly higher rate than responders in the moral norm, anticipated regret and positive self-image condition at 6 months. At both 6 and 15 months the standard declarative intention questions performed as well as the interrogative intention or enhanced intention questions in increasing registrations. Among those who did not return the questionnaire, there were no differences between conditions in registrations at 6 months. At 15 months, those in the moral norm condition registered at a significantly lower rate than those in the control condition.
What are the implications for practice and for future work?
The practical implications of this study are - somewhat ironically -- that if you want to reactivate lapsed donors then you should distribute an implementation intention intervention. This intervention increased registrations in comparison to the control condition at 6 and 15 months. Although the observed effect size was statistically small if this intervention could be incorporated into practice in a cost neutral way then it would be a valuable tool in reactivating lapsed donors. Acting to increase registrations using QBE type effects depends on whether lapsed donors can be motivated to return the materials, and thus guarantee that their intentions have been measured. If they can then the simple declarative intention items seem to work best although it should be noted that which intervention results in the highest registration rate could change as response rates increase. If measurement cannot be guaranteed then more options open up. If an increase in registrations is needed in the short term (6 months) then positive self-image and intention items should be administered to first-time donors. If a longer-term (15 months) increase is desired then Intention or anticipated regret and intention items results in an increase in registrations to donate in comparison to business as usual practices. Theoretically, in terms of the QBE, the analyses for donors who returned the questionnaires are the most informative. These show that for responding lapsed donors for whom there is evidence that intentions were measured (and who experienced the QBE as theoretically defined) the basic QBE is not enhanced by adding in measures of additional constructs or assessing intentions in alternative forms. Although outperformed by implementation intentions at 15 months, simply measuring declarative intentions significantly increased registrations at 6 and at 15 months in comparison to the business as usual control condition.
This analysis provides many opportunities for future research. In addition to determining how the QBE works and when it will be observed, the current analysis suggests opportunities in exploring ‘mere exposure’ effects as a means to reactivation of lapsed donors. That is, how simply sending a lapsed donor a questionnaire asking them their intentions to donate in the next 6 months results in an increase in registrations to donate not at 6 but at 15 months. For those specifically interested in the QBE as theoretically defined an additional opportunity arises in considering how to improve response rates. Traditionally this is achieved through including low monetary value tokens with questionnaires. However, how this may effect or interact with the QBE in a blood donation context needs to be empirically explored.
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Hemostatic effects of fibrinogen concentrate compared with cryoprecipitate in children after cardiac surgery: A randomized pilot trial
Galas FR, de Almeida JP, Fukushima JT, Vincent JL, Osawa EA, Zeferino S, Camara L, Guimaraes VA, Jatene MB, Hajjar LA
Journal of Thoracic & Cardiovascular Surgery. 2014;148((4):):1647-55.
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OBJECTIVES Acute acquired hypofibrinogenemia in children undergoing cardiac surgery is a major concern because it often results in perioperative bleeding and high rates of allogeneic blood transfusion. Fibrinogen concentrate has been proposed as an alternative to cryoprecipitate (the gold standard therapy), with minimal infectious and immunologic risks. Our objective was to investigate the efficacy and safety of fibrinogen concentrate in children undergoing cardiac surgery. METHODS In this randomized pilot study, patients were allocated to receive fibrinogen concentrate (60 mg/kg) or cryoprecipitate (10 mL/kg) if bleeding was associated with fibrinogen levels <1 g/dL after cardiopulmonary bypass weaning. The primary outcome was postoperative blood losses during the 48 hours after surgery. RESULTS A total of 63 patients were included in the study, 30 in the fibrinogen concentrate group and 33 in the cryoprecipitate group. The median 48-hour blood loss was not significantly different between the 2 groups (320 mL [interquartile range, 157-750] vs 410 mL [interquartile range, 215-510], respectively; P = .672). After treatment, plasma fibrinogen concentration increased similarly following administration of both products. There were no differences in allogeneic blood transfusion after intervention treatment. CONCLUSIONS A large trial comparing fibrinogen concentrate and cryoprecipitate in the management of children with acute acquired hypofibrinogenemia during heart surgery is feasible. The preliminary results of our study showed that the use of fibrinogen concentrate was as efficient and safe as cryoprecipitate in the management of bleeding children undergoing cardiac surgery. Copyright 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Clinical Commentary
Dr Simon Stanworth - NHS Blood & Transplant, Oxford, UK
What is known?
There are several different sources of fibrinogen for use in patients with major bleeding such as trauma or postpartum or surgery. The two main concentrated sources are fibrinogen concentrate or cryoprecipitate. Cryoprecipitate is the standard method of fibrinogen supplementation in UK. The evidence relating to the clinical effectiveness of cryoprecipitate is very limited; with very few randomised controlled trials (RCTs) completed to date. Fibrinogen concentrate (FgC) is increasingly available and a recent Cochrane review evaluating the effectiveness of FgC for patients with bleeding found limited data (six small trials, none in trauma) but reported no effect on overall mortality but did find a reduction in allogeneic transfusion.
What did this paper set out to examine?
Pilot trials are needed to inform the design of larger definitive trials which can answer fundamental questions about effectiveness of fibrinogen supplementation in patients with major bleeding. This study describes a pilot study of fibrinogen concentrate or cryoprecipitate to reduce bleeding in children undergoing cardiac surgery. Patients younger than 7 years and admitted for elective cardiac surgery and cardio-pulmonary bypass were screened and eligible for randomisation to receive fibrinogen concentrate (60mg/kg) or cryoprecipitate (10ml/kg) if they developed diffuse bleeding at wound surfaces and a fibrinogen concentration < 1g/L/.
What did they show?
A total of 63 patients were included in the pilot, 30 received fibrinogen concentrate and 33 cryoprecipitate. There were no differences in post-operative blood losses (primary outcome), and the median 48 hour blood loss was not significantly different between the two groups. Rises in plasma fibrinogen concentration were similar between the two groups, and there were no significant differences between the groups for adverse events and a range of other clinical outcomes.
What are the implications for practice and for future work?
In addition to documenting feasibility of recruitment, the pilot study supports the need for larger trials, not just to understand how different sources of fibrinogen should be used, but also to evaluate comparative differences between products. Cryoprecipitate is a pooled blood component) that has a variable, but high Fg concentration (15-20 g/L), but also contains other plasma proteins (FVIII, FXIII, von Willebrand’s factor and fibronectin) which may confer additional haemostatic benefits.
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Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial
Roberts I, Prieto-Merino D, Manno D
Critical Care (London, England). 2014;18((6):):685.
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INTRODUCTION To investigate the mechanism of action of tranexamic acid (TXA) in bleeding trauma patients, we examined the timing of its effect on mortality. We hypothesised that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of the injury when bleeding is most profuse. However, if TXA reduces mortality via an anti-inflammatory mechanism its effect should be greater over the subsequent days. METHODS Exploratory analysis, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examined hazard ratios (HR) and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths, according to the day since injury. The CRASH-2 trial is registered as ISRCTN86750102 and ClinicalTrials.gov NCT00375258. RESULTS The effect of TXA on mortality is greatest for deaths occurring on the day of the injury (HR all-cause mortality = 0.83, 0.73 to 0.93). This survival benefit is only evident in patients in whom treatment is initiated within 3 hours of their injury (HR <3 hours = 0.78, 0.68 to 0.90; HR >3 hours = 1.02, 0.76 to 1.36). Initiation of TXA treatment within 3 hours of injury reduced the hazard of death due to bleeding on the day of the injury by 28% (HR = 0.72, 0.60 to 0.86). TXA treatment initiated beyond 3 hours of injury appeared to increase the hazard of death due to bleeding, although the estimates were imprecise. CONCLUSIONS Early administration of tranexamic acid appears to reduce mortality primarily by preventing exsanguination on the day of the injury.
Clinical Commentary
What is known?
The CRASH-2 trial, an international, multicentre randomized controlled trial involving over 20 000 patients published in Lancet in 2010, has shown that administration of tranexamic acid (TXA), an antifibrinolytic, to bleeding trauma patients within 3 hours of injury significantly reduces death due to bleeding (p = 0.0077), as well as all-cause mortality (20% reduction)(p = 0.0035) as compared to placebo. TXA is a synthetic derivative of lysine that inhibits fibrinolysis by blocking the lysine binding sites on plasminogen as well as by interfering with the binding of plasmin to fibrin.
What did this paper set out to examine?
The authors set out to investigate the mechanism of action of TXA in bleeding in trauma patients by examining the timing of its effect on mortality in patients evaluated via the CRASH-2 trial. There is debate in the literature as to whether TXA functions by reducing inflammation by reducing plasmin, a pro-inflammatory mediator, or if TXA functions by simply reducing blood loss. The authors hypothesized that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of injury when bleeding should be most profuse. Their belief was that if TXA reduces mortality by an anti-inflammatory mechanism its effect should be greater in the days following the injury.
What did they show?
It is clear that for tranexamic acid to be most beneficial in bleeding trauma patients, it should be given within 3 hours of injury. The effect of TXA on mortality is greatest for deaths occurring on the day of injury and for deaths due to exsanguination. It is still unclear if TXA reduces mortality by an anti-inflammatory mechanism as well as by reducing blood loss. The authors merely used data from CRASH-2 and examined hazard ratios and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths according to the day since injury; markers of inflammation were not measured. Future RCTs looking at specific inflammatory mediators measured in bleeding trauma patients receiving TXA versus placebo may be informative.
What are the implications for practice and for future work?
It is clear that for tranexamic acid to be most beneficial in bleeding trauma patients, it should be given within 3 hours of injury. The effect of TXA on mortality is greatest for deaths occurring on the day of injury and for deaths due to exsanguination. It is still unclear if TXA reduces mortality by an anti-inflammatory mechanism as well as by reducing blood loss. The authors merely used data from CRASH-2 and examined hazard ratios and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths according to the day since injury; markers of inflammation were not measured. Future RCTs looking at specific inflammatory mediators measured in bleeding trauma patients receiving TXA versus placebo may be informative.