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Effects of tranexamic acid treatment in severely and non-severely injured trauma patients
Ageron FX, Shakur-Still H, Roberts I
Transfusion. 2022
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Abstract
BACKGROUND Urgent treatment with tranexamic acid (TXA) reduces bleeding deaths but there is disagreement about which patients should be treated. We examine the effects of TXA treatment in severely and non-severely injured trauma patients. STUDY DESIGN AND METHODS We did an individual patient data meta-analysis of randomized trials with over 1000 trauma patients that assessed the effects of TXA on survival. We defined the severity of injury according to characteristics at first assessment: systolic blood pressure of less than 90 mm Hg and a heart rate greater than 120 beats per minute or Glasgow Coma Scale score of less than nine or any GCS with one or more fixed dilated pupils. The primary measure was survival on the day of the injury. We examined the effect of TXA on survival in severely and non-severely injured patients and how these effects vary with the time from injury to treatment. RESULTS We obtained data for 32,944 patients from two randomized trials. Tranexamic acid significantly increased survival on the day of the injury (OR = 1.22, 95% CI 1.11-1.34; p < .01). The effect of tranexamic acid on survival in non-severely injured patients (OR = 1.25, 1.03-1.50) was similar to that in severely injured patients (OR = 1.22, 1.09-1.37) with no significant heterogeneity (p = .87). In severely and non-severely injured pateints, treatment within the first hour after injury was the most effective. DISCUSSION Early tranexamic acid treatment improves survival in both severely and non-severely injured trauma patients. Its use should not be restricted to the severely injured.
PICO Summary
Population
Severely and non-severely injured trauma patients enrolled in the two large randomised controlled trials: CRASH-2 and CRASH-3 (n= 32,944).
Intervention
Tranexamic acid (n= 16,499).
Comparison
Placebo (n= 16,445).
Outcome
Tranexamic acid significantly increased survival on the day of the injury (odd ratio (OR)= 1.22). The effect of tranexamic acid on survival in non-severely injured patients (OR= 1.25) was similar to that in severely injured patients (OR= 1.22) with no significant heterogeneity. In severely and non-severely injured patients, treatment within the first hour after injury was the most effective.
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Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): a pilot randomized trial
Nishijima DK, VanBuren JM, Linakis SW, Hewes HA, Myers SR, Bobinski M, Tran NK, Ghetti S, Adelson PD, Roberts I, et al
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2022
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Abstract
BACKGROUND The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage; however, the drug has not been evaluated in a trial in injured children. We evaluated the feasibility of a large-scale trial evaluating the effects of TXA in children with severe hemorrhagic injuries. METHODS Severely injured children (0 up to 18(th) birthday) were randomized into a double-blind randomized trial of 1) TXA 15 mg/kg bolus dose, followed by 2 mg/kg/hr infusion over 8 hours, 2) TXA 30 mg/kg bolus dose, followed by 4 mg/kg/hr infusion over 8 hours, or 3) normal saline placebo bolus and infusion. The trial was conducted at 4 pediatric Level I trauma centers in the United States between June 2018 and March 2020. We enrolled patients under federal exception from informed consent (EFIC) procedures when parents were unable to provide informed consent. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The target enrollment rate was at least 1.25 patients per site per month. RESULTS A total of 31 patients were randomized with a mean age of 10.7 years (standard deviation [SD] 5.0 years) and 22 (71%) patients were male. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. The enrollment rate using EFIC was 1.34 patients per site per month. All eligible enrolled patients received study intervention (9 patients TXA 15 mg/kg bolus dose, 10 patients TXA 30 mg/kg bolus dose, and 12 patients placebo) and had the primary outcome measured. No statistically significant differences in any of the clinical outcomes were identified. CONCLUSION Based on enrollment rate, protocol adherence, and measurement of the primary outcome in this pilot trial, we confirmed the feasibility of conducting a large-scale, randomized trial evaluating the efficacy of TXA in severely injured children with hemorrhagic brain and/or torso injuries using EFIC.
PICO Summary
Population
Severely injured children enrolled in the TIC-TOC trial across four centers in US (n= 31).
Intervention
15 mg/kg of tranexamic acid (TXA) dose, followed by 2 mg/kg/hr infusion (n= 9).
Comparison
30 mg/kg of TXA dose, followed by 4 mg/kg/hr infusion (n= 10). Saline placebo and infusion (n= 12).
Outcome
All patients had their primary outcome measured. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. No statistically significant differences in any of the clinical outcomes were identified.
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Effect of tranexamic acid on intracranial haemorrhage and infarction in patients with traumatic brain injury: a pre-planned substudy in a sample of CRASH-3 trial patients
Mahmood A, Needham K, Shakur-Still H, Harris T, Jamaluddin SF, Davies D, Belli A, Mohamed FL, Leech C, Lotfi HM, et al
Emergency medicine journal : EMJ. 2021;38(4):270-278
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Abstract
BACKGROUND Early tranexamic acid (TXA) treatment reduces head injury deaths after traumatic brain injury (TBI). We used brain scans that were acquired as part of the routine clinical practice during the CRASH-3 trial (before unblinding) to examine the mechanism of action of TXA in TBI. Specifically, we explored the potential effects of TXA on intracranial haemorrhage and infarction. METHODS This is a prospective substudy nested within the CRASH-3 trial, a randomised placebo-controlled trial of TXA (loading dose 1 g over 10 min, then 1 g infusion over 8 hours) in patients with isolated head injury. CRASH-3 trial patients were recruited between July 2012 and January 2019. Participants in the current substudy were a subset of trial patients enrolled at 10 hospitals in the UK and 4 in Malaysia, who had at least one CT head scan performed as part of the routine clinical practice within 28 days of randomisation. The primary outcome was the volume of intraparenchymal haemorrhage (ie, contusion) measured on a CT scan done after randomisation. Secondary outcomes were progressive intracranial haemorrhage (post-randomisation CT shows >25% of volume seen on pre-randomisation CT), new intracranial haemorrhage (any haemorrhage seen on post-randomisation CT but not on pre-randomisation CT), cerebral infarction (any infarction seen on any type of brain scan done post-randomisation, excluding infarction seen pre-randomisation) and intracranial haemorrhage volume (intraparenchymal + intraventricular + subdural + epidural) in those who underwent neurosurgical haemorrhage evacuation. We planned to conduct sensitivity analyses excluding patients who were severely injured at baseline. Dichotomous outcomes were analysed using relative risks (RR) or hazard ratios (HR), and continuous outcomes using a linear mixed model. RESULTS 1767 patients were included in this substudy. One-third of the patients had a baseline GCS (Glasgow Coma Score) of 3 (n=579) and 24% had unilateral or bilateral unreactive pupils. 46% of patients were scanned pre-randomisation and post-randomisation (n=812/1767), 19% were scanned only pre-randomisation (n=341/1767) and 35% were scanned only post-randomisation (n=614/1767). In all patients, there was no evidence that TXA prevents intraparenchymal haemorrhage expansion (estimate=1.09, 95% CI 0.81 to 1.45) or intracranial haemorrhage expansion in patients who underwent neurosurgical haemorrhage evacuation (n=363) (estimate=0.79, 95% CI 0.57 to 1.11). In patients scanned pre-randomisation and post-randomisation (n=812), there was no evidence that TXA reduces progressive haemorrhage (adjusted RR=0.91, 95% CI 0.74 to 1.13) and new haemorrhage (adjusted RR=0.85, 95% CI 0.72 to 1.01). When patients with unreactive pupils at baseline were excluded, there was evidence that TXA prevents new haemorrhage (adjusted RR=0.80, 95% CI 0.66 to 0.98). In patients scanned post-randomisation (n=1431), there was no evidence of an increase in infarction with TXA (adjusted HR=1.28, 95% CI 0.93 to 1.76). A larger proportion of patients without (vs with) a post-randomisation scan died from head injury (38% vs 19%: RR=1.97, 95% CI 1.66 to 2.34, p<0.0001). CONCLUSION TXA may prevent new haemorrhage in patients with reactive pupils at baseline. This is consistent with the results of the CRASH-3 trial which found that TXA reduced head injury death in patients with at least one reactive pupil at baseline. However, the large number of patients without post-randomisation scans and the possibility that the availability of scan data depends on whether a patient received TXA, challenges the validity of inferences made using routinely collected scan data. This study highlights the limitations of using routinely collected scan data to examine the effects of TBI treatments. TRIAL REGISTRATION NUMBER ISRCTN15088122.
PICO Summary
Population
Patients with traumatic brain injury from 10 hospitals in the UK and 4 in Malaysia, enrolled in the CRASH-3 trial (n= 1,767).
Intervention
Tranexamic acid (TXA).
Comparison
Placebo.
Outcome
One-third of the patients had a baseline Glasgow Coma Score of 3 (n= 579) and 24% had unilateral or bilateral unreactive pupils. 46% of patients were scanned pre-randomisation and post-randomisation (n= 812/1767), 19% were scanned only pre-randomisation (n= 341/1767) and 35% were scanned only post-randomisation (n= 614/1767). In all patients, there was no evidence that TXA prevents intraparenchymal haemorrhage expansion (estimate= 1.09) or intracranial haemorrhage expansion in patients who underwent neurosurgical haemorrhage evacuation (n= 363), (estimate= 0.79). In patients scanned pre-randomisation and post-randomisation (n= 812), there was no evidence that TXA reduces progressive haemorrhage and new haemorrhage. When patients with unreactive pupils at baseline were excluded, there was evidence that TXA prevents new haemorrhage. In patients scanned post-randomisation (n= 1431), there was no evidence of an increase in infarction with TXA. A larger proportion of patients without (vs. with) a post-randomisation scan died from head injury (38% vs 19%).
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Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT
Roberts I, Shakur-Still H, Aeron-Thomas A, Beaumont D, Belli A, Brenner A, Cargill M, Chaudhri R, Douglas N, Frimley L, et al
Health technology assessment (Winchester, England). 2021;25(26):1-76
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Abstract
BACKGROUND Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. OBJECTIVE To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. DESIGN Randomised trial and economic evaluation. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers and those assessing outcomes were masked to allocation. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. SETTING 175 hospitals in 29 countries. PARTICIPANTS Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. INTERVENTION Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. MAIN OUTCOME MEASURES Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. RESULTS Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). CONCLUSION Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. FUTURE WORK Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. LIMITATIONS Time to treatment may have been underestimated. TRIAL REGISTRATION Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. FUNDING The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.
PICO Summary
Population
Adults with traumatic brain injury enrolled in the CRASH-3 trial (n=9127).
Intervention
Tranexamic acid (TXA), (n= 4613).
Comparison
Matching placebo (n= 4514).
Outcome
The risk of head injury death was 18.5% in the TXA group versus 19.8% in the placebo group. In a pre-specified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the TXA group versus 14.0% in the placebo group. There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury, but in those with severe head injury there was no apparent reduction. Early treatment was more effective in mild and moderate head injury, but there was no obvious impact of time to treatment in cases of severe head injury. The risk of disability, vascular occlusive events and seizures was similar in both groups.
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Cost-effectiveness analysis of tranexamic acid for the treatment of traumatic brain injury, based on the results of the CRASH-3 randomised trial: a decision modelling approach
Williams J, Roberts I, Shakur-Still H, Lecky FE, Chaudhri R, Miners A
BMJ global health. 2020;5(9)
Abstract
INTRODUCTION An estimated 69 million traumatic brain injuries (TBI) occur each year worldwide, with most in low-income and middle-income countries. The CRASH-3 randomised trial found that intravenous administration of tranexamic acid within 3 hours of injury reduces head injury deaths in patients sustaining a mild or moderate TBI. We examined the cost-effectiveness of tranexamic acid treatment for TBI. METHODS A Markov decision model was developed to assess the cost-effectiveness of treatment with and without tranexamic acid, in addition to current practice. We modelled the decision in the UK and Pakistan from a health service perspective, over a lifetime time horizon. We used data from the CRASH-3 trial for the risk of death during the trial period (28 days) and patient quality of life, and data from the literature to estimate costs and long-term outcomes post-TBI. We present outcomes as quality-adjusted life years (QALYs) and 2018 costs in pounds for the UK, and US dollars for Pakistan. Incremental cost-effectiveness ratios (ICER) per QALY gained were estimated, and compared with country specific cost-effective thresholds. Deterministic and probabilistic sensitivity analyses were also performed. RESULTS Tranexamic acid was highly cost-effective for patients with mild TBI and intracranial bleeding or patients with moderate TBI, at £4288 per QALY in the UK, and US$24 per QALY in Pakistan. Tranexamic acid was 99% and 98% cost-effective at the cost-effectiveness thresholds for the UK and Pakistan, respectively, and remained cost-effective across all deterministic sensitivity analyses. Tranexamic acid was even more cost-effective with earlier treatment administration. The cost-effectiveness for those with severe TBI was uncertain. CONCLUSION Early administration of tranexamic acid is highly cost-effective for patients with mild or moderate TBI in the UK and Pakistan, relative to the cost-effectiveness thresholds used. The estimated ICERs suggest treatment is likely to be cost-effective across all income settings globally.
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The Effect of Tranexamic Acid on Functional Outcomes: An Exploratory Analysis of the CRASH-2 Randomized Controlled Trial
Nishijima DK, Kuppermann N, Roberts I, VanBuren JM, Tancredi DJ
Annals of emergency medicine. 2019
Abstract
STUDY OBJECTIVE Tranexamic acid improves survival in severely injured adults. However, its effectiveness on overall functional outcome is unknown. We hypothesized that tranexamic acid improves overall functional outcome compared with placebo in severely injured adults and conduct an exploratory analysis of the Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) data to investigate this hypothesis. METHODS We included injured adults from the CRASH-2 trial who were randomized 3 hours or less from injury. The primary outcome measure was functional status at hospital discharge or on day 28 if the subject was still in the hospital. Functional status was measured with the modified Oxford Handicap Scale, a 6-category ordinal functional outcome scale. We conducted 3 separate analyses using 3 different outcome measures to evaluate the effectiveness of tranexamic acid versus placebo on functional outcomes, including the mean utility-weighted modified Oxford Handicap Scale score (overall functional outcome), the area under the curve (based on functional outcome and rate of recovery), and a sliding dichotomy analysis (favorable versus unfavorable functional outcome) stratified by baseline mortality risk (stratified analysis). RESULTS There were 13,432 patients (6,679 randomized to placebo and 6,753 to tranexamic acid) included in the study cohort. The mean utility-weighted modified Oxford Handicap Scale score was 0.66 (SD 0.33) for patients randomized to tranexamic acid compared with a mean of 0.64 (SD 0.34) for those randomized to placebo (mean difference 0.02; 95% confidence interval [CI] 0.01 to 0.03). The area under the curve analysis demonstrated that patients randomized to tranexamic acid had a higher 28-day mean utility-weighted modified Oxford Handicap Scale score compared with those randomized to placebo (mean score 0.55 [SD 0.30] versus 0.53 [SD 0.31]; mean difference 0.02 [95% CI 0.01 to 0.03]). The sliding dichotomy analysis demonstrated heterogeneity of treatment effects across risk groups. The overall proportion of patients with favorable functional outcomes was higher in the tranexamic acid group (5,360/6,753 [79.4%]; 95% CI 78.4% to 80.3%) compared with the placebo group (5,174/6,679 [77.5%]; 95% CI 76.5% to 78.5%; difference 1.9% [95% CI 0.5% to 3.3%]; number needed to treat=52). When each risk group was tested separately, only the lowest-risk group (<6% baseline mortality risk) demonstrated a statistically significant effect of tranexamic acid toward favorable functional outcomes (tranexamic acid versus placebo adjusted odds ratio 0.78; 95% CI 0.67 to 0.90). There were no differences between tranexamic acid and placebo in the other risk groups. CONCLUSION Across 3 exploratory analyses, severely injured adult patients randomized within 3 hours from injury demonstrated better functional outcomes with tranexamic acid compared with placebo. When heterogeneity of treatment effects across risk groups was evaluated, only the lowest-risk group demonstrated a significant effect of tranexamic acid toward favorable outcomes. Given the overall safety and cost-effectiveness of tranexamic acid use in injured adults, our results further support the use of tranexamic acid for this population. Future trauma trials that evaluate tranexamic acid use should also consider functional status as an important outcome.
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Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients
Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron FX, Roberts I
Lancet (London, England). 2017;391((10116):):125-132. 125
Abstract
BACKGROUND Antifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics. METHODS We did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155. FINDINGS We obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2-3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1.20, 95% CI 1.08-1.33; p=0.001), with no heterogeneity by site of bleeding (interaction p=0.7243). Treatment delay reduced the treatment benefit (p<0.0001). Immediate treatment improved survival by more than 70% (OR 1.72, 95% CI 1.42-2.10; p<0.0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p=0.5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events. INTERPRETATION Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid. FUNDING UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation (CRASH-2 trial). London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation (WOMAN trial).
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Tranexamic acid in bleeding trauma patients: an exploration of benefits and harms
Roberts I, Edwards P, Prieto D, Joshi M, Mahmood A, Ker K, Shakur H
Trials. 2017;18((1)):48.
Abstract
BACKGROUND The CRASH-2 trial showed that tranexamic acid (TXA) administration reduces mortality in bleeding trauma patients. However, the effect appeared to depend on how soon after injury TXA treatment was started. Treatment within 3 h reduced bleeding deaths whereas treatment after 3 h increased the risk. We examine how patient characteristics vary by time to treatment and explore whether any such variations explain the time-dependent treatment effect. METHODS Exploratory analysis were carried out, 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 examine how patient characteristics (age, type of injury, presence or absence of head injury, Glasgow coma scale (GCS), systolic blood pressure and capillary refill time) vary with time to treatment and use univariable (restriction) and multivariable methods to examine whether any such variations explain the time-dependent effect of TXA. If not explained by differences in patient characteristics, we planned to conduct separate prespecified subgroup analyses for the early benefit and late harm. RESULTS There was no substantial variation in age or capillary refill by time to treatment. However, the proportion of patients with blunt trauma, the proportion with head injury and mean systolic blood pressure increased as time to treatment increased. Mean GCS decreased as time to treatment increased. Analyses restricted to patients with blunt trauma, those without head injury and those with a systolic blood pressure <100 mmHg showed that these characteristics did not explain the time-dependent treatment effect. In a multivariable analysis the interaction with time to treatment remained highly significant (p < 0.0001). Separate subgroup analyses that examine how the benefits of early TXA treatment and the harms of late TXA treatment vary by systolic blood pressure (≤75, 76-89, >89 mmHg); GCS (severe 3-8, moderate 9-12, mild 13-15); and type of injury (penetrating versus blunt) showed no significant heterogeneity. CONCLUSIONS The time-dependent effect of TXA in bleeding trauma patients is not explained by the type of injury, the presence or absence of head injury or systolic blood pressure. When given within 3 h of injury, TXA reduces death due to bleeding regardless of type of injury, GCS or blood pressure. TRIAL REGISTRATION ClinicalTrials.gov, NCT00375258 . Registered on 11 September 2006.
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Antifibrinolytic drugs for acute traumatic injury
Roberts I, Shakur H, Ker K, Coats T, CRASH-2 Trial collaborators
Cochrane Database of Systematic Reviews. 2015;5:CD004896.
Abstract
BACKGROUND Uncontrolled bleeding is an important cause of death in trauma victims. Antifibrinolytic treatment has been shown to reduce blood loss following surgery and may also be effective in reducing blood loss following trauma. OBJECTIVES To quantify the effects of antifibrinolytic drugs on mortality, vascular occlusive events, surgical intervention and receipt of blood transfusion after acute traumatic injury. SEARCH METHODS We searched the PubMed, Science Citation Index, National Research Register, Zetoc, SIGLE, Global Health, LILACS, and Current Controlled Trials to March 2004 and the Cochrane Injuries Group Specialised Register, CENTRAL, MEDLINE and EMBASE to July 2010. SELECTION CRITERIA We included all randomised controlled trials of antifibrinolytic agents (aprotinin, tranexamic acid [TXA] and epsilon-aminocaproic acid) following acute traumatic injury. DATA COLLECTION AND ANALYSIS The titles and abstracts identified in the electronic searches were screened by two independent authors to identify studies that had the potential to meet the inclusion criteria. The full reports of all such studies were obtained. From the results of the screened electronic searches, bibliographic searches, and contacts with experts, two authors independently selected trials meeting the inclusion criteria. MAIN RESULTS Four trials met the inclusion criteria, including 20,548 randomised patients. Two trials with a combined total of 20,451 patients assessed the effects of TXA on mortality; TXA reduced the risk of death by 10% (RR=0.90, 95% CI 0.85 to 0.97; P=0.0035). Data from one trial involving 20,211 patients found that TXA reduced the risk of death due to bleeding by 15% (RR=0.85, 95% CI 0.76 to 0.96; P=0.0077). There was evidence that early treatment (<= 3 hours) was more effective than late treatment (>3 hours). There was no evidence that TXA increased the risk of vascular occlusive events or need for surgical intervention. There was no substantial difference in the receipt of blood transfusion between the TXA and placebo groups. The two trials of aprotinin provided no reliable data. AUTHORS' CONCLUSIONS Tranexamic acid safely reduces mortality in bleeding trauma patients without increasing the risk of adverse events. TXA should be given as early as possible and within three hours of injury, as treatment later than this is unlikely to be effective. Further trials are needed to determine the effects of TXA in patients with isolated traumatic brain injury. Systematic Review
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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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Abstract
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.