Early Administration Of Tranexamic Acid Research Articles

Tranexamic Acid Administration to Pediatric Trauma Patients in a Combat Setting: The Pediatric Trauma and Tranexamic Acid Atudy (PED-TRAX): Eckert MJ, Wertin TM, Tyner SD, et al. J Trauma Acute Care Surg 2014;77:852–8.

Early administration of tranexamic acid (TXA) in adult trauma patients has been associated with decreased mortality and blood product administration. Limited data are available on the use of TXA in pediatric trauma. The goal of this study was to evaluate the use and efficacy of TXA in pediatric combat patients. The authors conducted a retrospective cohort study of all pediatric trauma admissions to the North Atlantic Treaty Organization Role 3 hospital, Camp Bastion, Afghanistan, from 2008 to 2012. All pediatric trauma patients < 18 years of age were included. The primary outcome for the study was mortality. Secondary outcomes included factors associated with TXA use and complications of TXA use. TXA administration was used at adult dosing, with a single fixed bolus dose of 1 g TXA administered within 3 h of injury. In total, 766 admitted pediatric trauma patients were included in the study, of which 10% received TXA. Overall injury severity score (ISS) for those treated with TXA was significantly higher than average (15 vs. 10, p < 0.05). Significant independent predictors of TXA administration were severe abdominal or extremity injury and severe metabolic acidosis, with base deficit > 5. However, the propensity analysis model showed significant unexplained variance in the decision to administer TXA with an R-squared value of .47. Unadjusted mortality was higher in patients who received TXA (15% vs. 9%), but this difference was not statistically significant (P = 0.06). After controlling for confounding factors including mechanism, injury severity, base deficit, hypotension, and Glasgow Coma Scale score, TXA administration was associated with reduced mortality (P = 0.03). There were nonstatistically significant trends toward improved survival in those patients receiving TXA in subpopulation analysis of those who received transfusions and those severely injured, with an ISS > 15. Analysis of additional outcomes besides mortality studied in propensity-matched groups of TXA vs. no TXA administration demonstrated advantage to the TXA group, with significantly improved neurologic status at the time of discharge or transfer, a higher likelihood of a near-normal GCS score, fewer patients with severe brain injury, and a lower likelihood of requiring mechanical ventilation at the time of discharge or transfer. There were no adverse outcomes associated with the administration of TXA. The authors concluded that the same favorable association of survival advantage and safety profile as seen in the adult trauma population held true in a pediatric trauma population, and furthermore, there may be added benefit of improved neurologic and pulmonary outcomes in patients treated with TXA. Limitations acknowledged by the authors included the retrospective nature of the study, and no information on blood loss or coagulation/thromboelastometry data, which limits the ability to directly measure the effects of TXA on blood loss or coagulation; and lack of data on timing of TXA administration of subsequent dosing. Another limitation noted was that the relatively small population might significantly limit safety conclusions.

Time since injury is the major factor in preventing tranexamic acid use in the trauma setting: An observational cohort study from a major trauma centre in a middle-income country.

Haemorrhage is responsible for about a third of in-hospital trauma deaths. The CRASH-2 trial demonstrated that early administration of tranexamic acid, ideally within 3 hours, can reduce mortality from trauma-associated bleeding by up to 32%. To explore whether, in our trauma network in a middle-income country, patients arrived at hospital soon enough after injury for tranexamic acid administration to be effective and safe. A prospective cohort study of 50 consecutive patients admitted to our trauma unit was undertaken. Inclusion criteria were as for the CRASH-2 study: systolic blood pressure &lt;90 mmHg and/or heart rate &gt;110 beats per minute, with injuries suggestive of a risk of haemorrhage. Patients with isolated head injuries were excluded. The mechanisms of injury, time since injury and any reasons for delay were recorded. Thirteen (26%) patients presented early enough for tranexamic acid administration. Of these, only three patients presented within the 1st hour. Eleven patients had a documented time of injury &gt;3 hours prior to presentation. We were unsure of the time of injury for 26 patients, although for most of these it was likely to be &gt;3 hours before presentation. The majority (74%) of bleeding trauma patients did not present within the timeframe allowed for safe administration of tranexamic therapy. Of those who did, most would have benefited from even earlier commencement of therapy. This raises the possibility that tranexamic acid may be more effective on a population basis if incorporated into prehospital rather than in-hospital protocols; future studies should explore the benefits and risks of this approach.

Management of traumatic haemorrhage--the US perspective.

As compared with European practice, the American approach to resuscitation from traumatic haemorrhage de-emphasises pre-hospital interventions in favour of rapid transport to definitive care; limits initial surgical interventions under the damage control model; uses crystalloid as the initial fluid of choice; and follows an empiric 1:1:1 approach to transfusion with red cells, plasma and platelets in hemodynamically unstable and actively bleeding patients. The use of bedside visco-elastic testing to guide coagulation support is not as widespread as in Europe, while the early administration of tranexamic acid is more selective.

Blood – the most important humour?*

Blood – the most important humour?*

Tranexamic acid administration to pediatric trauma patients in a combat setting: the pediatric trauma and tranexamic acid study (PED-TRAX).

Early administration of tranexamic acid (TXA) has been associated with a reduction in mortality and blood product requirements in severely injured adults. It has also shown significantly reduced blood loss and transfusion requirements in major elective pediatric surgery, but no published data have examined the use of TXA in pediatric trauma. This is a retrospective review of all pediatric trauma admissions to the North Atlantic Treaty Organization Role 3 hospital, Camp Bastion, Afghanistan, from 2008 to 2012. Univariate and logistic regression analyses of all patients and select subgroups were performed to identify factors associated with TXA use and mortality. Standard adult dosing of TXA was used in all patients. There were 766 injured patients 18 years or younger (mean [SD] age, 11 [5] years; 88% male; 73% penetrating injury; mean [SD], Injury Severity Score [ISS], 10 [9]; mean [SD] Glasgow Coma Scale [GCS] score, 12 [4]). Of these patients, 35% required transfusion in the first 24 hours, 10% received massive transfusion, and 76% required surgery. Overall mortality was 9%. Of the 766 patients, 66 (9%) received TXA. The only independent predictors of TXA use were severe abdominal or extremity injury (Abbreviated Injury Scale [AIS] score ≥ 3) and a base deficit of greater than 5 (all p < 0.05). Patients who received TXA had greater injury severity, hypotension, acidosis, and coagulopathy versus the patients in the no-TXA group. After correction for demographics, injury type and severity, vitals, and laboratory parameters, TXA use was independently associated with decreased mortality among all patients (odds ratio, 0.3; p = 0.03) and showed similar trends for subgroups of severely injured (ISS > 15) and transfused patients. There was no significant difference in thromboembolic complications or other cardiovascular events. Propensity analysis confirmed the TXA-associated survival advantage and suggested significant improvements in discharge neurologic status as well as decreased ventilator dependence. TXA was used in approximately 10% of pediatric combat trauma patients, typically in the setting of severe abdominal or extremity trauma and metabolic acidosis. TXA administration was independently associated with decreased mortality. There were no adverse safety- or medication-related complications identified. Therapeutic study, level IV.

Adjunct agents for bleeding.

This review provides a summary of the most recent clinical trials evaluating the hemostatic agents for the treatment of coagulopathy associated with critical bleeding. In particular, antifibrinolytic agents (i.e., aprotinin, tranexamic and ε-aminocaproic acids), desmopressin, recombinant activated factor VII, fibrinogen and prothrombin complex concentrates are evaluated. Among the various therapeutic options available, tranexamic acid is emerging as the most promising. Indeed, a recent randomized trial has shown a benefit survival of the early administration of tranexamic acid in patients with trauma-induced coagulopathy. Although preliminary data document a potential therapeutic role for prohemostatic pharmacologic approaches, further evidence arising from randomized controlled trials is needed to assess the safety and efficacy of such agents in the setting of critical bleeding.

Design of the Study of Tranexamic Acid during Air Medical Prehospital Transport (STAAMP) Trial: Addressing the Knowledge Gaps

Hemorrhage and coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. The development of trauma-induced coagulopathy and hyperfibrinolysis is associated with poor outcomes. Interest in the use of tranexamic acid (TXA) in hemorrhaging patients as an antifibrinolytic agent has grown recently. Additionally, several reports describe immunomodulatory effects of TXA that may confer benefit independent of its antifibrinolytic actions. A large trial demonstrated a mortality benefit for early TXA administration in patients at risk for hemorrhage; however, questions remain about the applicability in developed trauma systems and the mechanism by which TXA reduces mortality. We describe here the rationale, design, and challenges of the Study of Tranexamic Acid during Air Medical Prehospital transport (STAAMP) trial. The primary objective is to determine the effect of prehospital TXA infusion during air medical transport on 30-day mortality in patients at risk of traumatic hemorrhage. This study is a multicenter, placebo-controlled, double-blind, randomized clinical trial. The trial will enroll trauma patients with hypotension and tachycardia from 4 level I trauma center air medical transport programs. It includes a 2-phase intervention, with a prehospital and in-hospital phase to investigate multiple dosing regimens. The trial will also explore the effects of TXA on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research and thus required an investigational new drug approval from the U.S. Food and Drug Administration as well as a community consultation process. It was designed to address several existing knowledge gaps and research priorities regarding TXA use in trauma.

PTU-185 Update On The Halt-it Trial Progress: Tranexamic Acid For The Treatment Of Gastrointestinal Haemorrhage – An International, Randomised, Double Blind Placebo Controlled Trial

IntroductionGastrointestinal (GI) bleeding is a common medical emergency and an important cause of morbidity and mortality in high, middle and low income countries. Despite advances in resuscitative, pharmacological and endoscopic...

Tranexamic Acid, Fibrinogen Concentrate, and Prothrombin Complex Concentrate

Trauma-induced coagulopathy (TIC) occurs early after severe injury. TIC is associated with a substantial increase in bleeding rate, transfusion requirements, and a 4-fold higher mortality. Rapid surgical control of blood loss and early aggressive hemostatic therapy are essential steps in improving survival. Since the publication of the CRASH-2 study, early administration of tranexamic acid is considered as an integral step in trauma resuscitation protocols of severely injured patients in many trauma centers. However, the advantage of en route administration of tranexamic acid is not proven in prospective studies. Fibrinogen depletes early after severe trauma; therefore, it seems to be reasonable to maintain plasma fibrinogen as early as possible. The effect of prehospital fibrinogen concentrate administration on outcome in major trauma patients is the subject of an ongoing prospective investigation. The use of prothrombin complex concentrate is potentially helpful in patients anticoagulated with vitamin K antagonists who experience substantial trauma or traumatic brain injury. Beyond emergency reversal of vitamin K antagonists, safety data on prothrombin complex concentrate use in trauma are lacking.

Tranexamic acid for trauma: Filling the ‘GAP’ in evidence

Following findings of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial, tranexamic acid (TxA) use post trauma is becoming widespread. However, issues of generalisability, applicability and predictability beyond the context of study sites remain unresolved. Internal and external validity of the CRASH-2 trial are currently lacking and therefore incorporation of TxA into routine trauma resuscitation guidelines appears premature. The Pre-hospital Antifibrinolytics for Traumatic Coagulopathy and Haemorrhage (PATCH)-Trauma study is a National Health and Medical Research Council-funded randomised controlled trial of early administration of TxA in severely injured patients likely to have acute traumatic coagulopathy. The study population chosen has high mortality and morbidity and is potentially most likely to benefit from TxA's known mechanisms of action. This and further trials involving appropriate sample populations are required before evidence based guidelines on TxA use during trauma resuscitation can be developed.

Early administration of tranexamic acid reduces death from bleeding in trauma patients

Early administration of tranexamic acid reduces death from bleeding in trauma patients

Treatment of Acute Coagulopathy Associated with Trauma

Coagulopathy is frequently present in trauma. It is indicative of the severity of trauma and contributes to increased morbidity and mortality. Uncontrolled bleeding is the most frequent preventable cause of death in trauma patients reaching hospital alive. Coagulopathy in trauma has been long thought to develop as a result of hemodilution, acidosis, and hypothermia often related to resuscitation practices. However, altered coagulation tests are already present in 25–30% of severe trauma patients upon hospital arrival before resuscitation efforts. Acute coagulopathy associated with trauma (ACoT) has been recognized in recent years as a distinct entity associated with increased mortality, morbidity, and transfusion requirements. Transfusion and nontransfusion strategies aimed at correcting ACoT, particularly in patients with massive bleeding and massive transfusion, are currently available. Early administration of tranexamic acid to bleeding trauma patients safely reduces the risk of death. It has been proposed that early aggressive blood product transfusional management of ACoT with a red blood cell : plasma : platelets ratio close to 1 : 1 : 1 could result in decreased mortality from uncontrolled bleeding.

All we ever wanted to know about perioperative bleeding

All we ever wanted to know about perioperative bleeding

Potential value of pharmacological protocols in trauma

Diagnosis and treatment of trauma-induced coagulopathy (TIC) presents a challenge for trauma care providers. Viscoelastic tests (VETs) including thromboelastometry and thrombelastography are increasingly used to diagnose TIC and guide hemostatic therapy. We summarize the concept of individualized, goal-directed coagulation management using coagulation factor concentrates. Early and aggressive treatment is mandatory to improve the survival of severely bleeding trauma patients. High ratios of fresh frozen plasma to red blood cells are linked to improved outcome in coagulopathic patients; however, treatment is often delayed because most blood products must first be thawed. Lyophilized plasma potentially overcomes these problems. However, until now only limited data on the use of lyophilized plasma in major trauma are available. VETs provide a rapid and comprehensive overview of the coagulation process. Low maximum clot firmness is associated with increased transfusion requirements, and premature lysis of the clot is indicative of poor outcome. Improvement in clot firmness can be achieved by the administration of fibrinogen concentrate or platelet concentrate, depending on the cause of coagulopathy. Early administration of tranexamic acid improves clot stability and outcome in major trauma. Prothrombin complex concentrate increases thrombin generation, but is potentially associated with increased risk of thromboembolic complications. VETs are useful in the diagnosis of TIC, allowing precise deficits in the coagulation process to be identified and specifically targeted with coagulation factor concentrates.

The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients

Among trauma patients who survive to reach hospital, exsanguination is a common cause of death. A widely practicable treatment that reduces blood loss after trauma could prevent thousands of premature deaths each year. The CRASH-2 trial aimed to determine the effect of the early administration of tranexamic acid on death and transfusion requirement in bleeding trauma patients. In addition, the effort of tranexamic acid on the risk of vascular occlusive events was assessed. Tranexamic acid (TXA) reduces bleeding in patients undergoing elective surgery. We assessed the effects and cost-effectiveness of the early administration of a short course of TXA on death, vascular occlusive events and the receipt of blood transfusion in trauma patients. Randomised placebo-controlled trial and economic evaluation. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial co-ordinating centre staff) were masked to treatment allocation. All analyses were by intention to treat. A Markov model was used to assess cost-effectiveness. The health outcome was the number of life-years (LYs) gained. Cost data were obtained from hospitals, the World Health Organization database and UK reference costs. Cost-effectiveness was measured in international dollars ($) per LY. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results to model assumptions. Two hundred and seventy-four hospitals in 40 countries. Adult trauma patients (n = 20,211) with, or at risk of, significant bleeding who were within 8 hours of injury. Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury and other. Patients were allocated to TXA (n = 10,096) and to placebo (n = 10,115), of whom 10,060 and 10,067 patients, respectively, were analysed. All-cause mortality at 28 days was significantly reduced by TXA [1463 patients (14.5%) in the TXA group vs 1613 patients (16.0%) in the placebo group; relative risk (RR) 0.91; 95% confidence interval (CI) 0.85 to 0.97; p = 0.0035]. The risk of death due to bleeding was significantly reduced [489 patients (4.9%) died in the TXA group vs 574 patients (5.7%) in the placebo group; RR 0.85; 95% CI 0.76 to 0.96; p = 0.0077]. We recorded strong evidence that the effect of TXA on death due to bleeding varied according to the time from injury to treatment (test for interaction p < 0.0001). Early treatment (≤ 1 hour from injury) significantly reduced the risk of death due to bleeding [198 out of 3747 patients (5.3%) died in the TXA group vs 286 out of 3704 patients (7.7%) in the placebo group; RR 0.68; 95% CI 0.57 to 0.82; p < 0.0001]. Treatment given between 1 and 3 hours also reduced the risk of death due to bleeding [147 out of 3037 patients (4.8%) died in the TXA group vs 184 out of 2996 patients (6.1%) in the placebo group; RR 0.79; 95% CI 0.64 to 0.97; p = 0.03]. Treatment given after 3 hours seemed to increase the risk of death due to bleeding [144 out of 3272 patients (4.4%) died in the TXA group vs 103 out of 3362 patients (3.1%) in the placebo group; RR 1.44; 95% CI1.12 to 1.84; p = 0.004]. We recorded no evidence that the effect of TXA on death due to bleeding varied by systolic blood pressure, Glasgow Coma Scale score or type of injury. Administering TXA to bleeding trauma patients within 3 hours of injury saved an estimated 755 LYs per 1000 trauma patients in the UK. The cost of giving TXA to 1000 patients was estimated at $30,830. The incremental cost of giving TXA compared with not giving TXA was $48,002. The incremental cost per LY gained of administering TXA was $64. Early administration of TXA safely reduced the risk of death in bleeding trauma patients and is highly cost-effective. Treatment beyond 3 hours of injury is unlikely to be effective. Future work [the Clinical Randomisation of an Antifibrinolytic in Significant Head injury-3 (CRASH-3) trial] will evaluate the effectiveness and safety of TXA in the treatments of isolated traumatic brain injury (http://crash3.lshtm.ac.uk/). Current Controlled Trials ISRCTN86750102, ClinicalTrials.gov NCT00375258 and South African Clinical Trial Register DOH-27-0607-1919. The project was funded by the Bupa Foundation, the J P Moulton Charitable Foundation and the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 10. See HTA programme website for further project information.

Tranexamic Acid use in Trauma: Effective but not Without Consequences

Background: Administration of tranexamic acid (TXA) is associated with reduced mortality in civilian and military settings. The purpose of this study was to assess a TXA treatment guideline in patients with traumatic injury in a Level I trauma center. The guideline was to give TXA to patients going directly to OR, or with SBP < 90, or for whom our massive transfusion guideline was activated. The hypothesis was that TXA would confer mortality benefit without increasing thromboembolic complications (DVT/PE) or acute kidney injury (AKI). Methods: Records of TXA recipients were reviewed. TXA recipients were compared to a random sample of historical controls that met administration criteria but did not receive TXA. Outcomes were compared for patients meeting any criteria for TXA administration and also for those going directly to the OR. Results: From Dec 2011 through July 2012, 52 trauma patients received TXA. When compared to 74 controls (SBP < 90), TXA recipients trended towards lower mortality (5.8% vs 17.6%, p=.05), higher DVT/PE (11.5% vs 0, p=.004), and more AKI (25% vs11%, p=.02). However baseline characteristics were not well matched. When controls were selected from hypotensive patients going directly the OR, baseline matching was excellent. Among well matched direct to the OR cohorts TXA recipients had lower 24h mortality (4.3% vs 19.1%, p=.03), more DVT/PE (12% vs 0%, p=.012), a trend towards more AKI (28% vs 15%, p=.12) but no transfusion differences. Conclusion: In civilian trauma, early TXA administration confers early survival advantage without affecting blood product usage but may increase the risk of DVT/PE and AKI.

CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial

BackgroundWorldwide, over 10 million people are killed or hospitalized because of traumatic brain injury each year. About 90% of deaths occur in low- and middle-income countries. The condition mostly affects young adults, and many experience long lasting or permanent disability. The social and economic burden is considerable. Tranexamic acid (TXA) is commonly given to surgical patients to reduce bleeding and the need for blood transfusion. It has been shown to reduce the number of patients receiving a blood transfusion by about a third, reduces the volume of blood transfused by about one unit, and halves the need for further surgery to control bleeding in elective surgical patients.Methods/designThe CRASH-3 trial is an international, multicenter, pragmatic, randomized, double-blind, placebo-controlled trial to quantify the effects of the early administration of TXA on death and disability in patients with traumatic brain injury. Ten thousand adult patients who fulfil the eligibility criteria will be randomized to receive TXA or placebo. Adults with traumatic brain injury, who are within 8 h of injury and have any intracranial bleeding on computerized tomography (CT scan) or Glasgow Coma Score (GCS) of 12 or less can be included if the responsible doctor is substantially uncertain as to whether or not to use TXA in this patient. Patients with significant extracranial bleeding will be excluded since there is evidence that TXA improves outcome in these patients. Treatment will entail a 1 g loading dose followed by a 1 g maintenance dose over 8 h.The main analyses will be on an ‘intention-to-treat’ basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses for the primary outcome will be based on time from injury to randomization, the severity of the injury, location of the bleeding, and baseline risk. Interaction tests will be used to test whether the effect of treatment differs across these subgroups. A study with 10,000 patients will have approximately 90% power to detect a 15% relative reduction from 20% to 17% in all-cause mortality.Trial registrationCurrent Controlled Trials ISRCTN15088122; Clinicaltrials.gov NCT01402882

Avoidable mortality from giving tranexamic acid to bleeding trauma patients: an estimation based on WHO mortality data, a systematic literature review and data from the CRASH-2 trial

BackgroundThe CRASH-2 trial showed that early administration of tranexamic acid (TXA) safely reduces mortality in bleeding in trauma patients. Based on data from the CRASH-2 trial, global mortality data and a systematic literature review, we estimated the number of premature deaths that might be averted every year worldwide through the use of TXA.MethodsWe used CRASH-2 trial data to examine the effect of TXA on death due to bleeding by geographical region. We used WHO mortality data (2008) and data from a systematic review of the literature to estimate the annual number of in-hospital trauma deaths due to bleeding. We then used the relative risk estimates from the CRASH-2 trial to estimate the number of premature deaths that could be averted if all hospitalised bleeding trauma patients received TXA within one hour of injury, and within three hours of injury. Sensitivity analyses were used to explore the effect of uncertainty in the parameter estimates and the assumptions made in the model.ResultsThere is no evidence that the effect of TXA on death due to bleeding varies by geographical region (heterogeneity p = 0.70). Based on WHO data and our systematic literature review, we estimate that each year worldwide there are approximately 400,000 in-hospital trauma deaths due to bleeding. If patients received TXA within one hour of injury then approximately 128,000 (uncertainty range [UR] ≈ 72,000 to 172,000) deaths might be averted. If patients received TXA within three hours of injury then approximately 112,000 (UR ≈ 68,000 to 148,000) deaths might be averted. Country specific estimates show that the largest numbers of deaths averted would be in India and China.ConclusionsThe use of TXA in the treatment of traumatic bleeding has the potential to prevent many premature deaths every year. A large proportion of the potential health gains are in low and middle income countries.

Tranexamic acid: less bleeding and less thrombosis?

The early administration of tranexamic acid (TXA) to bleeding trauma patients reduces all-cause mortality without increasing the risk of vascular occlusive events. Indeed, the risk of arterial thrombosis appears to be reduced with TXA. In this commentary we hypothesize that TXA has an antithrombotic effect and explore potential mechanisms. These include inhibition of the inflammatory effects of plasmin, effects on platelets and effects on factors V and VIII. If proven, these antithrombotic effects would have major implications for the systemic use of TXA in surgical patients, where TXA has been clearly shown to reduce bleeding.

The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial

The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Tranexamic acid significantly reduced all-cause mortality. Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis, we undertook exploratory analyses of its effect on death due to bleeding. The CRASH-2 trial was undertaken in 274 hospitals in 40 countries. 20,211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or placebo. Patients were randomly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Both participants and study staff (site investigators and trial coordinating centre staff ) were masked to treatment allocation. We examined the effect of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage as assessed by systolic blood pressure, Glasgow coma score (GCS), and type of injury. All analyses were by intention to treat. The trial is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258, and South African Clinical Trial Register/Department of Health DOH-27-0607-1919. 10,096 patients were allocated to tranexamic acid and 10,115 to placebo, of whom 10,060 and 10,067, respectively, were analysed. 1063 deaths (35%) were due to bleeding. We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment (test for interaction p<0.0001). Early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding (198/3747 [5.3%] events in tranexamic acid group vs 286/3704 [7.7%] in placebo group; relative risk [RR] 0.68, 95% CI 0.57-0.82; p<0.0001). Treatment given between 1 and 3 h also reduced the risk of death due to bleeding (147/3037 [4.8%] vs 184/2996 [6.1%]; RR 0.79, 0.64-0.97; p=0.03). Treatment given after 3 h seemed to increase the risk of death due to bleeding (144/3272 [4.4%] vs 103/3362 [3.1%]; RR 1.44, 1.12-1.84; p=0.004). We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure, Glasgow coma score, or type of injury. Tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid is less effective and could be harmful. UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation.