CRASH-2 Trial Research Articles

Effect of early tranexamic acid treatment on fatigue in patients with mild traumatic brain injury: data from the CRASH-3 clinical trial

Background Each year world-wide about 65 million people sustain a mild traumatic brain injury (mTBI). Fatigue is a common and distressing symptom after mTBI. We examine the effect of tranexamic acid (TXA) on fatigue in patients with mTBI using data from the CRASH-3 trial. Methods The CRASH-3 trial randomised 9,202 patients with traumatic brain injury and no significant extracranial bleeding to receive TXA or placebo within 3 hours of injury. The primary outcome was death from head injury within 28 days of injury. The methods and results are presented elsewhere. Fatigue was recorded as “None”, “Moderate” or “Extreme.” This study examines the effect of TXA on extreme fatigue in the 2,632 patients with mTBI (Glasgow Coma Scale [GCS] score≥13). Our analyses were not prespecified. Results Our study primary outcome, extreme fatigue, was reported for 10 (0.8%) of 1,328 patients receiving TXA and 19 (1.5%) of 1,288 patients receiving placebo (risk ratio [RR]=0.51, 95% confidence interval [CI] 0.24-1.09). Death within 28 days of injury was reported for 34 (2.6%) of 1,328 patients receiving TXA versus 47 (3.6%) of 1,288 patients receiving placebo (RR=0.70, 95% CI 0.45-1.08). Among patients allocated to TXA, 44 (3.3%) patients either died or reported extreme fatigue versus 66 (5.1%) patients among those allocated to placebo (RR=0.65, 95% CI 0.44-0.94). This composite outcome is disproportionately influenced by deaths which account for 74% (81 from 110) of events. Conclusions We found no evidence that tranexamic acid reduces fatigue in patients with mTBI. Given, 1) our analyses were not prespecified, 2) our outcome measure is not based on a validated fatigue severity scale, and 3) TBI patients can suffer from hospital-induced delirium, which hinders clinician assessment, these results need to be replicated in another study. Registration ISRCTN (ISRCTN15088122, 19/07/2011), ClinicalTrials.gov (NCT01402882, 26/07/2011), EudraCT (2011-003669-14, 25/07/2011), Pan African Clinical Trial Registry (PACTR20121000441277, 30/10/2012).

Effect of early tranexamic acid treatment on fatigue in patients with mild traumatic brain injury: data from the CRASH-3 clinical trial.

Each year world-wide about 65 million people sustain a mild traumatic brain injury (mTBI). Fatigue is a common and distressing symptom after mTBI. We examine the effect of tranexamic acid (TXA) on fatigue in patients with mTBI using data from the CRASH-3 trial. The CRASH-3 trial randomised 9,202 patients with traumatic brain injury and no significant extracranial bleeding to receive TXA or placebo within 3 hours of injury. The primary outcome was death from head injury within 28 days of injury. The methods and results are presented elsewhere. Fatigue was recorded as "None", "Moderate" or "Extreme." This study examines the effect of TXA on extreme fatigue in the 2,632 patients with mTBI (Glasgow Coma Scale [GCS] score≥13). Our analyses were not prespecified. Our study primary outcome, extreme fatigue, was reported for 10 (0.8%) of 1,328 patients receiving TXA and 19 (1.5%) of 1,288 patients receiving placebo (risk ratio [RR]=0.51, 95% confidence interval [CI] 0.24-1.09). Death within 28 days of injury was reported for 34 (2.6%) of 1,328 patients receiving TXA versus 47 (3.6%) of 1,288 patients receiving placebo (RR=0.70, 95% CI 0.45-1.08). Among patients allocated to TXA, 44 (3.3%) patients either died or reported extreme fatigue versus 66 (5.1%) patients among those allocated to placebo (RR=0.65, 95% CI 0.44-0.94). This composite outcome is disproportionately influenced by deaths which account for 74% (81 from 110) of events. We found no evidence that tranexamic acid reduces fatigue in patients with mTBI. Given, 1) our analyses were not prespecified, 2) our outcome measure is not based on a validated fatigue severity scale, and 3) TBI patients can suffer from hospital-induced delirium, which hinders clinician assessment, these results need to be replicated in another study. ISRCTN (ISRCTN15088122, 19/07/2011), ClinicalTrials.gov (NCT01402882, 26/07/2011), EudraCT (2011-003669-14, 25/07/2011), Pan African Clinical Trial Registry (PACTR20121000441277, 30/10/2012).

130 Prediction of In-Hospital Mortality After Acute Traumatic Brain Injury managed by Tranexamic Acid: Secondary Exploration of CRASH-3 Trial via Automated Machine Learning

INTRODUCTION: Acute traumatic brain injury (acTBI) has significant morbidity and mortality (M&M) associated with it— increased intracranial pressure (ICP) among the attributed causative mechanisms. Tranexamic acid, therefore, is adopted to decrease ICP and subsequently the acTBI-associated M&M. METHODS: The study population comprised 12,743 patients from 175 hospitals in 29 countries experiencing acTBI randomly assigned to receive tranexamic acid or placebo. The current state of the art (SOTA) for automated Machine Learning (aML) was adopted to develop predictive models with the incorporation of the ensemble approach. Logloss and Macro weighted average Area Under the Receiver Operating Curve (mWA-AUROC) assessed the predictive discriminative ability of the developed models. RESULTS: An ensemble of Extreme Gradiant Boosting Machine, Light Gradiant Boosting Machine, CatBoost, Random Forest and Neural Network predicted IHM along with the cause of death in acTBI patients randomly assigned to Tranexamic acid management with an mWA-AUROC of 0.94, an accuracy of 85.8% and a logloss of 0.37. Motor and verbal responses along with pupillary reactions were recognized as the most influential predictors for IHM in such patients with maintenance dose of Tranexamic acid imparting moderate to minuscule influence. Boxplot indicates a relative decrease in logloss by adopting the ensemble approach. CONCLUSIONS: Our novel approach to developing predictive prognosticative models for acTBI patients managed by Tranexamic acid by exploring automated machine learning is the very first attempt of its nature. Adoption of the current SOTA for aML provides optimal predictions which, when incorporated into the respective management and prognosticative protocols, shall translate into a decrease in the M&M associated with TBI by assisting in risk stratification and complication triaging.

Estimated Cost-Effectiveness of Implementing a Statewide Tranexamic Acid Protocol for the Management of Suspected Hemorrhage in the Prehospital Setting

Introduction: Hemorrhage is responsible for up to 40% of all traumatic deaths. The seminal CRASH-2 trial demonstrated a reduction in overall mortality following early tranexamic acid (TXA) administration to bleeding trauma patients. Following publication of the trial results, TXA has been incorporated into many prehospital trauma protocols. However, the cost-effectiveness of widespread TXA adoption by EMS is unknown. Objective: To estimate the cost-effectiveness of statewide implementation of a TXA protocol. Methods: The North Carolina Trauma Registry was queried to identify potential TXA patients using the a priori criteria of age ≥18 years, suspected hemorrhage, penetrating or blunt injury, and prehospital blood pressure <90 mmHg and heart rate >110 bpm. Using life tables adjusted for age, sex, and race, and the absolute risk reductions in mortality with early TXA administration reported in the literature, the life-years gained were calculated for each potential life saved. Implementation costs consisted of initial stocking, training, and replacement costs. Projected reduction in hospitalization costs were based on estimates reported in the literature. Economic analyses were conducted from societal and state EMS system perspectives. To assess the robustness of the model, univariate and bivariate sensitivity analyses were performed on selected input variables. Results: Based on the TXA inclusionary criteria, 159 patients could potentially receive TXA per year. In the base-case scenario with a projected absolute mortality reduction of 3%, an additional 4.8 lives per year in NC would be saved, with an estimated 191 total life-years gained. The statewide implementation and operation cost was $305,122 in year 1, and continued operating costs were $6,042 in years 2 and 3, yielding a cost per life saved of $63,967 in year 1 and $1,267 in years 2 and 3. The cost per life-year gained was $1,595 in year 1 and $32 in years 2 and 3. Annual hospitalization costs would potentially be reduced by $1,828,072. Conclusion: Previous studies have demonstrated the clinical effectiveness of early TXA administration to patients with hemorrhage. Our modeling of the financial implications and clinical benefits of implementing a statewide TXA protocol suggests that prehospital TXA is a cost-effective treatment.

Use of tranexamic acid in major trauma: a sex-disaggregated analysis of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2 and CRASH-3) trials and UK trauma registry (Trauma and Audit Research Network) data

BackgroundWomen are less likely than men to receive some emergency treatments. This study examines whether the effect of tranexamic acid (TXA) on mortality in trauma patients varies by sex and whether the receipt of TXA by trauma patients varies by sex. MethodsFirst, we conducted a sex-disaggregated analysis of data from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH)-2 and CRASH-3 trials. We used interaction tests to determine whether the treatment effect varied by sex. Second, we examined data from the Trauma and Audit Research Network (TARN) to explore sex differences in the receipt of TXA. We used logistic regression models to estimate the odds ratio for receipt of TXA in females compared with males. Results are reported as n (%), risk ratios (RR), and odds ratios (OR) with 95% confidence intervals. ResultsOverall, 20 211 polytrauma patients (CRASH-2) and 12 737 patients with traumatic brain injuries (CRASH-3) were included in our analysis. TXA reduced the risk of death in females (RR=0.69 [0.52–0.91]) and in males (RR=0.80 [0.71–0.90]) with no significant heterogeneity by sex (P=0.34). We examined TARN data for 216 364 patients aged ≥16 yr with an Injury Severity Score ≥9 with 98 879 (46%) females and 117 485 (54%) males. TXA was received by 7198 (7.3% [7.1–7.4%]) of the females and 19 697 (16.8% [16.6–17.0%]) of the males (OR=0.39 [0.38–0.40]). The sex difference in the receipt of TXA increased with increasing age. ConclusionsAdministration of TXA to patients with bleeding trauma reduces mortality to a similar extent in women and men, but women are substantially less likely to be treated with TXA.

Tranexamic acid for trauma in the USA: is prejudice a barrier to saving lives?

The CRASH-2 clinical trial results were published in June, 2010. 1 CRASH-2 trial collaboratorsEffects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010; 376: 23-32 Summary Full Text Full Text PDF PubMed Scopus (1970) Google Scholar , 2 CRASH-2 collaboratorsThe importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011; 377: 1096-1101 Summary Full Text Full Text PDF PubMed Scopus (749) Google Scholar Our global collaboration had randomly allocated 20 211 trauma patients from 274 hospitals in 40 countries to receive tranexamic acid, an antifibrinolytic agent to prevent or reduce bleeding, or placebo. Timely tranexamic acid treatment reduced bleeding deaths by nearly one third and without any side-effects. 1 CRASH-2 trial collaboratorsEffects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010; 376: 23-32 Summary Full Text Full Text PDF PubMed Scopus (1970) Google Scholar , 2 CRASH-2 collaboratorsThe importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011; 377: 1096-1101 Summary Full Text Full Text PDF PubMed Scopus (749) Google Scholar We estimated that widespread use of tranexamic acid could prevent more than 120 000 trauma deaths each year worldwide, with 3500 deaths avoided each year in the USA. 3 Ker K Kiriya J Perel P Edwards P Shakur H Roberts I 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. BMC Emerg Med. 2012; 12: 3 Crossref PubMed Scopus (61) Google Scholar Within weeks of publication in 2010, the British Army was using tranexamic acid for treatment of trauma on the battlefield. In 2010, the war in Afghanistan was at its worst with thousands of civilian deaths due to violence and injury. 2010 was also a disastrous year for the US Army in this war with 496 soldiers killed. But the US Army was slow to adopt tranexamic acid.

Effect of age on the efficacy of tranexamic acid: An analysis of heterogeneity of treatment effect within the CRASH-2 dataset.

Trauma is a major cause of morbidity and mortality in older adults and will become more common as the population ages. Tranexamic acid (TXA) is a lysine analogue frequently used in the setting of significant trauma with hemorrhage. The aim of this study is to investigate the heterogeneity of treatment effect of TXA as it relates to patient age during trauma care. We included patients from the CRASH-2 trial who were randomized within 3h of injury. Patients were stratified into age groups <26years, 26 to 35years, 36 to 45years, 46 to 55years, and>55years. Multiple logistic regression models were utilized to evaluate adjusted odds ratios (OR) with 95% confidence intervals (CI) for mortality. Heterogeneity of treatment effect was evaluated using Akaike and Bayesian information criteria to determine the optimum logistic regression model after which a Wald Chi-square test was utilized to evaluate statistical significance. On univariate analysis, TXA administration decreased mortality within the <26years cohort (decrease of 2.1%, 95% CI 0.2 to 4.0), 46 to 55years cohort (decrease 6.7%, 95% CI 2.7 to 10.7), and>55years cohort (decrease of 5.3%, 95% CI 0.4 to 10.3). On adjusted analysis, when compared to the 36 to 45years cohort, the <26year cohort experienced a decreased mortality (OR 0.72, 95% CI 0.62 to 0.85) whereas the >55year cohort experienced increased mortality (OR 1.8, 95% CI 1.5 to 2.2). Assessment for heterogeneity of treatment effect of TXA administration between groups approached but did not reach statistical significance (p=0.11). Mortality related to trauma increases with age, however, there does not appear to be heterogeneity of treatment effect for TXA administration among different age groups.

The role of tranexamic acid in traumatic brain injury

Evidence from recent trials evaluating efficacy of antifibrinolytic agents in the context of traumatic brain injury may lead to changes in the management of patients with traumatic brain injury. Tranexamic acid (TXA) reduces the proteolytic action of plasmin on fibrin clots, resulting in an inhibition of fibrinolysis and stabilisation of established blood clots. There has been significant interest in use of the drug as a therapeutic agent in the context of severe haemorrhage; however, considerable controversies regarding its efficacy remain. A number of trials have demonstrated a small but significant decrease in mortality following its administration, but the results have been somewhat inconsistent and may not be generalisable. The results of the CRASH-3 trial were that there was no statistical difference in the number of traumatic brain injury related deaths (18.5% with TXA and 19.8% with placebo; relative risk [RR] 0·94; 95% confidence interval [CI] 0·86–1·02). Nonetheless, there was a subgroup of patients for whom TXA appeared to provide benefit, and this was in patients with mild and moderate injury (with a Glasgow Coma Score > 8). This is potentially a very important finding that may have huge potential implications; however, we believe it does not currently provide indisputable evidence to support the administration of TXA to all patients with TBI. Further work is required to better define the subset of patients who may benefit as well as to evaluate the long-term functional benefit in order to determine which types of severe traumatic brain injury patients would derive more benefits than harms from TXA.

Effect of early tranexamic acid treatment on fatigue in patients with mild traumatic brain injury: data from the CRASH-3 clinical trial

Background: Each year world-wide about 65 million people sustain a mild traumatic brain injury (mTBI). Fatigue is a common and distressing symptom after mTBI. We examine the effect of tranexamic acid (TXA) on fatigue in patients with mTBI using data from the CRASH-3 trial. Methods: The CRASH-3 trial randomised 9,202 patients with traumatic brain injury and no significant extracranial bleeding to receive TXA or placebo within 3 hours of injury. The primary outcome was death from head injury within 28 days of injury. The methods and results are presented elsewhere. Fatigue was recorded as “None”, “Moderate” or “Extreme.” This study examines the effect of TXA on extreme fatigue in the 2,632 patients with mTBI (Glasgow Coma Scale [GCS] score≥13). Our analyses were not prespecified. Results: Our study primary outcome, extreme fatigue, was reported for 10 (0.8%) of 1,328 patients receiving TXA and 19 (1.5%) of 1,288 patients receiving placebo (risk ratio [RR]=0.51, 95% confidence interval [CI] 0.24-1.09). Death within 28 days of injury was reported for 34 (2.6%) of 1,328 patients receiving TXA versus 47 (3.6%) of 1,288 patients receiving placebo (RR=0.70, 95% CI 0.45-1.08). Among patients allocated to TXA, 44 (3.3%) patients either died or reported extreme fatigue versus 66 (5.1%) patients among those allocated to placebo (RR=0.65, 95% CI 0.44-0.94). Conclusions: Early tranexamic acid treatment may reduce fatigue in mTBI patients, but these results need to be confirmed in a larger trial. Registration: ISRCTN (ISRCTN15088122, 19/07/2011), ClinicalTrials.gov (NCT01402882, 26/07/2011), EudraCT (2011-003669-14, 25/07/2011), Pan African Clinical Trial Registry (PACTR20121000441277, 30/10/2012).

Prehospital Tranexamic Acid (TXA) in Patients with Traumatic Brain Injury (TBI).

Traumatic brain injury (TBI) remains a significant medical and socioeconomic challenge. The initial injury may be complicated by haemostatic derangements leading to exacerbation of lesions and haemorrhagic progression. The results from the CRASH-3 trial have promoted the implementation of the antifibrinolytic tranexamic acid (TXA) into prehospital Emergency Medical Services (EMS) protocols. Very recently, the efficacy and safety of early out-of-hospital TXA compared to placebo was assessed in patients with moderate or severe TBI in a prospective, multicenter phase II trial, e.g. "The Prehospital TXA for TBI"-trial. Simultaneously, the results from a retrospective analysis of prospectively collected observational data into the Dutch pre-hospital TBI database were published which had assessed whether prehospital administration of TXA may be associated with mortality and functional outcomes in patients with severe TBI. Both studies are reviewed against their limitations and windows of opportunity are highlighted.

New and Off-Label Uses of Tranexamic Acid.

New and Off-Label Uses of Tranexamic Acid.

Including random centre effects in design, analysis and presentation of multi-centre trials

BackgroundIn large multicentre trials in diverse settings, there is uncertainty about the need to adjust for centre variation in design and analysis. A key distinction is the difference between variation in outcome (independent of treatment) and variation in treatment effect. Through re-analysis of the CRASH-2 trial (2010), this study clarifies when and how to use multi-level models for multicentre studies with binary outcomes.MethodsCRASH-2 randomised 20,127 trauma patients across 271 centres and 40 countries to either single-dose tranexamic acid or identical placebo, with all-cause death at 4 weeks the primary outcome. The trial data had a hierarchical structure, with patients nested in hospitals which in turn are nested within countries. Reanalysis of CRASH-2 trial data assessed treatment effect and both patient and centre level baseline covariates as fixed effects in logistic regression models. Random effects were included to assess where there was variation between countries, and between centres within countries, both in underlying risk of death and in treatment effect.ResultsIn CRASH-2, there was significant variation between countries and between centres in death at 4 weeks, but absolutely no differences between countries or centres in the effect of treatment. Average treatment effect was not altered after accounting for centre and country variation in this study.ConclusionsIt is important to distinguish between underlying variation in outcomes and variation in treatment effects; the former is common but the latter is not. Stratifying randomisation by centre overcomes many statistical problems and including random intercepts in analysis may increase power and decrease bias in mean and standard error estimates.Trial registrationCurrent Controlled Trials ISRCTN86750102, ClinicalTrials.gov NCT00375258, and South African Clinical Trial Register DOH-27-0607-1919

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

BackgroundEarly 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...

Tranexamic acid and traumatic brain injuries.

The CRASH-3 trial examined the use of tranexamic acid (TXA) in patients with intracranial bleeding secondary to traumatic brain injury. The trial demonstrated that TXA, an antifibrinolytic medication, reduces mortality in patients with mild to moderate head injuries. However, because of the trial's multiple limitations, TXA cannot yet be called the gold standard.

Tranexamic Acid for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality. In 2014, there were approximately 2.5 million emergency department visits for TBI in the United States, with 56,800 deaths attributed directly to TBI.1 Among survivors it is estimated millions more live with long-term disability.2 While one large study demonstrates a mortality benefit (NNT=67) for tranexamic acid (TXA) in multi-system trauma,3 no primary outcome benefit was demonstrated for TXA in the WOMAN trial4 of post-partum hemorrhage or in the HALT-IT trial5 of gastrointestinal bleeding. Here we summarize results from the CRASH-3 trial,6 as well as from a systematic review combining this trial with data from 6 smaller trials of TXA for TBI.7.

Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial

BackgroundThe CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death.MethodsThe CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis.ResultsThere were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94).ConclusionsTranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury.Trial registrationISRCTN15088122, registered on 19 July 2011; NCT01402882, registered on 26 July 2011.

Prehospital Administration of Tranexamic Acid in Patients with Head Injury

The CRASH-3 trial touted reduced mortality in patients with mild-to-moderate traumatic brain injury (TBI) who received tranexamic acid (TXA; NEJM JW

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

IntroductionAn 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...

Hot Off the Press: SGEM#293: CRASH in the US, CRASH in the US, CRASH-2 in the USA.

The CRASH-2 and CRASH-3 trials evaluated the use of tranexamic acid (TXA) in trauma patients, assessing the outcomes of mortality reduction as well as thromboembolic outcomes. Neither study included any significant number of US trauma patients. The discussed manuscript is a retrospective study of adult trauma patients, in the US, who received TXA and assess overall mortality and thromboembolic outcomes. We review the manuscript as well as the Hot-Off-the-Press podcast and social media commentary.

Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results

BackgroundEarly treatment with tranexamic acid may reduce deaths after traumatic brain injury (TBI). In mild and moderate TBI, there is a time to treatment interaction, with early treatment being most beneficial. Time to treatment was recorded by clinicians and is subject to error. Using monitoring data from the CRASH-3 trial, we examine the impact of errors in time to treatment on estimated treatment effects.MethodsThe CRASH-3 trial was a randomised trial of the effect of tranexamic acid on death and vascular occlusive events in 12,737 TBI patients. This analysis includes the 8107 patients with a Glasgow coma scale score of 9 to 15 since previous analyses showed that these patients benefit most from early treatment. Clinician-recorded time to treatment was checked against ambulance and hospital records for 1368/12,737 (11%) patients. Patients who died were preferentially selected for monitoring and we monitored 36% of head injury deaths. We describe measurement errors using Bland-Altman graphs. We model the effect of tranexamic acid on head injury death using logistic regression with a time-treatment interaction term. We use regression calibration, multiple imputation and Bayesian analysis to estimate the impact of time to treatment errors.ResultsClinicians rounded times to the nearest half or full hour in 66% of cases. Monitored times were also rounded and were identical to clinician times in 63% of patients. Times were underestimated by an average of 9 min (95% CI − 85, 66). There was more variability between clinician-recorded and monitored times in low- and middle-income countries than in high-income countries. The treatment effect estimate at 1 h was greater for monitored times OR = 0.61 (95% CI 0.47, 0.81) than for clinician-recorded times OR = 0.63 (95% CI 0.48, 0.83). All three adjustment methods gave similar time to treatment interactions. For Bayesian methods, the treatment effect at 1 h was OR = 0.58 (95% CI 0.43, 0.78). Using monitored times increased the time-treatment interaction term from 1.15 (95% CI 1.03, 1.27) to 1.16 (95% CI 1.05, 1.28).ConclusionsAccurate estimation of time from injury to treatment is challenging, particularly in low resource settings. Adjustment for known errors in time to treatment had minimal impact on the trial results.Trial registrationClinicalTrials.gov NCT01402882. Registered on 25 July 2011