The iPhone 11 of the emergency medicine world has just been released and you should be queueing for the results.
The badEM crew and some guests sat down to understand what this landmark trial means for us in Africa. After reading the appraisal listen to our podcast and to our opinion on what these results mean in our settings.
Trauma accounts for approximately five million deaths annually, (1) an estimated 90% of these occur in low- to middle-income (LMIC) countries. (2) Traumatic brain injury (TBI) has been described as the most important single injury contributing to morbidity and mortality following trauma. (2) In LMICs, the probability of death from TBI is double than in higher-income countries (HICs). (3) Expected to become one of the leading causes of death; TBI occurs predominantly in younger, economically active populations and may thus have far-reaching social effects.
TBI is often complicated by intracranial haemorrhage which may contribute to mortality by increasing intracranial pressure and culminating in cerebral herniation. It has been postulated that reducing intracranial haemorrhage by minimizing blood clot breakdown (fibrinolysis) may limit the size of intracranial haematomas and its subsequent deleterious effects. Tranexamic acid (TXA) has been shown to prevent fibrinolysis in extra-cranial traumatic haemorrhage, having a positive impact on mortality. (4)
According to a meta-analysis of two trials, (5,6) TXA may reduce mortality rates in patients with TBI. However, these studies are limited by small sample sizes and do not provide conclusive evidence around the safety and efficacy of TXA in TBI. The CRASH-3 trial aimed to determine the effect of TXA on morbidity, mortality and the incidence of adverse events in patients with TBI.
How was it done?
The CRASH-3 trial is an international, multi-centre, parallel-arm randomised controlled trial across 29 countries from 175 hospitals from July 2012 to January 2019 of adult patients with TBI.
Population: Adult patients with TBI within 3 hours of injury, GCS ≤12 or any intracranial haemorrhage (ICH) on CT, with no significant extracranial bleed. Changed from within 8 hours to 3 hours following new evidence during trial conduct.
Intervention: TXA 1g infused IV over 10 minutes (loading dose), followed by 1g IV over 8 hours.
Secondary: Early TBI death (within 24 and 48 hours after injury), all-cause and cause specific mortality, disability, vascular occlusive events (MI, stroke, DVT, PE), seizures, complications, neurosurgery, ICU LoS, adverse events within 28 days.
Importantly, patients were randomised only if the treating clinician had doubt as to whether TXA was indicated in the patient or not. This is an important ethical consideration when specific treatment has proven benefit in a subgroup that may potentially be sampled as part of a trial – an effective treatment is therefore not withheld from a patient that may benefit from it.
Patients were randomised centrally by an independent service, allocation was concealed and blinding of clinicians and the analysis team was maintained.
Delayed consent was sought from participants with proxy consent serving as initial inclusion. If a proxy was not available, a participant was enrolled if two clinicians agreed. It is unclear whether these clinicians were investigators in the trial. What is also unclear is whether the community was engaged prior to the start of the trial – this is normally a proviso for delayed consent trials. It is likely that this was done, but not discussed in the main paper.
What did the study find?
When excluding patients with severe TBI and those with unreactive pupils (severe TBI with poor prognosis at the outset), there was no difference in head injury death between TXA and placebo (RR=0.89, 95%CI 0.80-1.00). However, when considering the totality of available evidence in trials of patients with severe TBI, a meta-analysis of the two trials (including CRASH-3) shows TXA reduces death when compared to placebo (RR 0·89, 95% CI 0.80-0·99), with no evidence of increased adverse events.
Additionally, TXA, is effective in patient with mild to moderate TBI compared to patients with severe TBI (RR 0.78, 95%CI 0.64-95). Overarching, TXA is more effective the earlier the drug is administered, especially in mild to moderate TBI patients, whereas in severe TBI patients there is no effect by time to treatment. When considering the meta-analysis effects, one would need to treat 50 patients in
Although not statistically significant (One cannot help but wonder whether this is related to the specific challenges of access to emergency and neuro-intensive care in LMIC settings. We discuss some of these contextual findings in the podcast.
In CRASH-3 randomisation was done appropriately and allocation of the next assignment concealed from study participants and staff. Importantly, randomisation was successful as there was no major evidence of baseline clinical imbalances between groups. Investigators were blinded to which intervention was being received, and this is well described. Especially for patients, blinding is less critical as objective outcomes were being measured. Considering the large sample size of the trial there was minimal and non-differential loss to follow up of patients across the two trial arms. Furthermore, authors reported as per their published protocol in 2012, indicating appropriate outcome reporting. Overall, there seems to be minimal red flags indicating any major risk of bias that would cast doubt on the validity of the trial findings.
Traumatic brain injury is quite sensitive to early insults of hypotension, deranged carbon dioxide levels and hypoxia. It is unclear whether the patients included in the CRASH-3 trial suffered any of these insults earlier. When we consider that out-of-hospital (and/or early care) is often lacking in LMICs it is not surprising that TXA had a smaller effect in these settings. It would therefore be forgiven if TBI management in these settings was focused on preventing these secondary insults instead.
A secondary outcome of the study was the requirement for neurosurgery. This was not reported in the analyses. Were more patients in the TXA group afforded neurosurgery, and this might be the reason for the treatment effect? It is further important to consider that TBI management is multidisciplinary – do you have immediate access to neurosurgery? More importantly for LMICs, can TXA prevent the need for neurosurgery by limiting the size of the ICH? More on this in the podcast.
Considering the massive socio-economic impact that TBI-associated morbidity has on families and healthcare systems, it would have been nice to see an appreciable change in these with the use of TXA. Unfortunately, for all morbidity measures this does not seem to be the case (95% confidence intervals cross the line of no effect). In some instances, the mean RR favours placebo (i.e. patients seem worse off with TXA). We explain this with “survival bias” – patients who would have died from their injury now lives with a disability instead.
Although, we could go on forever about this well-executed trial, one other aspect related to LMICs in particular is the inclusion criteria – GCS ≤12 or any ICH CT. It is unclear how many patients were enrolled using the GCS criteria and how many were enrolled following imaging. More importantly, it is unclear how many patients were enrolled on GCS and later found to have no radiological evidence of ICH (could this have diluted the treatment effect?). In any event, considering that TXA is most likely to benefit patients with mild-to-moderate TBI with ICH and has a time-to-treatment effect that diminishes, the real question is whether this population will receive timely CT scans in the settings that we work within. At the very least, we know that giving TXA to a trauma patient with a concomitant TBI does not appear to cause harm.
Some of our friends have also reviewed the study. Please do read/listen to these as each person looked at the study from a difference lens. Great work friends.
Murray CJL, Barber RM, Foreman KJ, Ozgoren AA, Abd-Allah F, Abera SF, et al. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: quantifying the epidemiological transition. Lancet. 2015 Nov 28;386(10009):2145–91.
Eaton J, Hanif AB, Grudziak J, Charles A. Epidemiology, Management, and Functional Outcomes of Traumatic Brain Injury in Sub-Saharan Africa. World Neurosurg. 2017 Dec;108:650–5.
De Silva MJ, Roberts I, Perel P, Edwards P, Kenward MG, Fernandes J, et al. Patient outcome after traumatic brain injury in high-, middle- and low-income countries: analysis of data on 8927 patients in 46 countries. Int J Epidemiol. 2009 Apr 1;38(2):452–8.
CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects 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 Jul 3;376(9734):23–32.
Perel P, Al-Shahi Salman R, Kawahara T, Morris Z, Prieto-Merino D, Roberts I, et al. CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury, a nested randomised, placebo-controlled trial. Health Technol Assess (Rockv). 2012 Mar;16(13):iii–xii, 1–54.
Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, Thinkamrop B, Phuenpathom N, Lumbiganon P. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. BMC Emerg Med. 2013 Nov 22;13:20.