CRASH-3: What is the relevant outcome we are looking for?
Robert G. Hahn
CRASH-3 is a recent controlled clinical trial that deals with the potential benefit of tranexamic acid in isolated Traumatic Brain Injury (TBI) (1). The topic is highly relevant and appropriate, especially after results of CRASH-2 and WOMEN where tranexamic acid administration showed benefits in trauma and obstetric haemorrhage (2,3).
In CRASH-3, the authors recruited 12,373 adult TBI patients who had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding. Within 3 h of the injury, the treatment group received a bolus of 1 g of tranexamic acid followed by an infusion of 1 g over 8 hours.
At 28 days, treatment was associated with an incidence of head injury-related death of 18.5% compared with 19.8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86–1·02]). Subgroup analysis showed that tranexamic acid administration was associated with a significant reduction in the incidence of head injury-related death in the presence of mild to moderate TBI (RR 0·78 [95% CI 0·64–0·95]) but not in patients presenting with severe TBI (0·99 [95% CI 0·91–1·07]. Therefore, the results suggest a beneficial effect of early administration of tranexamic acid, but only in mild-moderate TBI (GCS 9-12). Known side effects of tranexamic, such as seizures and thrombotic events, were studied, but there were no significant differences between treatment and placebo.
CRASH-3 represents a well-conducted international trial with participation of centres from both low- and high-income countries across the globe, which makes the results generalisable worldwide.
Remarkably, the protocol was modified in the middle of the study shortening the injury-intervention time interval from 8 hours to 3 hours, which might be due to inefficacy in the original interval excluding 28% patients for the final analysis.
Two interesting editorials discussing the CRASH-3 study have been published. They have given divergent messages, one having an optimistic tone (4) and another being less optimistic (5).
Persisting unanswered questions makes it somehow adventurous to translate the results of CRASH-3 into clinical practice. The types of neurosurgical interventions performed in the different centres, the neuromonitoring approach used and the administration of corticosteroids are some of the details not clearly stated in the protocol. Also, long-term outcomes are not described, such as >28- day mortality and physician-measured functional status scale (Glasgow outcome Scale) upon discharge. Despite the limitations, we still conclude that early administration of tranexamic acid reduced head-injury related deaths in patients with mild to moderate TBI, while there was no effect in patients with severe TBI.
- CRASH-3 trial collaborators . Lancet. 2019 https://doi.org/10.1016/s0140-6736(19)32233-0
- CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R et al). Lancet 2010; 376(9734):23–32. https:// doi.org/10.1016/s0140-6736(10)60835-5
- Woman Trial Collaborators. Lancet 2017; 389(10084):2105–2116. https://doi.org/10.1016/S0140-6736(17)30638-4
- Cap AP. Lancet 2019https://doi.org/10.1016/s0140-6736(19)32312-8
- Fabio Silvio Taccone, Giuseppe Citerio Nino Stocchetti Intensive Care Med 2019 https://doi.org/10.1007 s00134-019-05879-5