The Pre-brief
After the results of the CRASH-2 trial in 2010, which showed a significant mortality benefit in patients with traumatic hemorrhage who received timely Tranexamic Acid (TXA)1, clinicians have routinely adopted its use in many settings. A subgroup analysis of CRASH-3 revealed a slight mortality benefit when TXA is given early to patients with a GCS of 9 or more2.
In this post, we will closely examine the role of TXA in patients with TBI. The latest study that specifically looked at this was published in JAMA in September 2020 under the title; Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury:3.
But, first, let’s get the pharmacology out of the way. TXA is a synthetic derivative of the amino acid Lysine that acts by competitively inhibiting plasminogen activation. At higher concentrations, it can also noncompetitively inhibit plasmin. The binding of TXA with plasminogen blocks its interaction with fibrin, preventing the degradation of fibrin clots, which can help the bleeding trauma patient.
Can this help TBI patients?
The study recruited adult patients who were treated by Emergency Medical Services (EMS) and had an initial Glasgow Coma Scale (GCS) of 12 or less and a systolic BP of 90 mmHg or more. 1063 patients were initially recruited, but 96 patients in the TXA arm did not get the drug, leaving a total of 966 patients to be included in the trial. Patients were randomized to either receive one of the following1:
- Placebo: Out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion
- Bolus only: Out-of-hospital 2g IV bolus of TXA and in-hospital placebo 8-hour infusion
- Bolus + maintenance: Out-of-hospital 1g IV bolus of TXA AND in-hospital TXA 1g 8-hour infusion
The majority of patients were male, and the average GCS score at enrolment was 8. The study’s primary outcome was neurological function at 6 months follow-up as assessed by the extended Glasgow Outcome Scale (see below). A favorable outcome was considered to be higher than 4. At that level, patients would be expected to be able to work in sheltered jobs, to have ongoing psychological issues, and to have limited social/leisure activities.
What did the study find?
There was no difference in the primary outcome of favorable neurological outcome on the GOSE score. Of the patients who completed the 6-month follow-up period, 60% of the placebo, 62% of the bolus only, and 58% of the bolus+infusion groups had a favorable outcome.
The overall mortality at 28 days was 16%, with 87% of being attributed to neurological injury. The combined adjusted analysis did not show a statistical difference in mortality between the groups (14% vs. 17%, P=0.26), the GOSE scores (6.8 vs. 7.6), or progression of ICH (16% vs. 20%). The rates of seizure were slightly higher in the bolus only group than other groups (5% vs. 2%).
The Downsides
This randomized and well-designed study shows that TXA did not result in significant neurologic recovery in patients with moderate to severe TBI. In the CRASH-3 trial, there was a significantly lower risk of head injury-related mortality in patients with mild to moderate TBI, which this study did not examine. The GCS score has many limitations when used as a measure of TBI severity as it fails to discriminate between ICH and other causes of CNS depression, such as toxic ingestion, sedation, shock, etc. Additionally, TXA was given to a large number of patients with either no or minimal injury or a nonsurvivable injury. Only 56% of patients had ICH on CT scan that would potentially benefit from TXA, with the remainder of patients potentially diluting the results.
The Debrief
This trial showed that giving TXA within two hours of injury to patients with moderate to severe TBI in the out-of-hospital setting did not result in significant neurologic benefit at 6-month follow-up. In my practice, I would continue giving TXA to patients who present with head injury and hemorrhagic shock.
References
- CRASH-2 trial collaborators, Shakur H, Roberts I, 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 Lond Engl. 2010;376(9734):23-32. doi:10.1016/S0140-6736(10)60835-5. PMID: 20554319
- Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. The Lancet. 2019;394(10210):1713-1723. doi:10.1016/S0140-6736(19)32233-0. PMID: 31623894
- Rowell SE, Meier EN, McKnight B, et al. Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury. JAMA. 2020;324(10):961. doi:10.1001/jama.2020.8958. PMID: 32897344
- Snapshot. Accessed October 11, 2020. https://criticalcarenorthampton.com/trauma-stuff/
