Background

The use of tranexamic acid (TXA) in traumatic brain injury (TBI) has been debated since early studies like CRASH-2, which found that TXA could reduce mortality in bleeding trauma patients. Subsequent trials, including CRASH-3, examined its potential benefits specifically for TBI patients, showing mixed results. While CRASH-3 found no overall survival benefit, it did suggest a decrease in mortality for patients with mild-to-moderate TBI and we do recommend it’s use as per UK guidelines.

This current study, a secondary analysis of the Prehospital TXA for TBI Trial, seeks to further clarify TXA’s role, focusing on patients with intracranial hemorrhage (ICH) confirmed by CT scans, to assess whether different TXA dosing regimens impact mortality and long-term neurological outcomes. The abstract is below, but as we always say, go read the paper yourself.

The Abstract

BACKGROUND
In the prehospital tranexamic acid (TXA) for traumatic brain injury (TBI) trial, TXA administered within 2 hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT).
METHODS
This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale score <13) and systolic blood pressure ≥ 90 mm Hg within 2 hours of injury to a 2-g out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-g out-of-hospital TXA bolus/1-g in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) ≤ 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors.
RESULTS
The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-g TXA bolus group (17%) compared with the other two groups (1-g bolus/1-g infusion 26%, placebo 27%). The estimated adjusted difference between the 2-g bolus and placebo groups was -8.5 percentage points (95% confidence interval [CI], -15.9 to -1.0) and between the 2-g bolus and 1-g bolus/1-g infusion groups was -10.2 percentage points (95% CI, -17.6 to -2.9). Disability Rating Scale at 6 months was lower in the 2-g TXA bolus group than the 1-g bolus/1-g infusion (estimated difference – 2.1 [95% CI, -4.2 to -0.02]) and placebo groups (-2.2 [95% CI, -4.3, -0.2]). Six- month GOSE did not differ among groups.
CONCLUSION
A 2-g out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28- day mortality and lower 6-month DRS than placebo and standard TXA dosing.

Rowell, S., et al. (2024). The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: A subgroup analysis from the prehospital TXA for TBI trial.
Journal of Trauma and Acute Care Surgery, 97(4), 572–580

What kind of study is this?

This study is a secondary analysis of the Prehospital TXA for TBI Trial, a double-blind, randomised, placebo-controlled trial conducted across the US and Canada. The original trial aimed to assess whether different dosing regimens of TXA administered within two hours of injury could reduce mortality and improve neurological outcomes in patients with moderate-to-severe TBI. This analysis focuses on the subgroup of patients with ICH, a specific group hypothesised to benefit the most from TXA’s antifibrinolytic properties. We covered this topic on the blog here back in 2020. Prehospital TXA for TBI Trial is a reminder that this is quite old data, and it’s unclear why this paper is emerging now. There’s nothing wrong with sub-analyses of PRCTs, but we must always be a bit more sceptical of the outcomes as often neither the design nor the outcomes were originally planned.

A reminder that the original trial design included three treatment arms:

1. A 2-g TXA bolus administered in the prehospital setting, followed by an in-hospital placebo infusion.
2. A 1-g TXA bolus in the prehospital setting, followed by a 1-g infusion over eight hours in-hospital.
3. A placebo group that received saline in both the prehospital and in-hospital phases.

This trial used randomisation and blinding to control for bias, and all participants had confirmed moderate-to-severe TBI, defined by a Glasgow Coma Scale (GCS) score below 13 and a systolic blood pressure above 90 mmHg.

Tell me about the patients

The study included 541 participants from the original trial who had confirmed ICH on initial head CT scans. Important to note that they only looked at patients with confirmed ICH, which is not the population that we decide to give TXA to (which is those that we ‘suspect’ of ICH). That difference is key as it probably means that all these patients have the potential to benefit, whereas those suspected but who do not have bleeding are probably just exposed to the risks (if any exist). Key inclusion criteria for the original trial were moderate-to-severe TBI (GCS < 13), systolic blood pressure ≥ 90 mmHg, and at least one reactive pupil. The median age of participants was around 43 years, with the majority being male. Patients were evenly distributed across the three treatment arms, and baseline characteristics such as injury severity and prehospital care were reasonably well-matched between the groups.

Importantly, the trial excluded patients with shock or severe hypoxia to isolate the effects of TXA on brain injury specifically and not on haemorrhagic shock management. Again, this means that we are looking at a subset of the trauma patients we see in practice. Nice for analysis, but each time we restrict, it becomes less ‘real-world practice’.

What were the outcomes?

The primary outcome measured was neurological function at six months, assessed by the Glasgow Outcome Scale-Extended (GOSE) and the Disability Rating Scale (DRS). IN addition they looked at a few secondary outcomes, including:

• 28-day mortality.
• Progression of intracranial haemorrhage, defined as a greater than 33% increase in haematoma volume.
• A composite outcome of ICH progression or mortality at 28 days.

Neurological outcomes were critical for assessing the long-term impact of TXA in TBI patients, as improved survival with significant disability may not represent a meaningful benefit.

What are the main results?

• 28-day mortality was significantly lower in the 2-g TXA bolus group (17%) compared to the placebo group (27%) and the 1-g bolus/1-g infusion group (26%). The absolute risk reduction was 8.5 percentage points compared to the placebo and 10.2 points compared to the 1-g bolus group.
• Six-month neurological outcomes showed no significant difference in the GOSE between groups, but patients in the 2-g bolus group had a lower DRS, indicating less disability. The estimated difference in DRS was -2.1 compared to placebo and -2.2 compared to the 1-g bolus group.
• ICH progression did not differ significantly between groups, though there was a trend toward less progression in the 2-g bolus group compared to placebo.

How robust are the findings?

It’s always great to see a randomised, double-blind design in trauma resuscitation. They have defined a specific group of patients with TBI and confirmed ICH, a population likely to benefit from antifibrinolytic therapy and where we might see the most benefit. I also like the fact that they have looked at 6-month outcomes and mortality.

However, there are concerns with this approach if we are to translate it into practice.

• The analysis is post-hoc, meaning it was not the primary focus of the original trial, which can introduce biases even in well-conducted studies. This is always my major concern woth these studies.
• Only including patients with defined ICH on scan means that this is not the group of patients I see when deciding to give TXA. Patients were only confirmed to have ICH after randomisation, raising the question of whether TXA affected ICH formation rather than just progression.
• Despite randomisation, the 2-g TXA bolus group had fewer penetrating injuries, which may have influenced mortality results, though sensitivity analyses attempted to adjust for this.
• There were differences in VTE rates with more in the 2g bolus group and placebo groups as compared to the 1g regime (small numbers though so not significant but needs watching).

We are also seeing an effect similar to some other trials of TXA where there is an early mortality benefit, but the later outcomes are not as appealing. The lack of a significant difference in GOSE scores at six months is consistent with other studies. The DRS scores suggest reduced disability, but the differences are small and may be of little clinical significance.

Should we change practice based on this study?

The findings of this study suggest that a 2-g bolus of TXA administered early in the prehospital setting could reduce mortality in patients with TBI and ICH. This aligns with other research indicating that early intervention with TXA may be beneficial in trauma patients, particularly those at risk for haemorrhage.

However, we are not seeing a big difference in long-term outcomes here, which is what I really want to see. That said we can only get better outcomes if we have more survivors. The 2g dosing does not appear to be worse in any way and there are practical reasons why it’s easier to give as a bolus. So if it is disadvantageous and easier, it’s certainly worth considering (and is increasingly done in practice here in Virchester). To be sure we would really need a larger trial specifically designed to assess the 2-g TXA bolus in TBI patients with ICH, ideally with long-term follow-up focusing on both survival and neurological function.

Ultimately, this is an interesting observation in a post hoc subgroup analysis. However, we should be wary of using this level of evidence to change practice.

Summary

Although a secondary analysis, this study offers insight into the potential benefits of a higher dose of TXA administered early to patients with TBI and confirmed ICH. The reduction in 28-day mortality is significant, and while functional outcomes were less impressive, the DRS scores indicate that survivors may experience less disability.

For me, I think this supports the current practice of using the 2g bolus, but the evidence here is pretty weak to support that position. I would follow your local guidelines and not change practice specifically on this paper.

References

1. Rowell, S., et al. (2024). The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: A subgroup analysis from the prehospital TXA for TBI trial. Journal of Trauma and Acute Care Surgery, 97(4), 572–580. DOI:10.1097/TA.0000000000004354
2. Simon Carley, “JC: TXA in severe head injury. St Emlyn’s,” in St.Emlyn’s, September 13, 2020
3. CRASH-2 Trial Collaborators (2010). The CRASH-2 randomised controlled trial: Effect of tranexamic acid in trauma patients with significant haemorrhage. The Lancet, 376(9734), 23–32. DOI: 10.1016/S0140-6736(10)60835-5
4. CRASH-3 Trial Collaborators (2019). 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, 394(10210), 1713–1723. DOI: 10.1016/S0140-6736(19)32233-0
5. Perel, P., et al. (2012). Effect of tranexamic acid on mortality in patients with traumatic bleeding: A systematic review and meta-analysis. BMJ, 345, e5836. DOI: 10.1136/bmj.e5836
6. Lynn, M., et al. (2017). Prehospital use of tranexamic acid for traumatic brain injury. The American Journal of Emergency Medicine, 35(5), 742–746. DOI: 10.1016/j.ajem.2017.01.061
7. National Institute for Health and Care Excellence (NICE). (2020). Head injury: Assessment and early management. NICE Clinical Guidelines, CG176. Available online at NICE guidelines

These sources should provide well-rounded support for discussing TXA, its effects in TBI treatment, and guidelines relevant to prehospital care and trauma management.