The effectiveness of TXA in traumatic bleeding has been controversial. It’s not that the evidence has been absolutely definitive over the years, and let’s face it there are many areas of our practice that happens, but it seems that TXA is an incredibly emotive topic to some commentators (notably in North America). In trauma patients the largest trials (CRASH-2 and CRASH-3) demonstrated survival benefits from haemorrhagic causes, but there were reasonable questions raised about the generalisability of the results. There were also questions raised about the decision to use haemorrhagic outcomes vs. all cause mortality in some trials. These are good questions and in part have led to the controversies that still exist today. My personal view has been that on the evidence available at the time I was happy to recommend TXA use in trauma as there is probably a benefit, and very little evidence of harm (and it’s cheap and easy to do).
Like many others I have been excitedly awaiting the results of the PATCH trial from Australia. This trial aimed to look at the impact of TXA in a high functioning trauma system. This is an important topic for us to address as it may give insights into how TXA might function in other high income countries with established trauma systems (the inclusion of LMICs in the CRASH studies was a common source of criticism).
The trial was presented at the (awesome) Critical Care Reviews meeting this month in Belfast. Sadly I was unable to go this year, but I cannot recommend the meeting strongly enough. It’s an incredible few days and it should be on the bucket list for any researcher involved in critical care research. You can watch the trial presentations on the CCR23 website and visit NEJM to read the full paper. The abstract is below.
What kind of trial is this?
This is a multicentre, international randomised controlled trial (RCT) which is an appropriate design for testing an intervention such as TXA. This was a placebo controlled trial with patients and clinicians masked to the intervention.
Tell me about the patients.
The authors were interested in identifying patients with known or potentially severe injuries. This study used the COAST score to identify patients thought to be at risk of major bleeding. This is arguably a better entry criteria than those used in other TXA trauma trials, and at first glance appears to be more objective in that it gives a numerical score, although it still requires a degree of subjective assessment. Arguably the COAST score has more objectivity than in many other TXA trials (a good thing IMHO). The COAST score is shown below. It has a maximum score of 7. In the trial they used a score of 3 or above to identify patients.
Pregnant patients and nursing home residents were excluded.
What about the intervention?
The TXA regime was the same as in the CRASH-2 and CRASH-3 studies. That is 1g of TXA as a slow bolus and then 1g as an 8-hour infusion. Interestingly, in my practice we are moving away from the infusion and often giving two boluses of 1g, or a 2g bolus in head injury, but for this trial they used the original regime which is helpful when we compare results later.
What about the outcomes?
The primary outcome of the PATCH trial us functional outcome at 6-months as measured using the Extended Glasgow Outcome Score. At St Emlyn’s we generally like functional outcomes in resuscitation trials as they tell us more about what interventions mean to patients. Previous TXA trials have rarely done this and so this outcome is important. They also reported a range of secondary outcomes including those reported in previous trials of TXA.
The primary outcome was defined as a ‘favourable’ outcome on the GOS-E. The scale is shown below. In this study scores of 5-8 are considered a positive outcome. Scores of 1-4 are considered a negative outcome.
Glasgow Outcome Scale – Extended Version
■ 1 Dead
■ 2 Vegetative State: Condition of unawareness with only reflex responses but with periods of spontaneous eye opening.
■ 3 Low Severe Disability
■ 4 Upper Severe Disability: Patient who is dependent for daily support for mental or physical disability, usually a combination of both. If the patient can be left alone for more than 8h at home it is upper level of SD, if not then it is low level of SD.
■ 5 Low Moderate Disability
■ 6 Upper Moderate Disability: Patients have some disability such as aphasia, hemiparesis or epilepsy and/or deficits of memory or personality but are able to look after themselves. They are independent at home but dependent outside. If they are able to return to work even with special arrangement it is upper level of MD, if not then it is low level of MD.
■ 7 Low Good Recovery
■ 8 Upper Good Recovery: Resumption of normal life with the capacity to work even if pre-injury status has not been achieved. Some patients have minor neurological or psychological deficits. If these deficits are not disabling then it is upper level of GR, if disabling then it is lower level of GR.
Tell me about the results.
For various reasons the trial took 7 years to complete. Between 2014 and 2021 they recruited 1310 patients across Australia, Germany, and New Zealand. Patients were pretty comparable at baseline. The overall death rate in the trial was just under 21% at 6 months indicating that these were a severely injured group.
There was no difference in the primary outcome, with 307 of 572 patients (53.7%) in the tranexamic acid group and 299 of 559 patients (53.5%) in the placebo group having a favourable outcome (GOS-E of 5 or above) at 6 months.
In effect this meant that for every 100 patients treated with TXA you would roughly have an additional 4 survivors. One would have upper severe disability on GOS-E and 3 would have lower severe disability. The NNT for TXA in terms of survival in this trial is 23 which is remarkable. To further understand the complexities of this I would recommend the editorial in NEJM and also Karim Brohi’s editorial at CCR23 summarised on his twitter feed below.
It think the most telling summary slide for me is the one below from Karim Brohi’s editorial which indicates where TXA sits in terms of mortality benefits as compared to other trials and databases.
So should we stop using TXA?
With PATCH results released at CCR23 it was not long before some on social media were calling for it’s abandonment based on a non statistically significant difference for the GOS-E end point but I think it’s a bit more complicated than that.
- This trial (once again) shows that TXA reduces mortality in trauma patients. This is a consistent finding across a range of trials and a range of settings. This trial reinforced my belief that it saves lives, probably through a reduction in adverse bleeding outcomes. The effectiveness of TXA in reducing deaths in this trial within a high functioning trauma system, and with severely injured patients is one of the highest effects we have seen to date.
- The primary outcome of GOS-E used in this trial shows no difference at the pre-defined point chosen by the authors. This raises clinical and philosophical questions about what is a positive or negative outcome at a 6-month time point. Clinically there is much evidence in the TBI literature that patients can continue to improve well beyond the 6-month end point used in this trial. Several trials demonstrate that patients in the Upper Severe Disability group can improve to a good functional outcome within 2-3 years.
- There is a philosophical question too about whether a disability outcome is a worse outcome than death. My experience of working with adult and paediatric major trauma patients and their families tells me that this question is complex and nuanced. There are likely patients in the groups defined as negative outcomes in this trial, who might believe better to be disabled and alive than dead. It is not my place to decide these matters and I would be very uncomfortable withholding a life saving treatment because I was concerned that some patients (and I would not know who) would be disabled at 6 months.
- There may be future interventions in early care, definitive care and rehabilitation that may improve the outcomes of survivors further, but in order for them to be realised the patients must first survive. TXA increases the number of early survivors who have the potential to benefit from such interventions.
- There is no great surprise that patients with major trauma suffer disabling outcomes. Major trauma is frequently a life changing disease and it is probably unrealistic to expect that all patients will have high functioning outcomes.
With these factors in mind my view is that we should continue to give TXA as we now have many trials that show a mortality benefit.
We should recognise that trauma care is a long journey and that interventions beyond the resus room extending right through to the rehabilitation phase are incredibly important to patients and families. Well done to the authors and research teams that put this excellent trial together.
References and further reading.
- Prehospital Tranexamic Acid for Severe Trauma. https://www.nejm.org/doi/full/10.1056/NEJMoa2215457?query=recirc_curatedRelated_article
- Tranexamic Acid for Trauma Patients — More Lives to Save and Outcomes to Consider. https://www.nejm.org/doi/full/10.1056/NEJMe2305075
- Critical Care Reviews.
- Simon Carley, “Differential prescribing of TXA by gender. St Emlyn’s,” in St.Emlyn’s, May 31, 2022, https://www.stemlynsblog.org/differential-prescribing-of-txa-by-gender-st-emlyn-s/.
- Simon Carley, “JC: Tranexamic Acid (TXA) in Head Injury. The CRASH-3 results. St Emlyn’s,” in St.Emlyn’s, October 14, 2019, https://www.stemlynsblog.org/jc-tranexamic-acid-txa-in-head-injury-the-crash-3-results-st-emlyns/.
- Simon Carley, “JC: TXA in severe head injury. St Emlyn’s,” in St.Emlyn’s, September 13, 2020, https://www.stemlynsblog.org/jc-txa-in-severe-head-injury-st-emlyns/.
- Simon Carley, “JC: Can we give tranexamic acid (TXA) via the IM route? St Emlyn’s,” in St.Emlyn’s, October 1, 2020, https://www.stemlynsblog.org/jc-can-we-give-tranexamic-acid-txa-via-the-im-route-st-emlyns/.
- Janos Baombe, “JC: Does earlier TXA save lives? St.Emlyn’s,” in St.Emlyn’s, November 12, 2017, https://www.stemlynsblog.org/earlier-txa-saves-lives-review-st-emlyns/.
- Favorable Functional Recovery in Severe Traumatic Brain Injury Survivors beyond Six Months. J Neurotrauma. 2019 Nov 15; 36(22): 3158–3163. Published online 2019 Oct 23. doi: 10.1089/neu.2018.6153
- Recovery Trajectories and Long-Term Outcomes in Traumatic Brain Injury: A Secondary Analysis of the Phase 3 Citicoline Brain Injury Treatment Clinical Trial. JAMA Neurol. 2021;78(8):982-992. doi:10.1001/jamaneurol.2021.2043