JC: Tranexamic Acid (TXA) in Head Injury. The CRASH-3 results. St Emlyn’s

St Emlyn’s had sight of a pre-publication copy of the CRASH-3 trial from the trial team. This allowed us to prepare this blog in advance of publication. The trial authors have not been involved in this review and have allowed us to say whatever we like without interference or oversight. The podcast is below, but please read on for more info on the trial.

Tranexamic acid (TXA) is now well established in the management of bleeding trauma patients. CRASH-2​1​ and subsequent trials have shown that it is highly effective and that the benefits are best realised if given early. This effect is seen in other bleeding conditions, such as post partum haemorrhage where TXA was shown to decrease bleeding and save lives​2​. If you need a reminder (in cartoon form) on how TXA works, click the link below.

By Hywell Roberts for LSHTM https://vimeo.com/user23820206

What about in head injured patients though? They are a slightly different group to our poly/bleeding trauma patients. The amount of bleeding that they sustain intracranially is substantially smaller and to a degree is ‘controlled’ in that you can only bleed so much within the cranium before you die. However, TXA has been shown to reduce the overall amount of bleeding in most circumstances where it has been tested, and with a low side effect profile, including in small studies of TXA in head injury​3​. Could TXA be used to reduce the amount of bleeding following isolated brain injury and if so would that have an effect on mortality? This is especially interesting as TXA was not shown to be of benefit in patients with spontaneous intracranial bleeding​4–6​ and so the outcome is far from certain.

Today we have the results of CRASH-3​7​ to answer this question. CRASH-3​8​ is a placebo controlled, double blind, randomised controlled trial of TXA in isolated head injury.

The abstract is below, but as always we strongly recommend you read the full paper yourself and come to your own conclusions. The paper si currently open access, so there is no excuse not to.

CRASH-3

What sort of paper is this?

It’s a placebo controlled RCT which is exactly what we want to see when researchers test an intervention such as a drug therapy. The research group have extensive experience in running international RCTs. Patients were randomised using an envelope system, primitive but reasonable under the circumstances.

Tell me about the patients.

They recruited isolated head injury patients with what sounds like two time entries into the program.

  • Patients with GCS <13 on arrival
  • Any patient with GCS 13-15 and blood on CT scan

Patients had to be recruited within 3 hours of injury, although when the trial started they recruited up to 8 hours post injury. That changed when subsequent evidence suggested that TXA was not beneficial after 3 hours​8​. Patients with a significant extra-cranial injury were excluded.

It’s important to understand what the authors describe as mild/moderate/severe in this paper. My understanding is that they stratified according to the following definitions.

  • Mild GCS 14-15
  • Moderate GCS 9-13
  • Severe GCS 3-8
  • GCS 3 with or without pupillary signs.

Patients were recruited across a 7-year period (2012-2019) in 175 hospitals in 29 countries. They ranged across a whole range of health economies, notably with North America not participating (more on this later).

What did they do?

Once recruited the patients received 1g TXA as a bolus and then an 8-hour infusion of 1g of TXA. This is the same regime as in previous trials like CRASH-2​1​ and WOMAN​2​. The infusion is quite interesting as a concept. At the recent RCEM conference one of the lead investigators alluded to the origin of the infusion. It was suggested that the decision to use an infusion in CRASH-2 was because of the need to maintain TXA in the system of a patient who may be bleeding it out. That’s not really a concern in isolated head injury and might not then be needed – although we don’t really know.

CRASH-3

The outcomes?

At this stage they are reporting the early outcomes. Death at 28 days post injury and any perceived complications. Death was the primary endpoint of the study.

So what did they find?

They recruited 12,737 patients to the trial of which 9,202 were recruited within 3 hours. The headline results are a little complex as it rather depends on which group you look at. In essence the main results can be summarised as follows:

  1. Overall head injured related deaths if treated within 3 hours: 18.5% TXA vs. 19.8% placebo (855 vs 892 events, relative risk = 0·94, 95% CI 0·86-1·02). So NOT significant statistically.
  2. If we excluded GCS 3 or bilateral unreactive pupils at baseline deaths: 12·5% TXA vs 14·0% placebo (485 vs 525 events, RR=0·89, 95% CI 0·80-1·00).
  3. Mild/Moderate head injury deaths: 5.8% TXA vs 7.5% placebo (166 vs 207 events,  RR=0·78 95%CI 0·64-0·95). So this is statistically significant.
  4. Deaths in severe head injury: 39.6% TXA vs 40.1% placebo (689 events vs 685 events, RR=0·99, 95%CI 0·91-1·07) not statistically significant.
  5. Deaths of both pupils react: 11.5% TXA vs 13.2% placebo. Statistically significant
  6. Deaths if one or more unreactive pupil: 52.3% TXA vs. 50.8%. Not statistically significant.

So you might say that this was a negative trial, and I ‘m sure that there will be some people who argue this. The overall headline figure is that there is not a statistically significant difference if you give TXA to all patients with head injury (GCS <13 or intracranial blood). The significant findings are in the sub-groups. At St Emlyn’s we are always deeply sceptical about sub-group analyses, but on this occasion we think they can be justified.

It’s worth noting that these subgroup analyses were pre-specified. You must always be cautious about subgroup analyses, but on this occasion, I think they are reasonable. Pre-specified and based on pathophysiology seems OK to me.

In the secondary outcomes there was no increase in thromboembolic events. There was no significant difference in disability either, but remember that there were more people alive to answer that question in the TXA group.

Talk to me about timings.

There is a big push in trauma patients to get TXA in early as there is relationship between early administration and better outcomes in other trials​9–11​. In CRASH-3 a similar relationship was found with better outcomes if the drug is given as soon as possible post injury. This relationship makes pathophysiological sense and is in keeping with a combined analysis of past large RCTs in trauma and post partum bleeding​12​.

Make it really simple to explain.

OK. Not everyone loves stats as much as St Emlyn, so let’s convert the positive findings into numbers needed to treat.

  1. If your patient as a GCS of 9-15 with any blood on CT then you need to treat 59 patients with TXA to save one head injury related death at 28 days.
  2. If your patient has bilaterally reactive pupils you need to treat 58 patients with TXA to save head injury related death at 28 days
  3. If your patient does not have unreactive pupils and is not GCS 3 then you need to treat 67 patients to save one head injured related death at 28 days.

That’s close or better an NNT than TXA in bleeding trauma​1​ and is getting close to my usual benchmark of aspirin in MI (42 since you are asking).

Even better, have a look at this infographic from Kirsty Challen on the key messages from the trial (with slightly different groupings to the above).

CRASH-3
From Kirsty Challen @kirstychallen

Note that these are the head injury related deaths. and not all cause mortality. Since the trial did not show an increase in thromboembolic events between groups then it’s tricky to see how TXA might have raised or lowered non-head injured related deaths. Similarly TXA could not have an impact no non-head injured deaths. The overall difference in all cause mortality had a RR of 0.96 (0.89-1.04), which is roughly an NNT of 60 (but not statistically significant). The rationale for using head injury deaths as opposed to all cause deaths may be controversial. You can read more about their rationale in the detailed statistical analysis plan​13​.

Also note that NNTs are susceptible to local factors and won’t stay the same across different populations. We present them here as a way of comparing the data, but be mindful that these would not translate directly to your practice.

OK, but doesn’t TXA have complications?

It’s a debatable topic. Patients who are critically unwell or injured have higher rates of thromboembolic events irrespective of whether they are taking TXA or not, but it’s a legitimate concern as it could be pathophysiologically argued that TXA might increase thromboembolic rates. The authors have looked for this and have found no increase in rates between TXA and placebo. There are reports of increased thromboembolic events in the use of TXA, but those are mostly observational studies where survivor bias may influence the results​14​. In many other trials with better methodologies there appears to be no convincing increase in events​15,16​.

So we give it to every trauma patient then?

Well probably. We know that it works in bleeding trauma​1​ and we now know that it works in isolated head injury. However, we don’t really know if it works in multi-system trauma or in kids. However, it’s probably reasonable to extrapolate that it is safe to give to polytrauma patients and there is already a consensus to give TXA to bleeding children patients at a reduced dose. Since we are unlikely to get a separate trial for either group I think it’s reasonable to go ahead and use it (personal opinion).

We may still need to think about the way that we give the TXA. As mentioned earlier the bolus followed by an infusion was (allegedly) chosen on the basis that the patient who is bleeding out may bleed out their TXA and so need an infusion to keep levels up in the newly transfused blood. However, infusions are a pain in practice and I wonder if we might see a trial of a different regime at some point.

There are of course skeptics many around the use of TXA​17–22​, predominantly in North America and Australia, although both regions have begun to adopt the therapy in trauma in recent years for bleeding trauma patients. There are some who still believe that it should only be given once fibrinolysis is proven on TEG or ROTEM​21​. The idea of such targeted therapy is intellectually attractive, but is not borne out by the pathophysiology – think horses, doors and bolted if you want to wait until fibrinolysis is known before treating it. There will also be others who dismiss the findings here because it involves patients in low or middle income countries. It’s true that LMICs have different healths systems, but that did not seem to affect the results in this paper.

What do others think?

It’s likely that ths study will generate a lot of debate and that’s great. We would recommend you have a look at some of the other #FOAMed reviews out there to get a more global perspective

The bottom line.

Until we see/hear otherwise the @stemlyns view is that:

  • TXA has been shown to reduce bleeding related deaths in a variety of settings  suggesting that it fundamentally improves outcomes for patients with life threatening bleeding.
  • TXA should be given to all mild/moderate head injured patients with evidence of bleeding on CT scan.
  • TXA should be given to all patients who have bilaterally reactive pupils and blood on CT scan.
  • Patients with head injury PLUS extra-cranial injury TXA should be given to patients within 3 hours.

It’s cheap and easy to give, it’s safe and effective. Maybe it’s not that ‘cool’ does not arrive by helicopter and it doesn’t cost thousands, but that should not put you off. There is an old saying that the ideal product is quick, cheap and good. The joke is that you can only have 2 of 3. Well maybe this is one occasion when you can have all 3.

vb

S

References

  1. 1.
    Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. March 2013. doi:10.3310/hta17100
  2. 2.
    The Lancet. WOMAN: reducing maternal deaths with tranexamic acid. The Lancet. May 2017:2081. doi:10.1016/s0140-6736(17)31111-x
  3. 3.
    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;13:20. https://www.ncbi.nlm.nih.gov/pubmed/24267513.
  4. 4.
    Rezaie S. Tich – 2. REBEL EM. https://rebelem.com/tich-2-txa-for-spontaneous-ich/. Published July 30, 2018. Accessed October 14, 2019.
  5. 5.
    Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. The Lancet. May 2018:2107-2115. doi:10.1016/s0140-6736(18)31033-x
  6. 6.
    Horner D. Tich Tich Boom. St Emlyn’s. http://www.stemlynsblog.org/jc-tich-tich-boom-txa-in-ich-st-emlyns/. Published May 22, 2018. Accessed October 14, 2019.
  7. 7.
    Roberts I. CRASH-3. The Lancet. https://www.thelancet.com/. Published October 14, 2019. Accessed October 14, 2019.
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    London School of Hygiene and Tropical Medicine L. CRASH 3. Clinical Trials. https://clinicaltrials.gov/ct2/show/NCT01402882. Published July 26, 2011. Accessed October 10, 2019.
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    Roberts I, Edwards P, Prieto D, et al. Tranexamic acid in bleeding trauma patients: an exploration of benefits and harms. Trials. 2017;18(1):48. https://www.ncbi.nlm.nih.gov/pubmed/28143564.
  10. 10.
    CRASH-2 collaborators., Roberts I, Shakur H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096-1101, 1101.e1-2. https://www.ncbi.nlm.nih.gov/pubmed/21439633.
  11. 11.
    Roberts I. Tranexamic acid in trauma: how should we use it? J Thromb Haemost. 2015;13 Suppl 1:S195-9. https://www.ncbi.nlm.nih.gov/pubmed/26149023.
  12. 12.
    Gayet-Ageron A, Prieto-Merino D, Ker K, et al. Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients. The Lancet. January 2018:125-132. doi:10.1016/s0140-6736(17)32455-8
  13. 13.
    Roberts I. Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, randomised controlled trial. Research Gate. https://www.researchgate.net/publication/326525129_Tranexamic_acid_for_significant_traumatic_brain_injury_The_CRASH-3_trial_Statistical_analysis_plan_for_an_international_randomised_double-blind_placebo-controlled_trial. Published July 2018. Accessed October 14, 2019.
  14. 14.
    Myers S, Kutcher M, Rosengart M, et al. Tranexamic acid administration is associated with an increased risk of posttraumatic venous thromboembolism. J Trauma Acute Care Surg. 2019;86(1):20-27. https://www.ncbi.nlm.nih.gov/pubmed/30239375.
  15. 15.
    El-Menyar A, Sathian B, Wahlen B, et al. Prehospital administration of tranexamic acid in trauma patients: A 1:1 matched comparative study from a level 1 trauma center. Am J Emerg Med. April 2019. https://www.ncbi.nlm.nih.gov/pubmed/31060862.
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    Neeki M, Dong F, Toy J, et al. Tranexamic Acid in Civilian Trauma Care in the California Prehospital Antifibrinolytic Therapy Study. West J Emerg Med. 2018;19(6):977-986. https://www.ncbi.nlm.nih.gov/pubmed/30429930.
  17. 17.
    Binz S, McCollester J, Thomas S, et al. CRASH-2 Study of Tranexamic Acid to Treat Bleeding in Trauma Patients: A Controversy Fueled by Science and Social Media. Journal of Blood Transfusion. 2015:1-12. doi:10.1155/2015/874920
  18. 18.
    Thomas S, Moore E, Moore H, et al. Tranexamic Acid for Trauma Resuscitation in the United States of America. Semin Thromb Hemost. December 2016:213-223. doi:10.1055/s-0036-1586226
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    Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE. Tranexamic acid in trauma. Journal of Trauma and Acute Care Surgery. June 2013:1575-1586. doi:10.1097/ta.0b013e318292cc54
  20. 20.
    Khan M, Jehan F, Bulger EM, et al. Severely injured trauma patients with admission hyperfibrinolysis. Journal of Trauma and Acute Care Surgery. November 2018:851-857. doi:10.1097/ta.0000000000002022
  21. 21.
    Huebner BR, Dorlac WC, Cribari C. Tranexamic Acid Use in Prehospital Uncontrolled Hemorrhage. Wilderness & Environmental Medicine. June 2017:S50-S60. doi:10.1016/j.wem.2016.12.006
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    Brohi K. Tranexamic Acid in trauma. SMACC. https://smacc.net.au/2015/10/karim-brohi-on-tranexamic-acid-in-trauma/. Published 2015. Accessed 2019.

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Professor Simon Carley MB ChB, PGDip, DipIMC (RCS Ed), FRCS (Ed)(1998), FHEA, FAcadMed, FRCEM, MPhil, MD, PhD is Creator, Webmaster, owner and Editor in Chief of the St Emlyn’s blog and podcast. He is Professor of Emergency Medicine at Manchester Metropolitan University and a Consultant in adult and paediatric Emergency Medicine at Manchester Foundation Trust. He is co-founder of BestBets, St.Emlyns and the MSc in emergency medicine at Manchester Metropolitan University. He is an Education Associate with the General Medical Council and is an Associate Editor for the Emergency Medicine Journal. His research interests include diagnostics, MedEd, Major incidents & Evidence based Emergency Medicine. He is verified on twitter as @EMManchester

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