TXA has been widely adopted as an effective drug for improving outcomes of patients who are bleeding from a variety of sources, even though many of the trials’ conclusions are contentious. One of the major concepts we have discussed on the Journal Jam Podcast is that prior probability matters. When assessing a trial, one’s interpretation is often shaped by the science that is already available. So when trying to determine how to interpret a somewhat controversial study like CRASH-3, it is really helpful to take a deep dive into all the available evidence for TXA. This will help us decide when to use TXA in the ED and to gain a broad understanding of this drug. That is our goal here. With the help of a special guest, EBM guru Dr. Ken Milne of the The SGEM, Anton and Justin look at all the various potential indications for TXA and review the available evidence. Should we be using TXA for epistaxis, postpartum hemorrhage, hyphema or hemoptysis? Is it a miracle drug that stops all bleeding? Or has it been drastically overhyped? Was CRASH-2 enough to be definitive, or does the classic EBM mantra of “we need more studies” remain true?…
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Podcast production by Justin Morgenstern and Anton Helman.
Podcast editing and sound design by Anton Helman. Blog summary by Anton Helman, June 2021.
Cite this podcast as: Helman, A. Morgenstern, J. Milne, K. Journal Jam 18 – The Evidence for TXA – Should Tranexamic Acid Be Routine For The Bleeding Patient. Emergency Medicine Cases. June, 2021. https://emergencymedicinecases.com/evidence-txa-tranexamic-acid-bleeding. Accessed [date]
Perioperative TXA – tranexamic acid to reduce bleeding, transfusions and mortality associated with surgery
Cochrane review 2011 
65 trials with 4800 patients of TXA in the perioperative period
- TXA reduced the need for blood transfusion by 18%
- TXA did not reduce the total volume of blood being transfused
- Post-operative blood loss was reduced by an average of 247 mL
- There was no difference in mortality, reoperation for bleeding, MI, stroke or thromboembolic phenomena
250 small RCTs, each with only approximately 100 patients, show a consistent signal that perioperative blood loss is reduced, but no patient-oriented outcome benefit and no change in mortality.
TXA for GI bleeds – The HALT-IT trial
Cochrane review 2014 
8 low quality small RCTs totalling only 851 patients
- Statistically significant reduction in mortality and need for surgery with TXA, but no difference in mortality or need for surgery when the large number of lost patients were taken into account
- No statistically significant reduction in rebleeding or transfusion requirements or thrombotic events
HALT-IT trial 
HALT IT was a pragmatic, international, multi-center, placebo-controlled RCT with 12,009 patients with GI bleeds (90% upper GI).
There was no difference in all cause mortality, death due to bleeding, rebleeding, surgery, endoscopy, need for transfusion, or total blood products transfused between the TXA group and placebo group.
The only statistically significant difference was an increase in venous thromboembolic events from 0.4% to 0.8%.
TXA for postpartum hemorrhage – WOMAN trial, TRAAP trial and TRAAP-2 trial
Two large RCTS looked at TXA for prevention of postpartum hemorrhage, the TRAAP trial  and the TRAAP 2 trial .
In the TRAAP trial there was no difference in the primary outcome of blood loss of at least 500 mL.
In the TRAAP-2 trial there was a statistically significant reduction in postpartum hemorrhage, defined as estimated blood loss > 1L or need for transfusion within 2 days – 27% with TXA versus 36% with placebo. However for single outcomes there was only a 30 mL difference in bleeding, no difference in transfusion, no difference in hemoglobin level, no difference in ICU admissions and no difference in surgery or invasive procedures. There was a small increase in venous thromboembolic events (0.1% in the placebo group versus 0.4% in the TXA group).
The WOMAN trial  was a large RCT with 20,060 women worldwide that found no statistically significant difference in the primary outcome of all cause mortality or hysterectomy. A secondary outcome of “death due to bleeding” had a 0.4% decrease in the TXA group (1.5% vs 1.9%).
TXA for nontraumatic ICH – TICH-2 trial and ULTRA trial
The TICH-2 trial  was an RCT of 2325 patients with non-traumatic intracranial hemorrhage. There were no differences in the patient-oriented outcomes of functional outcomes at 3 months or mortality. There was a statistically significant difference in the non patient-oriented outcome of hematoma size (3.7 mL vs 4.9 mL).
TXA for nontraumatic subarachnoid hemorrhage (SAH) Cochrane review 2013 
- 10 small RCTS totalling 1904 patients
- No statistically significant difference in functional outcomes or all-cause mortality
- Statistically significant improvement in rate of bleeding
- Statistically significant increase in cerebral ischemia
The ULTRA trial 2021  was an RCT of 955 with nontraumatic SAH. There were no difference in neurologic outcome or mortality between the TXA and placebo groups.
TXA for epistaxis
Cochrane review in 2018 
- 6 small moderate-low quality RCTs totalling 692 patients
- Decreased rate of rebleeding
- No statistically significant differences in transfusions, repacking, surgery or embolization
The NoPac trial  was an RCT of 496 adult patients with epistaxis who had failed basic first aid measures that showed no statistically significant difference in the primary outcome of need for anterior packing. There were no differences in any of the secondary outcomes (other treatments for epistaxis, hospital admission, blood transfusion, or recurrent epistaxis (rebleeding).
The pattern of research findings for TXA for most indications is that small, lower quality studies are positive, fueling the use of TXA, while large higher quality studies are negative.
TXA for non-massive hemoptysis
Cochrane review 2016 
- 2 small RCTs totalling 70 patients
- No difference in remission by 1 week
- Duration of bleeding shortened by mean of 19 hours
2018 RCT compared nebulized TXA in non-massive hemoptysis in 47 patients 
- Significant improvement in resolution of bleeding (96% vs 50%)
- A signal of mortality benefit but not statistically significant
TXA for hyphema
Cochrane review 2019 
5 studies totalling 581 patients looking at oral TXA
- No improvement in the primary outcome of visual acuity
- Reduced the risk of secondary hemorrhage
- Non-statistically significant increase in glaucoma
TXA for dysfunctional uterine bleeding (DUB)
Cochrane review 2018 
- 13 low quality RCTs totalling 1312 patients
- Approximately 50 mL decrease in total bleeding per cycle
- Self reported improvement in symptoms approximately 60% in women taking NSAIDs and 60% in woman taking TXA
- Most studies did not report harms; the studies that did report harms showed no difference
TXA for polytrauma – the CRASH-2 trial
CRASH-2 trial was an RCT of 20,211 adult trauma patients with significant hemorrhage comparing TXA 1g bolus then 1g over 8 hours to placebo with 3 hours of injury 
- Statistically significant improvement in all-cause mortality with NNT of 67 to save 1 life over 28 days
- No difference in the number of patients requiring a blood transfusion (50.4% vs 51.3%)
- No statistically significant increase in thromboembolic events
CRASH-2 is the only large TXA RCT showing a statistically significant decrease in all-cause mortality with a NNT of 67
STAAMP trial was an RCT comparing TXA to placebo in the prehospital setting in trauma patients with hypotension or tachycardia 
- No statistically significant difference in the primary outcome of 30-day mortality (8.1% vs 9.9%)
TXA for for isolated head injury – the CRASH-3 trial
2021 meta-analysis of 9 RCTs totalling 14,747 patients 
- No statistically significant difference in mortality
- No statistically significant difference in functional status
- Non-statistically significant decrease in hematoma size of 2.5mL
CRASH-3 RCT totalling 12,737 adult patients with isolated traumatic brain injury and GCS < 13 or any intracranial bleed on CT 
- No statistically significant difference in the primary outcome of head injury related death
- No statistically significant difference in all cause mortality
- Subgroup with GCS 9-15 showed a reduction in head injury related death
Timing and safety of TXA
While there is some suggestion that the earlier TXA is given the better, it may also be true that the later it is given, the more harms such as thromboembolic events, and possibly even mortality. Although, overall TXA appears to be a safe drug, there is likely a small increase in thromboembolic events in patients receiving TXA, which should be taken into account, especially for patients with thromboembolic risk factors.
Take home points for TXA in bleeding patients
- The pattern of research findings for TXA for most indications is that small, lower quality studies are positive, fueling the use of TXA in practice, while large higher quality studies are negative
- Only a single high quality large RCT has shown TXA to significantly reduce all-cause mortality
- While it may be true that the earlier TXA is given after bleeding commences the better, it may also be true that the later it is given, the more harms it portends
- Conclusions drawn from subgroup analyses should generally be considered hypothesis generating, and not practice-changing
- Replication of study results in essential for widespread evidence-based adoption of a drug in practice
- It is important to attempt to weigh the risk to the patient of ongoing bleeding, the patient’s hemodynamics, the ability of the patient to compensate for blood loss, the patient’s thromboembolic risk factors and the patient’s values in deciding whether or not to administer TXA in any given clinical scenario
References for The Evidence for TXA – Should tranexamic acid be routine for the bleeding patient?
1.Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, Fergusson DA, Ker K. Anti‐fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD001886.
2.Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. The Cochrane database of systematic reviews. 2014.
3.Brenner, A., Afolabi, A., Ahmad, S.M. et al. Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial. Trials 20, 467 (2019).
4.Sentilhes L, Winer N, Azria E, Sénat MV, Le Ray C, Vardon D, for the Groupe de Recherche en Obstétrique et Gynécologie (GROG), et al. Tranexamic acid for the prevention of blood loss after vaginal delivery. N Engl J Med. 2018;379:731–42.
5.Sentilhes, L., Daniel, V., Deneux-Tharaux, C. et al. TRAAP2 – TRAnexamic Acid for Preventing postpartum hemorrhage after cesarean delivery: a multicenter randomized, doubleblind, placebo- controlled trial – a study protocol. BMC Pregnancy Childbirth 20, 63 (2020).
6.WOMAN trial collaborators . Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2017.
7.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. Lancet (London, England). 2018; 391(10135):2107-2115.
8.Baharoglu MI, Germans MR, Rinkel GJ, et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. The Cochrane database of systematic reviews. 2013.
9.Post R, Germans MR, Tjerkstra MA, et al; ULTRA Investigators. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet. 2021 Jan 9;397(10269):112-118.
10.Joseph J, Martinez-Devesa P, Bellorini J, Burton MJ. Tranexamic acid for patients with nasal haemorrhage (epistaxis). The Cochrane database of systematic reviews. 2018.
11.Reuben A, Appelboam A, et al. The use of tranexamic acid to reduce the need for Nasal Packing in Epistaxis (NoPac): randomised controlled trial. Annals of Emergency Medicine. 2021.
12.Prutsky G, Domecq JP, Salazar CA, Accinelli R. Antifibrinolytic therapy to reduce haemoptysis from any cause. The Cochrane database of systematic reviews. 2016.
13.Wand O, Guber E, Guber A, Epstein Shochet G, Israeli-Shani L, Shitrit D. Inhaled Tranexamic Acid TXA for Hemoptysis Treatment: A Randomized Controlled Trial. Chest. 2018; 154(6):1379-1384.
14.Gharaibeh A, Savage HI, Scherer RW, Goldberg MF, Lindsley K. Medical interventions for traumatic hyphema. Cochrane Database of Systematic Reviews 2019, Issue 1. Art. No.: CD005431.
15.Shakur H, Beaumont D, Pavord S, Gayet‐Ageron A, Ker K, Mousa HA. Antifibrinolytic drugs for treating primary postpartum haemorrhage. Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD012964.
16.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 (London, England). 2010; 376(9734):23-32.
17.Guyette FX, et al. STAAMP Study Group. Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial. JAMA Surg. 2020 Oct 5;156(1):11–20. doi: 10.1001/jamasurg.2020.4350. Epub ahead of print. Erratum in: JAMA Surg. 2021 Jan 1;156(1):105.
18.Lawati KA, Sharif S, Maqbali SA, Rimawi HA, Petrosoniak A, Belley-Cote EP, Sharma SV, Morgenstern J, Fernando SM, Owen JJ, Zeller M, Quinlan D, Alhazzani W, Rochwerg B. Efficacy and safety of tranexamic acid in acute traumatic brain injury: a systematic review and meta-analysis of randomized-controlled trials. Intensive Care Med. 2021 Jan;47(1):14-27.
19.CRASH 3 Trial Collaborators. 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. Lancet (London, England). 2019.
Additional FOAMed resources for TXA
Justin Morgenstern, “TXA for GI bleeds: No benefit (The HALT-IT trial)”, First10EM blog, June 19, 2020. Available at: https://first10em.com/halt-it-trial/
Justin Morgenstern, “TXA for GI bleeds”, First10EM blog, March 9, 2020. Available at: https://first10em.com/txa-for-gi-bleeds/.
Justin Morgenstern, “CRASH 3: TXA is no wonder drug”, First10EM blog, October 28, 2019. Available at: https://first10em.com/crash-3/.
Justin Morgenstern, “Nebulized TXA for Hemoptysis (Wand 2018)”, First10EM blog, May 27, 2019. Available at: https://first10em.com/nebulized-txa-for-hemoptysis-wand-2018/.
Justin Morgenstern, “TXA in ICH (TICH-2)”, First10EM blog, June 25, 2018. Available at: https://first10em.com/tich-2/.
Justin Morgenstern, “The CRASH-2 trial (a review)”, First10EM blog, February 17, 2020. Available at: https://first10em.com/the-crash-2-trial/.
SGEM: TXA for SAH
SGEM: You can’t stop GI Bleeds with TXA
SGEM: TXA for traumatic head bleeds
SGEM: WOMAN – The TXA trial for postpartum hemorrhage
REBEL EM: Topical TXA in Epistaxis
At about the 1 hour mark the discussion turns to the need for replication. There is an important point offered about correcting our level of certainty based on pre-test probability. Can you explain how to calculate the corrected certainty of the CRASH-2 results? The P=0.003 based on pre-test probability of 50% = 90% certainty. Or if the pre-test probability was 5% = 50% certainty is calculated. Do you have any recommendations for further reading on this principle?
This is a great question Stephen. It is all about converting the p value into a Bayes factor, which allows you do adjust your pretest probability into a post-test probability. One of the best articles describing this was Nuzzo 2014 in Nature: https://www.nature.com/articles/506150a
I find it easiest to just look this up every time, because the conversation to a Bayes factor is not a simple calculation. There is a table here that I use: https://www.ebm2point0.com/how-to-convert-p-values-into-something-useful-the-probability-that-a-finding-is-real/
There is a bunch more info on the https://www.ebm2point0.com/ website about this system.
The hard part is coming up with the pre-test probability. I think we consistently over-estimate this in medicine. We can probably get a reasonable objective starting point by considering all of the phase 3 trials that are done, and what percentage are actually positive. Based on that, I doubt we should ever be much higher than a 10% pretest probability, even with decent observational and animal data – its just really hard to have an major positive impact on human physiology.
All the best