REVIEW OF TRANEXAMIC ACID USES IN THE EMERGENCY DEPARTMENT

By Perry Lee, MD (PGY-3)

Tranexamic Acid (TXA) is an antifibrinolytic that inhibits the enzymatic breakdown of fibrin by plasmin.[i]  It was first developed in 1962 by Japanese wife and husband researchers, hoping to find an effective treatment for post-partum hemorrhage which was a leading cause of maternal death in Japan at that time.[ii]  Given its effectiveness and relative cheap cost, TXA has routinely been included on the World Health Organization’s List of Essential Medicines.[iii]  Below is a list of uses for TXA commonly encountered in the emergency department (ED) with supporting research. 

TRAUMA
 

• CRASH-2 trial (2010)[iv] and subgroup analysis (2011)[v]

 
The CRASH-2 trial was the first major landmark article that showed improved survival in patients with traumatic injuries with known or suspected significant hemorrhage.  The trial concluded a decrease in all-cause mortality at 4 weeks in the TXA group (14.5% vs 16% in placebo group).  Specifically, there was a decrease in death from hemorrhage in the TXA group (4.9% vs 5.7% in placebo group).  No difference was found in the rate of vascular occlusive events (1.7% vs 2.0% in placebo group)
 
A follow up subgroup analysis of the CRASH-2 data showed the time sensitivity of TXA administration.  The analysis showed that patients who received TXA within 1 hour showed the highest mortality benefit (5.3% vs 7.7% in placebo group).  This mortality benefit extended into patients that received TXA within 3 hours of injury (4.8% vs 6.1% in placebo group).  More importantly, the data showed an increased risk of death due to bleeding when TXA was administered more than 3 hours after injury (4.4% vs 3.1% in placebo group).
 

• Take home:

1. TXA improved all-cause mortality in trauma patients
2. Administration is time sensitive and should be given within 3 hours of injury, ideally within 1 hour
3. Dosing: IV loading dose of 1,000 mg over 10 minutes, followed by 1,000 mg over the next 8 hours

 
 
POST-PARTUM HEMORRHAGE
 

• WOMAN trial (2017)[vi]

 
The WOMAN trial was a study to examine the effects of TXA used in post-partum hemorrhage (PPH). The original primary outcome was all-cause mortality and/or hysterectomy. However the primary outcome was changed to death from bleeding partway through the study as it was found that the decision to perform a hysterectomy was commonly made at time of randomization and therefore could not be affected by the invention of receiving TXA.  The study did show a reduction in mortality due to bleeding (1.5% vs 1.9% in placebo group) with a improved benefit if given <3hrs (1.2% vs 1.7% in placebo group), similarly to the CRASH-2 trial. 
 

• Take home:

• TXA showed benefit in PPH, however with understanding that the primary outcome was changed during trial.
• Dosing (off-label use): IV 1,000 mg over 10 minutes given within 3 hours of vaginal birth or cesarean section; if bleeding continues after 30 minutes or stops and restarts within 24 hours after the first dose, a second dose of 1,000 mg may be given.

 
 
EPISTAXIS
 

• Topical TXA (2013)[vii]

 
This study examines the use of intravenous (IV) TXA as a topical agent in the setting of non-traumatic epistaxis.  It compared TXA (500mg in 5ml) soaked cotton pledget soaked vs anterior nasal packing (ANP) defined as cotton pledget soaked in epinephrine (1:100000) + lidocaine (2%) for 10 minutes, then packing covered with tetracycline which was removed after 3 days.  They concluded an improvement in cessation of bleeding at 10 minutes (71% vs 31.2% in ANP group).  They also found an improved discharge time of 2 hours or less (95.3% vs 6.4% in ANP group) and decreased rebleeding within 24 hours (4.7% vs 11% in ANP group).
 

• Topical TXA for patients on antiplatelet (2018)[viii]

 
This was a follow up study examining the topical use of TXA in the setting of non-traumatic epistaxis, specifically in patients taking antiplatelets including Asprin, Clopidigrel, or both.  The intervention and control were exactly the same as the previous study in 2013. This trial also showed improved cessation in bleeding at 10 minutes in the TXA group (73% vs 29% in the ANP group). Improvement in rebleeding rate at 24 hours was also seen in the TXA group (5% vs 10% in ANP group).  No adverse events reported in either group.
 

• Take home:
  • Topical TXA for epistaxis is a viable option in non-traumatic epistaxis, even if patient is on an antiplatelet
  • Dosing (off-label): cotton pledget soaked in 500mg in 5mL TXA

 
 
NON-MASSIVE HEMOPTYSIS
 

• Nebulized TXA (2018)[ix]

 
This study examined the use of nebulized TXA 500mg TID vs placebo (nebulized 5ml of 0.9% normal saline) in the setting of non-massive hemoptysis. Patients were excluded hemodynamic or respiratory instability or massive hemoptysis (>200ml/24hr).  They found resolution of hemoptysis within 5 days of admission (96% vs 50% in placebo) and shorter hospital length of stay (5.7 days vs 7.8 days in placebo).
 

• Take home:

• Dosing (off-label): Nebulized 500mg in 5mL TXA.

 
 
UPPER GASTROINTESTINAL BLEED
 

• Cochrane Review (2014)[x]

 
This systematic review and meta-analysis compared 8 randomized control trials (RCT) on TXA for upper gastrointestinal bleeding (UGIB) published from 1973 to 2011.  The various studies compared different control groups including placebo, no intervention, and antiulcer mediations.  Overall, the analysis showed an improvement in all cause mortality in patients who received TXA (4.9% vs 8.4% in the control group). 
 

• Take home:
  • Limited conclusion can be drawn from this data, however TXA can be considered in severe UGIB.
  • Look out for the HALT-IT trial in the near future specifically designed to address this question!

 
 
INTRACRANIAL HEMORRHAGE
 

• TICH-2 (2018)[xi]

 
This study examined functional status at 90 days in patients who received TXA in the setting of intracranial hemorrhage from an acute stroke.  They concluded that there were NO significant difference of functional status define by a modified Rankin Score at 90 days (22% vs 21% in placebo group)
 

• Take home:
  • At this time, TXA is NOT clinically recommended in spontaneous hemorrhagic strokes.

 


[i]Geoff Watts (2016). "Obituary Utako Okamoto". The Lancet. 387 (10035): 2286. 

[ii]http://www.txacentral.org/history

[iii]WHO Model List of Essential Medicines (20th List). 2017.

[iv]Shakur H, et al. "Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage". The Lancet. 2010. 376(9734):23-32.

[v]Roberts I, 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):1096-10.

[vi]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. 2017 May 27;389(10084):2105-2116.

[vii]Zahed R, et al. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med. 2013 Sep;31(9):1389-92.

[viii]Zahed R. "Topical Tranexamic Acid Compared With Anterior Nasal Packing for Treatment of Epistaxis in Patients Taking Antiplatelet Drugs: Randomized Controlled Trial". Acad Emerg Med. 2018. 25(3):261-266.

[ix]Wand O et al. Inhaled Tranexamic Acid for Hemoptysis Treatment: A Randomized Controlled Trial. Chest 2018. Chest. 2018 Dec;154(6):1379-1384.

[x]Bennett C et al. Tranexamic Acid for Upper Gastrointestinal Bleeding (Review). Cochrane Database Syst Rev 2014. PMID: 25414987

[xi]Sprigg N et al. Tranexamic Acid for Hyperacute Primary IntraCerebral Haemorrhage (TICH-2): An International Randomised, Placebo-Controlled, Phase 3 Superiority Trial. Lancet 2018. PMID: 29778325