Resident Eagle: TXA and Head Trauma

Resident Eagle is a new column authored by top EMS physicians and medical directors from the U.S. Metropolitan Municipalities EMS Medical Directors Consortium (the "Eagles"), who represent America’s largest and key international cities. Every month they will discuss the latest cutting-edge issues and findings in emergency care. 

Tranexamic acid (TXA) emerged as a promising prehospital therapy for trauma patients with severe bleeding and hemorrhagic shock following 2010’s CRASH-2 trial. In this column we’ll offer a quick review of TXA and its use in trauma and discuss the recent CRASH-3 trial, which is likely to expand its indication for administration in the field. 

What We Already Know

TXA has been used for decades to treat bleeding. It stabilizes clot formation by inhibiting clot breakdown.¹

CRASH-2 was a landmark trial published in The Lancet. It demonstrated a 1.5% reduction in mortality in favor of TXA use in patients with or at risk from serious hemorrhage.² No increased risk of blood clots (strokes, MI, DVT, PE) was observed in the TXA-treated group. The observed effect on mortality equated to a number needed to treat (NNT) of 67 to save one life.

For an inexpensive drug with no demonstrated risk, that's impressive. In a subanalysis, time to treatment was inversely associated with survival. In other words, early treatment less than an hour from injury resulted in the greatest benefit: an absolute mortality benefit of 2.4%, which equates to an NNT of 42.² This is the golden hour of prehospital and early ED care, well within the timeline of prehospital medicine. 

The estimated mortality benefit of TXA was even larger in another analysis: MATTERs, a retrospective observational study of combat injuries at a center in Afghanistan.³ In patients with penetrating injuries requiring one unit of packed red blood cells (PRBCs) within an hour of arrival, TXA was associated with mortality reduction of 6.5%.

The mortality benefit was even more pronounced in the sickest patient population, those requiring massive transfusion (more than 10 units of PRBCs), with an estimated mortality reduction of 13.7%. While the military model differs from the civilian system in important ways, TXA’s range of estimated benefit–if given early–makes it one of the most important lifesaving drugs in trauma.

While isolated head trauma patients were excluded from CRASH-2, TXA should also theoretically benefit patients at risk of intracranial hemorrhage. There is only so much room in the rigid cranium for the brain and cerebrospinal fluid. An expanding intracranial hematoma is dangerous—not primarily because of blood loss but due to its space-occupying effects, which can cause compressive injury and even herniation of vital brain structures. But few prior studies have examined the effects of TXA on patients with isolated traumatic brain injury (TBI), and those that have were small.

A meta-analysis from 2015 concluded there was evidence of a statistically significant reduction in intracranial hemorrhage progression with TXA, without a clear mortality benefit or improvement in overall neurological status.⁴ The TICH-2 trial attempted to evaluate TXA in spontaneous (nontraumatic) intracranial hemorrhage.⁵ This trial demonstrated no difference between TXA and placebo in functional status at 90 days but did show a small improvement in hematoma expansion on the second day, and mortality at the seventh. (These are secondary outcomes and so merely hypothesis-generating.)

So welcome CRASH-3, a massive international randomized controlled trial  investigating the use of TXA in patients with isolated TBI and its effects on death and disability from traumatic brain injury. 

CRASH-3 Study

This was a pragmatic RCT involving 175 hospitals and 29 countries. Patients were included if they could be treated within three hours of injury, had either a GCS less than 13 or intracranial hemorrhage on CT, and had no extracranial bleeding (these were isolated TBI patients). Patients were randomly assigned to receive TXA (loading dose 1 g over 10 minutes, then infusion of 1 g over eight hours) or matching placebo (0.9% normal saline). The primary endpoint was head injury-related death in the hospital within 28 days of injury.⁶ 

Investigators randomized a massive 12,737 patients, 9,202 of whom were able to be randomized within three hours. These groups matched well on baseline characteristics.

Despite a trend toward reduced mortality with TXA, the difference in the primary outcome of head injury-related death was not statistically significant overall (18.5% with TXA, 19.8% with placebo). So why does it matter? Investigators preplanned a sensitivity analysis excluding patients with a GCS of 3 or blown pupils. These are patients with generally catastrophic brain injury who are therefore unlikely to benefit from any therapy, including TXA. The more of these patients in your trial, the harder it might be to detect an effect of a drug that reduces bleeding.

Patients with a GCS of 3 or blown pupils have probably already bled into their cranium so much that TXA would be too little, too late. They therefore added a separate sensitivity analysis excluding those patients deemed beyond the help of the drug. When subjects with a GCS of 3 or bilateral unreactive pupils were excluded, the drug demonstrated an effect on head injury-related death (12.5% in the TXA group vs. 14.0% in the placebo group). This gives an NNT of 68 to prevent one head injury-related death.

Despite a negative primary endpoint, one subgroup had people talking. Looking specifically at patients with mild to moderate head injury (GCS 9 to 15), authors noted a reduction in head injury-related death. In other words, patients without severe TBI (GCS less than 8 and/or fixed/dilated pupils) may benefit most from TXA, but only if treated early. The authors quote a 10% reduction in efficacy with each 20-minute delay to treatment. Such a time-dependent therapy is well within the scope of prehospital medicine.

Importantly, there was also no difference between the groups in terms of adverse or vaso-occlusive events, an ongoing concern with use of antifibrinolytic agents like TXA.

Strengths and Weaknesses

This is the largest trial to date to study TXA in TBI. Blinding and randomization were appropriately performed with no evidence of bias. Furthermore, almost all patients who met inclusion criteria were captured.

Perhaps the greatest strength of CRASH-3 is that it demonstrates the safety of TXA use in a large group of patients with TBI. Furthermore, when given in a timely manner to patients without severe TBI, TXA is likely to be beneficial. Therefore, the administration of TXA in carefully selected TBI patients in the field is reasonable at this time based on current best evidence, although the treatment does not currently constitute the standard of care in all EMS environments.

If you’re already giving TXA for major trauma, consider the addition of isolated TBI patients. In urban environments with short transport times to trauma centers, develop protocols in coordination with trauma leaders. It may make sense to reserve TXA for patients who show bleeding on initial ED CT scan, but an argument can be made for overtreating head-injured patients across a spectrum of GCS and without a CT scan in order to reduce head injury-related mortality.  

References

1. Nishida T, Kinoshita T, Yamakawa K. Tranexamic acid and trauma-induced coagulopathy. J Intensive Care, 2017; 5:5.

2. CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, 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 Mar 26; 377(9,771): 1,096-101.

3. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg, 2012 Feb; 147(2).

4. Zehtabchi S, Abdel Baki SG, Falzon L, Nishijima DK. Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis. Am J Emerg Med, 2014 Dec; 32(12): 1,503-9.

5. Sprigg N, Flaherty K, Appleton JP, et al.; TICH-2 Investigators. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet, 2018 May 26; 391(10,135): 2,107-15.

6. 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, 2019 Nov 9; 394(10,210): 1,713-23.

Scott Youngquist, MD, MSC, FACEP, FAEMS, FAHA is medical director for the Salt Lake City Fire Department. 

Andrew Pugh, MBBS, MRCP, is an EMS fellow and third-year emergency medicine resident at the University of Utah.