Tranexamic Acid in Trauma. CRASH-2, MATTERs, and CRASH-3.

Author: Brad Kinney MD, Emergency Medicine Physician. May 6, 2020.

BLUF

• Tranexamic Acid (TXA) is an anti-fibrinolytic medication used in trauma resuscitation, and is a foundational element of Damage Control Resuscitation (DCR).
• TXA should be administered to all bleeding trauma patients, and those at risk of significant bleeding. If you transfuse, or consider transfusing, give TXA.
• Give TXA ASAP, but do not administer if greater than 3 hours since injury.
• TXA Dosing: 1 gram over 10 minutes, followed by a 1 gram drip over the next 8 hours.
• Consider TXA in isolated TBI patients without significant extracranial hemorrhage.
• The CRASH-2 Trial, the MATTERs Study, and the CRASH-3 Trial are the landmark studies defining TXA use in trauma.

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BACKGROUND

Traumatic injury is a leading cause of death worldwide, and uncontrolled hemorrhage is responsible for many of those deaths. Hemorrhage control and trauma care evolved rapidly within the last two decades to include new equipment and improved resuscitation strategies, but no medications have shown a mortality benefit until Tranexamic Acid (TXA).

TXA is an “anti-fibrinolytic” medication that prevents clot breakdown, thus preventing further hemorrhage, and is now an essential element of trauma resuscitation due to three groundbreaking studies: the CRASH-2 Trial, the MATTERs Study, and the CRASH-3 Trial. This article briefly discusses the main points of these landmark investigations; for a deeper analysis of their nuances, reference the listed sources.

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The CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage 2) study, published in The Lancet in 2010, was a massive, multi-center, prospective, randomized, double-blinded, placebo-controlled trial that compared the mortality of bleeding trauma patients who were given TXA versus those given placebo.

• Demographics: 20,211 patients (10,096 TXA, versus 10,115 placebo), 274 hospitals, 40 countries, ~84% males, mean age ~34, ~67% blunt vs. ~33% penetrating trauma, ~68% SBP >90, ~68% GCS 13-15, mean time since injury ~2.8 hours.
• Included: Bleeding adult trauma (>18 years old), Systolic BP <90, Heart Rate >110, <8 hours since injury, or those deemed at risk of significant hemorrhage.
• Primary outcome: Death within 4 weeks from “bleeding, vascular occlusion (myocardial infarction, stroke, pulmonary embolism), multi-organ failure, head injury, and other.”
• Secondary outcomes: “Vascular occlusive events (myocardial infarction, stoke, pulmonary embolism, and deep vein thrombosis), surgical intervention (neurosurgery, thoracic, abdominal, and pelvic surgery), receipt of blood transfusion, and units of blood products transfused.”
• Results: All-cause mortality (TXA 14.5% vs. 16.0%, p=0.0035) and death due to bleeding (TXA 4.9% vs. 5.7%, p=0.0077) were significantly reduced with early administration of TXA versus placebo, with no significant difference in measured adverse events.

Discussion: The CRASH-2 trial was a very large, well-designed study conducted in multiple centers across the world with diverse trauma care capabilities. Despite the heterogeneity of the locations, the resuscitation capabilities, and the acuity of the patients included, CRASH-2 demonstrated a statistically and clinically significant mortality benefit with the early administration of TXA in bleeding trauma patients.

CRASH-2 criticisms often stem from a fundamental misunderstanding of the pragmatic study design and the purpose of this trial. Pragmatic studies allow practitioners to continue usual care except for the measured intervention, and subsequently yield results that are much more clinically practical than the results of rigid, focused, explanatory trials. Pragmatic trials also embrace variation, but therefore must have a very large sample size to achieve statistical power. But, if a statistically significant effect is discovered, the benefit can be widely generalized to a diverse population worldwide. So what some consider weaknesses innate to pragmatic trial design, others consider strengths. Pragmatic trial design is becoming more common, and may actually be the future for emergency medicine research.

Some criticize the number of lower acuity patients included in CRASH-2 (only about half in each group were transfused), but, this should have biased the study toward the null hypothesis, and a significant mortality benefit was still demonstrated. Overall, CRASH-2 was a very well performed positive study that demonstrated a significant mortality benefit with TXA administration in bleeding trauma patients.

Conclusion: Give TXA to bleeding trauma patients as early as possible – but not more than three hours after injury. Or, according to the trial authors, if you transfuse, or consider transfusing, give TXA.

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The MATTERs Study was a retrospective observational study that examined the UK Joint Theatre Trauma Registry data for combat trauma injured patients admitted to a single Role 3 Surgical Hospital over the course of two years starting on January 1, 2009. Mortality was compared in patients who were given TXA versus those who received no TXA.

• Demographics: 896 patients (293 TXA, versus 603 no TXA), 1 hospital (Camp Bastion, Afghanistan), ~95% males, mean age ~24, ~1/3 GSW and ~2/3 explosion, ~45% GCS=8 or less, ~17% SBP=90 or less.
• Included: NATO military personnel and Afghan host nationals with a “combat-related injury” requiring “at least 1 unit of PRBCs within 24 hours of admission” to Camp Bastion.
• Primary outcomes: 24 hour, 48 hour, and in-hospital mortality within 30 days.
• Secondary outcomes: Transfusion requirements, coagulation parameters, TXA dose/timing, and DVT/PE incidence.
• Results: In-hospital mortality was reduced in the TXA group vs. no TXA group (17.4% vs. 23.9%, p=0.03), and at 48 hours (11.3% vs. 18.9%, p=0.004). In a massive transfusion subgroup, in-hospital mortality was reduced in the TXA vs. no TXA group (14.4% vs. 28.1%, p=0.004), and at 48 hours (10.4 vs. 23.5, p=0.003).

Discussion: In contrast to the CRASH-2 trial which was a massive, heterogenous, study conducted in hospitals with widely varying trauma resuscitation capabilities; the MATTERs study was a much smaller, homogenous study of a young and generally healthy military population where trauma care was streamlined and modernized. MATTERs showed a significant mortality benefit with TXA administration similar to CRASH-2, but in a much more severely injured population. These two studies complement each other perfectly. According to MATTERs, we should give TXA to critically injured bleeding trauma patients – these patients receive the greatest benefit. But according to CRASH-2, we should also give TXA to the many “less injured” bleeding trauma patients – they receive significant benefit as well. Reserving TXA for ONLY the critically injured would rob the larger population of less critically injured trauma patients of a small, but significant mortality benefit.

A small benefit in a large number of patients with more moderate injuries equals more lives saved than a large benefit in the relatively few critically ill and bleeding patients.

Dr. Tim Coats, a primary author of CRASH-2, on EMCRIT podcast 67.

Conclusion: TXA should be administered as early as possible to the bleeding trauma patient. Critically injured bleeding trauma patients benefit the most, but TXA should still be given to all bleeding trauma patients in all capable centers across the globe.

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The CRASH-3 trial, published in The Lancet in 2019, was a large, multi-center, prospective, randomized, double-blinded, placebo-controlled trial that compared mortality in traumatically brain injured (TBI) patients who were given TXA with those given placebo.

• Demographics: 12,737 patients, 175 hospitals, 29 countries, ~80% males, mean age ~42, mean time since injury ~1.9 hours.
• Included: “Adults with TBI who were within 3 hours of injury, had a GCS score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding.”
• Primary outcomes: “Head injury-related death in hospital within 28 days of injury.”
• Secondary outcomes: “Early head injury-related death (within 24 hours after injury), all-cause and cause-specific mortality, disability, vascular occlusive events (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism), seizures, complications, neurosurgery, days in intensive care unit, and adverse events within 28 days of randomisation.”
• Results: “The administration of TXA to patients with TBI within 3 hours of injury reduces head injury-related death, with no evidence of adverse effects or complications. We found a substantial reduction in head injury-related deaths with TXA in patients with mild and moderate head injuries but no apparent reduction in those with severe head injury.”

Discussion: CRASH-2 showed a decreased mortality in bleeding trauma patients given TXA, but excluded patients with isolated Traumatic Brain Injury (TBI). The CRASH-3 collaborators performed the CRASH-3 trial to determine whether TXA administration would also benefit this isolated, previously excluded TBI subgroup. Severe TBI patients – GCS=3, non-reactive pupils – were excluded from the final analysis since TXA, an antifibrinolytic, would likely do nothing to salvage this population. Their final data showed no “overall” mortality benefit of TXA 18.5% versus placebo 19.8%, RR=0.94 (0.86-1.02), but subgroup analysis of those with mild to moderate TBI (GCS 9-15) did show a significant mortality benefit – TXA 5.8% versus placebo 7.5%, RR=0.78 (0.64-0.95).

While the data technically did not show a statistical difference in the primary outcome, they did show a “very strong trend toward reduced mortality.” As expected, the severely injured showed no mortality benefit or benefit related to timing of TXA administration, but the less severely injured subgroup showed a significant mortality benefit, and more of a benefit when TXA was given earlier. While the data are not without controversy, due to the relatively safe profile of TXA, patients with isolated TBI after trauma may benefit from early TXA administration. Personally, I would rather err on the side of giving TXA than not giving TXA in these patients.

Conclusion: CRASH-3 was a methodologically sound study that demonstrated reduced “head injury-related death” for mild to moderate TBI patients who were given TXA and without significant adverse recorded events. The data show that early administration is key.

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INTEL

1. CRASH-2 trial collaborators. 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 2010; 376: 23-32. PMID: 20554319
2. Morrison JJ et al. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) Study. Arch Surg 2012; 147 (2): 113-9. PMID: 22006852
3. 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; 394(10210): 1713-1723. PMID: 31623894
4. Roberts et al. Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial. Crit Care Dec 13;18(6):685. PMID 25498484
5. Coats TJ. Future research in emergency medicine: explanation or pragmatism? Large or small? Simple or complex? Emerg Med J 2011 Dec 28(12):1004-7. PMID 21785146
6. Salim Rezaie. Tranexamic Acid (TXA) for Everything that Bleeds? REBEL EM Blog. March 25, 2019. Available at: https://rebelem.com/tranexamic-acid-txa-for-everything-that-bleeds/.
7. Salim Rezaie. CRASH-3: TXA for ICH? REBEL EM Blog. October 15, 2019. Available at: https://rebelem.com/crash-3-txa-for-ich/.
8. Daniel Deweert. ED Crash Course: TXA Matters! emDocs Blog. March 21, 2016. Available at: http://www.emdocs.net/ed-crash-course-txa-matters/
9. Brandon C. Busuito. TXA Use in Trauma: An Update. emDocs Blog. December 10, 2014. Available at: http://www.emdocs.net/txa-use-trauma-update/
10. Josh Farkas. Pulmcrit: Tranexamic acid for Traumatic Brain Injury (CRASH3). PulmCrit Blog, Available at: https://emcrit.org/pulmcrit/crash3/
11. Scott Weingart. Podcast 67 – Tranexamic Acid (TXA), Crash 2, & Pragmatism with Tim Coats. EMCrit Blog. Published on February 19, 2012. Accessed on June 1st 2019. Available at https://emcrit.org/emcrit/tranexamic-acid-trauma/.
12. Noble S, Chitnis J. Case report: use of topical tranexamic acid to stop localised bleeding Emergency Medicine Journal 2013;30:509-510. Accessed on May 5, 2020. Available at: https://emj.bmj.com/content/30/6/509