Resident Eagle: TXA in TBI, Part 2

Resident Eagle is a monthly column profiling the work of top EMS physicians and medical directors from the Metropolitan EMS Medical Directors Global Alliance (the "Eagles"), who represent America’s largest and key international cities. 

As discussed in last month’s opening column about nonmechanical hemostasis in prehospital trauma care, the use of TXA had overall positive results when reported by the CRASH-2 investigators, who used it for presumed post-traumatic hemorrhage more than a decade ago.¹ Despite that apparent success and many other positive studies from nontrauma literature, some ambivalence has remained, particularly with the various reports of risks from complications.^2–4 Even CRASH-2 results indicated worse outcomes if the drug was administered later in the course of injury.¹ 

While CRASH-2 focused on post-traumatic hemorrhage, the CRASH-3 study examined the use of TXA for those with mild to moderate head injury with the concern that if accompanying intracranial bleeding occurs, it can be life-threatening.⁵

The classic statement about patients with an epidural hematoma is that they are those who “first talked, then died.” The relatively thin temporal bone is traversed by the middle meningeal artery (left or right), and when fractured it can sever the artery and result in rapid hemorrhage. That hemorrhage quickly accumulates and forms the epidural mass effect, and that can quickly compress the brain. Herniation can ensue within minutes. While not an arterial laceration, “subdural” hematomas from shearing of the veins underneath the dura mater can be more extensive and create their own havoc. 

While these intracranial “masses” can eventually be evacuated and controlled surgically, time to neurosurgical intervention can also be delayed. Likewise, less amenable to anatomic surgical interventions, other regions of intracranial bleeding pose other challenges. In either case, the earlier the intervention, the better the outcome. That is where the prehospital administration of TXA comes into play.

Like its predecessor trial in general trauma patients with bleeding, the number of patients enrolled in CRASH-3 was quite large, involving 175 hospitals in 29 countries. Published in November 2019, it was again a 1:1 trial of TXA for TBI vs. placebo. As in CRASH-2, the treatment protocol provided 1 gram over 10 minutes early on (within three hours of injury), followed by a second gram over eight hours (bolus/maintenance approach).^1,5,6 Again, with nearly 13,000 patients entered, the study power was relatively strong, and overall takeaway results were postive.⁵ Overall, TXA administration fell just short of demonstrating a significant difference in mortality (18.5%) vs. placebo (19.8%; RR 0.94; 95% CI: 0.086–1.02) when comparing those treated within three hours (n=9,202). 

However, the study did identify a significant difference in terms of reducing the risk of head injury-related deaths, the presumptive targeted group for treatment (RR 0.78; 95% CI: 0.64–0.95), but only among those with mild to moderate head injury, not those with severe head injury.⁵

Once again, rapid intervention was key. The earlier the treatment was administered, the more effective it was in this study of patients with mild to moderate head injury (p=0.005). Also, the risk of vascular occlusive events and seizures was similar (no increased risk). Given the very large study size, this was encouraging information. In summary, there was apparent safety and some efficacy identified in certain subgroups, particularly among those with mild to moderate TBI. However, as discussed in the next section, like its predecessor study, debate over the interpretation of results and their applicability elsewhere also ensued. 

The ROC TXA Study

Both CRASH-2 and CRASH-3 indicated a certain degree of efficacy, and even relative safety, for very early administration of TXA in certain subgroups of internal hemorrhage and head trauma patients. However, relative percentage differences between study cohorts (in both clinical trials) were not that pronounced, and questions remain regarding the applicability of the findings to other trauma systems, such as those in North America. Furthermore, the lack of efficacy with more severe head injury raised additional questions about the CRASH study dosing schedule (1-gram bolus and 1 gram extended over the next eight hours), an approach that may not be entirely logical for most trauma cases.

While the results of CRASH-3 were still being freshly debated, another pivotal study was being published in the September 8, 2020 issue of JAMA.⁷ This clinical trial, funded and organized through the U.S. National Institutes of Health (NIH), U.S. Department of Defense, American Heart Association, and their sister organizations in Canada, was conducted by the Resuscitation Outcomes Consortium (ROC) and involved dozens of EMS agencies and 20 trauma centers across the U.S. and Canada.⁷

In contrast to CRASH-3, this investigation involved patients with moderate or severe TBI and used a protocol that compared three study arms in a double-blinded placebo control design. Patients received either: 1) 2 grams of TXA up front in the prehospital setting (“bolus-only”); 2) a 1-gram bolus plus the 1-gram eight-hour follow-up infusion protocol (“bolus/maintenance” approach); or 3) a placebo.^5,7 Beyond crude survival rates, the study evaluated whether TXA would result in an improved six-month Glasgow Outcome Scale–Extended (GOSE) and Disability Rating Scale in patients with moderate to severe TBI.⁷

When combining both TXA-treated groups versus placebo, there was a trend, but no statistically significant differences were identified on the primary study outcome (65% with favorable neurological status at six months vs. 62%). However, nearly 60% of those studied had significant hemorrhage within the skull confirmed by computerized tomography (CT). Among those patients with intracranial bleed, mortality rates at four weeks were 18% in the 2-gram bolus-only group vs. 26% in the 1-gram bolus/1-gram “maintenance” infusion group and 27% in the placebo group. While no significant differences were identified between the 1-gram bolus/1-gram maintenance group and placebo group, the better outcomes were indeed significant for the 2-gram prehospital bolus vs. either the bolus/maintenance (1+1) group (p=0.01) or placebo group (p=0.03).⁵ In addition, the transfusion requirement in the 2-gram bolus-only group was also lower than the other two groups.⁷

These findings raise the fundamental issue of interpretation of study results and how evidence is presented.^8,9,10 The design of this clinical trial created some statistical compromise by dividing applicable patients into three different groups (n=345 in the bolus-only group, 312 in the bolus/maintenance group, and 309 in the placebo group), and only 85% of patients (n=819) were available for follow-up at six months. Accordingly, considering that those with intracranial bleeding constitute less than 60% of the study populations, this creates an even stronger statistical argument that the reduced mortality among those with intracranial bleeding was a compelling finding and that other positive results may have been masked by inadequate patients numbers, including the additional dilutional effects produced when combining both TXA-treated legs, with and without bleeds, and comparing that combined diluted cohort against the placebo.

Therefore, the subgroup analysis of 28-day mortality rates for patients found to have intracranial bleeding becomes even more fundamental and emphasizes several salient points. First, the 2-gram bolus up front makes more sense, both physiologically and logistically, and that perspective is further justified by the findings here. These results also verified that versus CRASH-3, TXA can have distinct advantages in patients with moderate-to-severe injuries when given well within the first hour as a very early bolus. In the ROC TXA TBI study, most persons received the TXA bolus within the first hour after injury (i.e., median time 40 minutes for the TXA bolus group). This may explain many of the differences with prior studies.^1,5,7

Another key finding was that 657 TXA-treated patients (in both TXA study arms) did not have an intracranial bleed. Considering this subgroup would not directly benefit from TXA in this setting, the findings from these equally injured patients provided a built-in safety analysis. Indeed the TXA-treated patients without intracranial hematoma had no additional complications detected (e.g., vascular occlusions, seizures) when compared to placebo (nontreatment) patients. Those who received the 2-gram bolus did have a higher percentage of seizures when compared with the placebo and 1+1 bolus/maintenance cohorts (17/345 vs. 7/309 and 5/312, respectively).^3,11 However, there were no differences in ultimate outcomes between patients who had seizures and those who did not.^7,11 Similarly CRASH-3, with lesser-injured patients, had similar positive findings with regard to complications and safety.^5,7

Therefore, TXA, particularly when given early to patients with TBI, has no apparent high-risk downside and likely will have an important lifesaving upside for the targeted subgroups, those with significant TBI and intracranial bleeding. In essence, based on the current available evidence, the assimilated safety profiles from these large trials indicate that the earliest possible administration of TXA is the key to both efficacy and safety of the intervention. Conversely, delayed administration invokes the greater potential for both complications and lack of efficacy, and that may also explain poor outcomes and complications in other studies.

Takeaways for Now

Over the past year, two new clinical trials have been published that may help address the ambiguity about TXA and its proper dosing. In summary, these two trials and others have indeed indicated safety and efficacy if:

• A one-time 2-gram bolus alone, given by IV or intraosseous route, is provided to patients with moderate to severe head injury;  
• That infusion is given as soon as possible in the prehospital setting and preferably well within the first hour after injury and not provided if significant time has elapsed;
• Monitoring and preparation for complications, particularly seizures, are in place;
• Local EMS, EM, and trauma specialists create consensus that the same approach can be used in internal bleeding.

Numerous other related studies have addressed the use of TXA in trauma and severe hemorrhage, including the landmark MATTERs trial conducted by the U.S. military in which TXA was originally provided as an adjunct to administering blood products.¹² Publications since then have been largely opinion pieces, meta-analyses, and reports from smaller, correlative, or retrospective studies regarding TXA in trauma care, including in-hospital TEG-guided use of TXA as previously discussed.^2,13–21 Many of the smaller studies, with most being conducted at well-respected research institutions, have indicated either neutral findings or even associations with adverse outcomes.^{2,13,14,18–21}

Accordingly, assimilating all prior work, the reviews are therefore understandably mixed. However, the three main clinical trials discussed in this review still might be considered the best available evidence in the realm of trauma care.^1,5,7 Several trials, such as the Pittsburgh-based STAAMP or St. Louis-based TAMPITI trials, have publications pending, and those results should be considered in any future consensus. In the meantime, larger-scale literature borrowed from other disciplines has also provided inferential positive outcomes and safety insights for trauma care, such as the 20,000-patient WOMAN trial conducted among patients with postpartum hemorrhage.²² Pooling the assimilated findings of the larger CRASH-2, CRASH-3, and ROC-TXA-TBI trials and the WOMAN trial, routine prehospital use of TXA will likely become more widely adopted for moderate to severe head injury when given with previously discussed caveats.^15,23

Again, that adopted practice should now also come with the recommendation of administering the TXA as only one 2-gram bolus (intravenous or intraosseous) given as soon as possible after injury in the prehospital setting, and most advisedly within the first hour.^7,23 With that approach, however, one may expect to witness seizures in a finite number of patients based on the ROC-TXI-TBI results.⁷ Clinicians need to be prepared for that potential, but that should be the norm with or without TXA.⁷ However, based on all accumulated information, they should also have a degree of confidence that TXA is likely to be relatively safe and pose low risk for additional complications if given very early after injury.^1,11,5,7,23

With those same caveats, several civilian trauma systems and the U.S military’s Tactical Combat Casualty Care (TCCC) guidelines have already adopted the use of the 2-gram bolus as early as possible for indicated patients, including both presumptive hemorrhagic shock and TBI cases.²³ Many of the advances reviewed in this discussion can be attributed not only to the visionary research and early adoption of those interventions by the U.S. military and others, but also to the funding of civilian trauma studies such as the ROC TXA study and other related trials.^12,23–26 Civilian EMS agencies providing whole blood in the field, another prehospital intervention advanced by the military experience, have also indicated their decision to use a 2-gram TXA bolus as an adjunct to their programs.²⁸ 

What We Still Need to Consider

Although many clinical programs will now likely adopt TXA for both TBI and presumptive hemorrhage, questions still persist, such as use of TXA in children, intramuscular use, and differences according to age, weight, size, sex, and use of blood products or other treatments. Also, is there a way to prevent or better mitigate potential seizures? Will future research using 2 grams up front indicate long-term benefit in functional outcomes within targeted populations?^5,7

Over the past four decades, challenges to the status quo have been put forward such as the consideration of not aggressively infusing crystalloid fluids in actively bleeding patients or re-emphasizing the lifesaving effect of tourniquets.^27–32 Those studies questioned the prior binary approach of simply declaring an intervention to be “effective” or “not effective” at all times and in all patients. Moreover, as this discussion has emphasized, timing, dosing, and proper identification of patient subgroups should be a key focus in research interpretation as well as study design.^8–10 Appreciation of those multidimensional concerns must be an integral part of our collective critical thinking processes, especially when interpreting scientific data, and recognizing that traditionally data may be reported in terms of simple binary conclusions.^8–10 As previously stated, research might be best spelled re-search when it comes to delivering the best care possible.^8,10

The ROC-TXA-TBI study team appreciated that principle in designing their study by proactively including key subgroup analyses such as examining the mortality rates in those with confirmed intracranial bleed.⁷ Had that not been done, this pivotal study (like so many other clinical trials in resuscitation medicine before it) might have been dismissed as an overall neutral trial, and its intervention deemed ineffective when indeed it has lifesaving potential.^9,10,33  

Authors' Conclusions

Combining the results of trauma-related clinical TXA studies to date, several conclusions can be drawn:

• Tranexamic acid (TXA) is probably of lifesaving value in patients with moderate to severe head injury if given as a 2-gram bolus (over one minute) and administered prehospitally as soon as possible after injury (definitely within the first hour).
• TXA is likely safe and poses low risk for complications, but only if given early.
• While these findings do not fully clarify the issue of treating those with presumed uncontrollable post-traumatic (internal truncal) bleeding, it provides encouragement and support for the original findings of CRASH-2, results which would promote its very early use in that circumstance as well.
• Extrapolating from the current findings in TBI and even the CRASH-2 findings, giving a 2-gram bolus immediately is likely an advantageous approach in either case.
• Clinicians should closely monitoring and prepare for complications, particularly seizures in patients with TBI, with or without TXA infusion;
• The authors still encourage clinicians and investigators to continually reassess these deductions and maintain vigilance with the understanding that not all interventions are right for all persons at all times.

References

1. CRASH-2 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 July 10; 376: 1,713–23.

2. Myers SP, Kutcher ME, Rosengart MR, et al. Tranexamic acid administration is associated with an increased risk of post-traumatic venous thromboembolism. J Trauma Acute Care Surg, 2019 Jan; 86: 20–7.

3. Lecker I, Wang DS, Whissell PD, Avranmescu S, Mazer CD, Orser BA. Tranexamic acid–associated seizures: causes and treatment. Ann Neurol, 2016 Jan; 79: 18–26.

4. Moore EE, Moore HB, Gonzalez E, Sauaia A, Banerjee A, Silliman CC. Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient. Transfusion, 2016 Apr; 56(Suppl 2): S110–S114.

5. CRASH-3 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet, 2019 November 9; 394: 23–32.

6. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ, 2012; 344: e3054.

7. Rowell SE, Meier EN, McKnight B, et al. Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury. JAMA, 2020; 324(10): 961–74.

8. Pepe PE, Aufderheide TP. EBM vs. EBM: combining evidence-based and experienced based medicine in resuscitation research. Current Opin Crit Care, 2017; 23: 199–203.

9. Pepe PE, Aufderheide TP, Lamhaut L, et al.; writing group for the International Resuscitation Collaborative. Rationale and strategies for development of an optimal bundle of management for cardiac arrest. Critical Care Explor, 2019 [in press].

10. Pepe PE, Aufderheide TP. Only a Sith deals in absolutes: why we need both evidence-based and experience-based thinking in resuscitation research. J Emerg Med Serv, 2020 [in press].  

11. Kirksey MA, Wilson LA, Fiasconaro M, Poeran J, Liu J, Memtsoudis SG. Tranexamic acid administration during total joint arthroplasty surgery is not associated with an increased risk of perioperative seizures: a national database analysis. Reg Anesth Pain Med, 2020 Jul; 45: 505–8.

12. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg, 2012; 147: 113–9.

13. Neeki M, Dong F, Toy J, et al. Tranexamic acid in civilian trauma care in the California prehospital antifibrinolytic therapy study. J Emerg Med, 2018; 19: 977–86.

14. Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg, 2015; 26: 390–4.

15. Fischer K, Awudi E, Varon J, Surani S. Role of tranexamic acid in the clinical setting. Cureus, 2020 May; 12: e8221 [epub online].

16. 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. Lancet, 2018; 391: 125–32.

17. Cap AP, Baer DG, Orman JA, Aden J, Ryan K, Blackbourne LH. Tranexamic acid for trauma patients: a critical review of the literature. J Trauma, 2011; 71 (1 Suppl): S9–S14.

18. Valle EJ, Allen CJ, Van Haren RM. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg, 014; 76: 1,373–8.

19. Dixon A, Emigh B, Spitz K. Does tranexamic acid really work in an urban U.S. level I trauma center? A single level 1 trauma center’s experience. Am J Surg, 2019 Dec; 210: 1,110–3.

20. Moore HB, Moore EE, Huebner BR, et al. Tranexamic acid is associated with increased mortality in patients with physiological fibrinolysis. J Surg Res, 2017; 220: 438–43.

21. Boutonnet M, Abback P, Le Saché F, et al. Tranexamic acid in severe trauma patients managed in a mature trauma care system. J Trauma Acute Care Surg, 2018; 84(6S Suppl 1): S54–S62.

22. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other co-morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blinded, placebo-controlled trial. Lancet, 2017; 389: 2,105–16.

23. Drew B, Auten J, Donham B, et al. The use of tranexamic acid in tactical combat casualty care. JSOM, 2020; 20(30): 34–42.

24. Lipsky A, Abramovich A, Nadler R, et al. Tranexamic acid in the prehospital setting: Israel Defence Forces’ initial experience. Injury, 2014; 45: 66–70.

25. Pusateri AE, Weiskopf RB, Bebarta V, et al. Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock, 2013; 39: 121–6.

26. Morte D, Lammers D, Bingham J, et al. Tranexamic acid administration following head trauma in a combat setting: Does tranexamic acid result in improved neurologic outcomes? J Trauma Acute Care Surg, 2019; 87: 125–9.

27. Joint Committee to Create a National Policy to Enhance Survivability from Intentional Mass Casualty and Active Shooter Events. The Hartford Consensus III: Implementation of Bleeding Control. Bull Am Coll Surg, 2015; 100: 20–6.

28. Pepe PE, Roach JP, Winckler CJ. State of the art review: Prehospital resuscitation with low titer O+ whole blood by civilian EMS teams—rationale and evolving strategies for use. In: Vincent JL (ed.), 2020 Annual Update in Intensive Care and Emergency Medicine. Berlin: Springer International Publishing, 2020; pp. 366–76.

29. Pepe PE. Chapter 6: Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. In: Cohn S, Feinstein A (eds.), 50 Landmark Papers Every Trauma Surgeon Should Know. CRC Press, 2020; pp. 23–9.

30. Diebel ME, Diebel LN, Liberati DM. Protective effects of plasma products on the endothelial-glycocalyx barrier following trauma-hemorrhagic shock: Is sphingosine-1 phosphate responsible? J Trauma Acute Care Surg, 2019; 87(5): 1,061–9.  

31. Coons BE, Tam S, Rubsam J, Stylianos S, Duron V. High volume crystalloid resuscitation adversely affects pediatric trauma patients. J Pediatr Surg, 2018; 53: 2,202–8.

32. Morrison CA, Carrick MM, Norman MA, et al. Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial. J Trauma, 2011; 70: 652–63.  

33. Cone DC, Spaite DW, Coats TJ. Out-of-hospital tranexamic acid for traumatic brain injury. JAMA, 2020; 324: 946–7.

Paul E. Pepe, MD, MPH, FAEMS, MCCM, is coordinator of the Metropolitan EMS Medical Directors (aka “Eagles”) Global Alliance and medical director for special operations and tactical medicine for the the Broward County (Fla.) Sheriff’s Office. 

Jonathan Jui, MD, MPH, FACEP, FAEMS, is a Resuscitation Outcomes Consortium (ROC) co-investigator and longstanding EMS medical director for the city of Portland and Multnomah County, Ore., as well as the Oregon State Police. 

James P. Roach, DO, FACEP, is chair of the Cleveland Clinic Florida Emergency Department and chief medical officer for the Broward Sheriff’s Office in Broward County, Fla.

John B. Holcomb, MD, FACS, a retired colonel from the U.S. Army, is a general surgeon and senior scientist at the University of Alabama Center for Injury Science and was previously commander of the U.S. Army Institute of Surgical Research, as well as a 19-year member of the U.S. DOD Joint Trauma System Committee on Tactical Combat Casualty Care.