Trauma

Enthusiasm for Prehospital Use of TXA May Be Premature

Issue 5 and Volume 41.

Tranexamic acid (TXA), an antifibrinolytic drug, has been used by clinicians since 1986 when it was first approved by the Food and Drug Administration for the reduction and prevention of hemorrhage in patients with hemophilia undergoing tooth extraction. Since then, it’s been used as an “off-label” medication in cardiac and orthopedic surgery as a means to reduce intraoperative blood loss.

Recently this off-label use has expanded to trauma patients based on enthusiasm from two studies known as CRASH-2 and MATTERS (discussed later). Today TXA is used in some hospitals in the United States, and there’s been increasing interest in expanding its use to prehospital care.

The April 2015 JEMS article “TXA in the USA: Tranexamic acid’s potentially bright future relies on collaborative data,” by Jeffrey M. Goodloe, MD, NRP, FACEP and Ryan Gerecht, MD, CMTE, highlighted many of the points that advocates of expanded use have been making.1 Other articles and press releases about the use of TXA by EMS have provided similar information regarding the drug.2

However, these articles have, for unclear reasons, failed to objectively critique the listed studies or failed entirely to mention studies that paint even a slightly negative view of TXA.

There are many issues regarding the use of this drug for trauma patients that haven’t been answered, which is why many in the trauma surgeon community haven’t yet come out in favor of its unbridled use. As a trauma surgeon and member of the JEMS Editorial Board, I present this article to clarify several areas and present cautions about the use of TXA.

HEMORRHAGE & COAGULOPATHY

Hemorrhage in the trauma patient can be divided into surgical and nonsurgical bleeding. Those with surgical bleeding are considered to have bleeding from vessels that can be controlled with a surgical intervention such as suturing or tying.

Bleeding coming from raw surfaces, or regions without visible blood vessels, is known as nonsurgical bleeding and is usually a result of a complex derangement in normal coagulation that needs proper resuscitation.

Although bleeding defects were once thought to be a result of dilution of clotting factors, we now know there’s a much more complicated interplay of all the elements of normal clotting known as the acute coagulopathy of trauma.

One factor in this interplay is what happens with fibrin breakdown. It’s been shown that approximately 34% of trauma patients in shock are found to have an abnormal process known as hyperfibrinolysis, which has been shown to be an independent predictor of mortality and can lead to organ failure.3,4 A recently published article even finds that there are different “flavors” of hyperfibrinolysis.5

Because TXA is an antifibrinolytic, and can potentially stop/reverse the abnormal process, it may be beneficial in only those patients with hyperfibrinolysis. Identifying the patients who are hyperfibrinolytic requires thromboelastography (TEG), which can only be done in the hospital.

DISSECTING STUDIES

At first glance the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) trial appears to be a standout trial. Researchers had an enrollment of more than 20,000 patients in over 40 countries and showed statistically significant 28-day survival benefit for those getting TXA as well as a reduction in death due to bleeding.6

It was also found that mortality goes up if the drug was given greater than three hours from the injury. Diving deeper into this study, however, raises significant questions as to its broad application and validity.

To begin with, although this was a multi-institutional trial, only 1.4% of the sites were in trauma systems that would be equivalent to the very modern trauma systems that exist in the U.S. This makes the trial results difficult to apply in our country. Additionally, and perhaps more importantly, in a trial of trauma patients in shock, less than 50% of the enrolled patients met the blood pressure or heart rate criteria, and only 50.8% were actually transfused with blood products.

Additional problems with the trial included a lack of clarity on how they monitored or cared for the patients and lack of injury severity scoring. There was also no reported data on blood loss and a lack of disclosure about serious adverse events.

This study also needed 20,000 patients to demonstrate only a 0.8% absolute reduction in death caused by hemorrhage. Finally, it’s an odd phenomenon that a drug given under a three-hour window provides mortality benefits, but once it falls on the other side of that timeframe, mortality actually increases.

The military application of TXA in trauma emergency resuscitation study (MATTERS) is a retrospective trial performed in a U.S. military hospital in Afghanistan over approximately two years. Researchers identified 896 consecutive patients (both military and civilian) who were severely injured and transfused at least one unit of red blood cells within 24 hours of admission.7

This trial demonstrated that the use of TXA reduced 48-hour all-cause mortality and reduced in-hospital mortality. The confounding factors of this are that it was a retrospective trial, which changes how you can look at the results.

Additionally, the protocol for administration of TXA changed during the study time period, going from physician-driven to protocol-driven administration. Lastly and perhaps most importantly, we see a statistically significant increase in both deep vein thrombosis and pulmonary embolism in the TXA group.

In a retrospective trial published in 2014 from the Ryder Trauma Center in Miami, authors looked at their experience with TXA from 2009 to 2013. The patients were given TXA at the discretion of the trauma attending at the same dosing as CRASH-2 and MATTERS.8

Looking at patients who required emergency surgery and transfusions, they found that for the highest-acuity patients, TXA was associated with a higher mortality no matter what time it was administered.

They concluded that the lack of benefit from TXA was due to the timely interventions provided in their mature trauma center. The problems with this study are its retrospective single-center nature and a relatively low volume of patients.

A recently published retrospective trial out of Houston looked at the area’s experience with TXA from 2009 to 2013. In addition to using similar criteria and dosing as CRASH-2, the authors also identified patients who had hyperfibrinolysis based on TEG.9

Their hypothesis was that by identifying the patients who had hyperfibrinolysis, and therefore the problem that TXA can reverse, they’d see an increase in survival for trauma patients.

After analysis, however, they identified that TXA wasn’t associated with a reduction in mortality. In fact, after adjusting for several variables, there was an increased 24-hour mortality, which didn’t translate into overall mortality.

Other interesting findings were that there was no increased chance of thrombosis and that a repeat TEG didn’t show the hyperfibrinolysis had corrected after being given TXA. Limitations of this study include its retrospective nonrandomized nature and relatively small sample size of those getting TXA.

There are ongoing prehospital trials in Pittsburgh and Australia that have no data available at the time of this writing.

CONCLUSION

The ongoing search for hemorrhage control has led the trauma community to embrace multiple methods and medications that have ultimately never panned out. In the case of TXA, the newest in a long list of medications with promise to stop nonsurgical bleeding, we’ve only seen one study that meets gold standard criteria for research in the form of a randomized prospective controlled trial.

In that study, however, there are multiple methodologic flaws that should provide pause to all those who might be involved with the care of the trauma patient.

Additionally, we now know that all bleeding in the trauma patient isn’t the same. Administering a medication without information that can currently only be provided in a trauma center can actually be harmful to our patients.

While on the surface it’s easy to see why some groups have an unbridled enthusiasm for TXA, in reality, there’s little at this moment to suggest its use will actually stop bleeding in all patients being taken care of in mature trauma systems. There are too many unanswered questions about the use of TXA in regions with mature trauma systems. We don’t know, for example, the optimal dosing, patient population, timing, drug interactions, side effects or complications that exist in relation to our trauma patients.

Similar to what we saw with Factor VII several years ago, highly coordinated and expeditious trauma care that includes rapid transport, modern resuscitative techniques (i.e., balanced transfusions) and rapid movement of the patient to definitive treatment is what has been shown to be the major factors that contribute to success.

Although our natural tendency is a desire to provide some intervention for sick patients, the best prehospital care of the bleeding trauma patient should focus on rapid transport. Rapid delivery of a trauma patient in shock without an intervention isn’t a failure of prehospital care.

Ultimately, the best care of the bleeding trauma patient is in the hospital, and, until good data supports it prehospital use, TXA should be reserved for prospective studies and in-hospital use.

REFERENCES

1. Goodloe JM, Gerecht R. TXA in the USA: Tranexamic acid’s potentially bright future relies on collaborative data. JEMS. 2015;40(4):30-35.

2. MONOC becomes first New Jersey service to carry TXA. (Feb. 28, 2015.) JEMS. Retrieved March 16, 2016, from www.jems.com/articles/2015/02/monoc-medics-first-new-jersey-carry-txa.html.

3. Kashuk JL, Moore EE, Sawyer M, et al. Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg. 2010;252(3):434-442.

4. Napolitano LM, Cohen MJ, Cotton BA, et al. Tranexamic acid in trauma: How should we use it? J Trauma Acute Care Surg. 2013;74(6):1575-1586.

5. Moore EE, Moore HB, Gonazalez E, et al. Postinjury fibrinolysis shutdown: Rationale for selective tranexamic acid. J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S65-S69.

6. Shakur H, Roberts R, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusions in trauma patients with significant hemorrhage (CRASH-2): A randomized, placebo controlled trial. Lancet. 2010;376(9734):23-32.

7. Morrison JJ, Dubose JJ, Rasmussen TE, et al. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg. 2012;147(2):113-119.

8. Valle EJ, Allen CJ, Van Haren RM, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014;76(6):1373-1378.

9. Harvin JA, Peirce CA, Mims MM, et al. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015;78(5):905-911.