Patient Care, Trauma

Tranexamic Acid’s Potentially Bright Future Relies on Collaborative Data

Issue 4 and Volume 40.

Have you heard of tranexamic acid, or TXA for short? If you work with multisystem trauma patients, you likely recognize its growing adoption in EMS and trauma center protocols for hemorrhagic shock.

In April 2013, JEMS featured an article introducing TXA to many EMTs and paramedics.1 It acknowledged TXA as a medication used for decades in cardiovascular surgery and focused on two groundbreaking studies supporting its use for trauma patients in need of significant blood transfusion. The article also discussed how TXA combats significant hemorrhage by functioning as an antifibrinolytic, though more current studies indicate that how TXA helps our patients is likely more complex, giving us more than antifibrinolytic action alone.2

Two Key Studies

The two key studies discussed are still the most relevant for EMS use of TXA. The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) study stands as the largest TXA study, including over 20,000 adult trauma patients at 274 hospitals in 40 countries.3 If you haven’t heard much about it, it’s likely because no hospitals in the United States and only one in Canada were involved in any part of it. Nevertheless, agencies adopting TXA as a local standard of care commonly use the CRASH-2 enrollment criteria as their indications—trauma patients must have clinical assessment consistent with significant external or internal hemorrhage and tachycardia greater than 110 beats per minute, systolic blood pressure less than 90 mmHg, or both vital sign abnormalities.

CRASH-2 helped identify patients in which TXA made a real difference in their survival outcome. Factoring all causes of death, 16% of patients who didn’t get TXA died, compared with 14.5% of patients who did get TXA. This is statistically significant when applied over thousands of patients. Of those who died primarily due to bleeding, 5.7% weren’t given TXA, but only 4.9% of deaths occurred among those who received TXA—a relative 15% improvement in survival. Of note, these survival benefits were most evident when TXA was administered within three hours of injury, and more so when administered within the first hour post-injury.4

Although TXA alone isn’t the decision-maker between life and death in seriously injured and bleeding patients, it’s important to realize it can improve survival as a part of an organized trauma system that includes early notification and EMS response, accurate and efficient scene and transport care, appropriate triage to a trauma center, and continuity of that care in the ED, operating suite and ICU. Because survival becomes difficult in so many of these critical patients, TXA deserves serious consideration in local and regional standards of care.

One major point to remember whenever we reflect on the CRASH-2 study is that all the patients who received TXA first received it in the hospital. Although the time delay from injury to TXA administration was often within 1–2 hours, that’s still a remarkable difference from the time it takes for paramedics to routinely arrive at the patient’s side in large, urban EMS systems.

The second major TXA study, Military Application of Tranexamic Acid in Trauma Emergency Resuscitation study, or MATTERs, helped demonstrate TXA could be effective when given outside the hospital. Much smaller in the number of patients involved—though the sample size was still nearly 900—MATTERs showed an even greater benefit to TXA in trauma patients thought to require massive blood transfusion, with 28.1% mortality being reduced nearly 50% to 14.4%.5

The CRASH-2 and MATTER studies are largely to credit for sparking enthusiasm for TXA use in EMS in the U.S. over past two years. Despite several agencies adopting TXA into their trauma protocols, there has yet to be large-scale U.S. civilian EMS-based study. There are several reasons for this.

First, not all interventions are studied in detail and submitted to medical journals in formal writings of impact findings.

Secondly, even when such study is performed, there’s often a lag between study enrollment, analysis and publication that can stretch far beyond two years.

Lastly, the numbers of patients must be high enough for any study to have widespread adoptability and garner a consensus that it has merit. A report of a single patient may stimulate a bit of interest here and there, but rarely has widespread standard of care ever been linked to a single patient experience. And although 10 patients—or, even better, 50—are more than one in simple math, they’re not functionally much different when it comes to analyzing meaningful cause and effect in an intervention, especially something in a very dynamic, complex clinical situation such as traumatic hemorrhagic shock.

TXA has a half-life of about two hours, maintaining antifibrinolytic action in some tissues for up to 17 hours and in the blood for approximately 7–8 hours.

 

The USA TXA Experience

Despite the lack of a U.S. civilian EMS-based study on TXA, many encouraging commonalities can be seen among EMS agencies that have adopted TXA over these past two years:

>> Collaboration with local trauma surgeons and trauma systems;

>> Ability for paramedics to accurately identify patients who meet CRASH-2 or very similar criteria; and

>> Although there aren’t widespread claims of “miracle cures” by TXA, there are also no widespread concerns of TXA-linked thromboembolic complications, such as pulmonary embolism, deep venous thrombosis, acute myocardial infarction or stroke.

The American College of Emergency Physicians out-of-hospital severe hemorrhage control policy statement even states that systems should consider the use of TXA. Encouragingly, the trauma-related interest in TXA has spawned interest in how TXA might help serious nontraumatic hemorrhage, such as gastrointestinal bleeding, intracerebral bleeding and even epistaxis.6–8

Roadmap to TXA

The processes utilized both in metropolitan Cincinnati and metropolitan Oklahoma City and Tulsa, Okla., can serve as a useful map in going from TXA pondering to reliable, accurate and coordinated TXA administration.

Both systems use committed physician medical oversight capabilities, specifically the Academy of Medicine of Southwest Ohio Prehospital Protocol Committee and the Medical Control Board for the EMS System for Metropolitan Oklahoma City and Tulsa, respectively. These deliberative bodies foster healthy debate and dialogue when determining if procedures or medications are appropriate for the needs of patients served.

They also serve as conduits for critically important input from the medical community, and consulted with trauma centers, trauma surgeons, emergency physicians and surgical intensivists when these agencies were considering TXA. Through such collaboration, evidenced-based treatment protocols and educational resources were developed.

Both agencies’ protocols allow and encourage paramedics to initiate TXA administration when indicated, regardless of how close they are to a trauma center. This acknowledges the critical role EMS plays in the continuum of care for the severely injured. Furthermore, it recognizes the complex patient care logistics and inherent task saturation that can occur in a busy trauma center, thus potentially delaying hospital-based administration of TXA.

Both protocols use CRASH-2 and MATTERs dosing in adult trauma patients. This is 1 g of TXA mixed in at least 100 mL normal saline or lactated Ringer’s and given IV or intraosseously (IO) over 10 minutes. Of note, neither protocol directs the EMS initiation of the second 1 g dose (this is an 8-hour continuous infusion). This is based partially on relatively short transport times, but primarily on pharmacokinetics.

Clinical and research pharmacists at the University of Cincinnati College of Medicine highlight the fact TXA has a half-life of about two hours, maintaining antifibrinolytic action in some tissues for up to 17 hours and in the blood for approximately 7–8 hours.9 Thus, based on customary EMS patient course of care times, the continuous TXA infusion is deferred to the receiving trauma center. In some trauma center protocols, this can allow for laboratory testing to determine if additional TXA is needed after the prehospital bolus.

Furthermore, it simplifies logistics for EMS providers with multiple other management priorities and potential interventions to perform during transport.

Recognizing the challenging, dynamic nature of traumatic hemorrhagic shock care, both EMS systems developed patient eligibility checklists to confirm TXA is indicated. The checklist used in Cincinnati is nicely organized and serves as a great example list. (See Table 1, below.)

Table 1: Academy of Medicine of Cincinnati TXA checklist

To administer TXA: Mix 1g of TXA in 100mL of 0.9% normal saline or lactated Ringer’s and infuse over 10 minutes IV or IO. (If given as an IV push, may cause hypotension.) Use dedicated IV/IO line if possible and do no administer in the same IV or IO line as blood products, factor VIIa or penicillin.

 

The CRASH-2 study noted time matters, and future studies could further validate this point. The difference in time of evaluation for TXA could largely explain why metropolitan Oklahoma City and Tulsa—a 100-paramedic ambulance EMS system that serves two major metropolitan areas—has used TXA only 10 times from April 1, 2013, until Jan. 15, 2015, while Cincinnati—a three-helicopter system serving a region that includes everything from urban to super-rural settings—administered TXA nearly 50 times since November 2013. In short, it may well be that large, urban EMS systems are able to respond to suspected hemorrhagic trauma patients so quickly that patients have yet to compensate with tachycardia or begin to decompensate, evidenced by declining systolic blood pressures.

Expanding TXA Use

We believe TXA will find future use in patient types not typically treated with it. There’s a growing body of literature—both expert opinion and clinical trial types—that supports the use of TXA in pediatric trauma patients. One study focusing on pediatric injury involving 766 patients aged 18 years or younger, looked specifically at the 66 (9%) patients who received TXA.10 These patients often had severe abdominal or extremity injury. Even though the TXA patients had greater injury severity, hypotension, acidosis and coagulopathy than the patients who didn’t get TXA, they had improved survival. Given the benefits shown in adults, this finding may not come as a surprise; however, this evidence can serve as the basis for the next generation of EMS TXA protocols. The EMS System for Metropolitan Oklahoma City and Tulsa is now promoting TXA administrations in serious, suspected hemorrhagic shock trauma patients age 10 or above.

The decision for EMS administration of TXA to suspected or confirmed pregnant patients will vary from system to system. TXA is known to pass through the placenta and appear in umbilical cord blood at a concentration level nearly equal to that found in the mother’s blood.10 As an FDA pregnancy category B, there are no adequate and well-controlled studies of TXA in pregnant women to date. Metropolitan Cincinnati likely has the safest and most effective position at present: EMS avoids TXA in women who are known or suspected to be pregnant with a fetus of viable gestational age (defined as at least 24 weeks). These women may receive TXA at the receiving trauma center if indicated by laboratory assessment there. For those severely injured women who are pregnant with a pre-viable fetus, EMS does administer TXA per the standard Southwest Ohio protocol.

Patient eligibility checklists help crews to quickly confirm that TXA is indicated for a patient.

 

Conclusion

This remains an exciting time for EMS and the applicability of TXA in our practices of medicine. In the absence of a large-scale U.S. civilian EMS-based study, the minority of EMS systems that have adopted TXA should analyze their use of it. Are the right patients—at least the ones we believe to be right—getting TXA? Is it being administered correctly? What are the outcomes after the patients arrive at the trauma center? Small numbers of patients will likely not yield firm conclusions, but perhaps multiple systems can pool their findings into a multicenter study.

For any EMS agency, whether already utilizing TXA or considering doing so, we believe the most important things to recognize are how critically important careful review of the evidence-based literature and collaboration with your local subject matter experts are to the overall success of your efforts. We do have useful and relatively clear peer-reviewed scientific writings that support TXA and specifically its use in EMS. But there are still many questions to answer and different interpretations of the literature regarding a variety of clinical and logistical aspects of its administration. Enthusiasm, accurate patient assessment and a true continuum of effective emergency care, from citizen recognition to definitive surgical care, will undoubtedly continue to advance our trauma care capabilities and successes.

For sample TXA protocols, visit www.okctulomd.com under the “training & protocols” tab for metropolitan Oklahoma City and Tulsa, and www.lempert.com/protocol/2015protocols.html for Southwest Ohio.

References

1. Goodloe JM, Howerton DS, McAnallen D, et al. TXA: A difference maker for trauma patients. JEMS. 2013;38(4):60–65.

2. Roberts I, Prieto-Merino D, Manno D. Mechanism of action of tranexamic acid in bleeding trauma patients: Sn exploratory analysis of data from the CRASH-2 trial. Crit Care. 2014;18(6):685.

3. CRASH-2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomized placebo controlled trial. Lancet. 2010; 376(9734):23–32.

4. CRASH-2 collaborators, Roberts I, Shakur H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: An exploratory analysis of the CRASH-2 randomized controlled trial. Lancet. 2011;377(9771):1096–1101.

5. 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.

6. Bennett C, Klingenberg SL, Langholz E, et al. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2014;11:CD006640.

7. Sprigg N, Renton CJ, Dineen RA, et al. Tranexamic acid for spontaneous intracerebral hemorrhage: A randomized controlled pilot trial. J Stroke Cerebrovasc Dis. 2014;23(6):1312–1318.

8. Zahed R, Moharamzadeh P, Alizadeharasi S, 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;31(9):1389–1392.

9. U.S. Food and Drug Administration Safety Information. (January 2011.) Cyklokapron (tranexamic acid) injection prescribing information. NDA 19-281/S-030. Retrieved Feb. 13, 2015, from www.accessdata.fda.gov/drugsatfda_docs/label/2011/019281s030lbl.pdf.

10. Eckert MJ, Wertin TM, Tyner SD, et al. Tranexamic acid administration to pediatric trauma patients in a combat setting: The pediatric trauma and tranexamic acid study (PED-TRAX). J Trauma Acute Care Surg. 2014;77(6):852–858.

For sample TXA protocols visit www.okctulomd.com under the “training & protocols” tab for metropolitan Oklahoma City and Tulsa and www.lempert.com/protocol/2015protocols.html for Southwest Ohio.