The Role of Tranexamic Acid in EMS & Preoperative Trauma Management

 

 
 
 

David S. Howerton, NREMT-P | Duffy McAnallen, NREMT-P | Howard Reed, NREMT-P | Jeffrey M. Goodloe, MD, NREMT-P, FACEP | From the April 2013 Issue | Wednesday, March 27, 2013


You’re responding to a reported 25-year-old male with gunshot wounds. After your scene safety check, you make contact with a young adult male who admits to being in an altercation just minutes before your arrival. He is your only patient. He states he heard a gun fire twice and believes it was a 9mm caliber handgun.

You note that the patient is diaphoretic and pale while confirming an intact airway, assessing increased respirations, and palpating a rapid, thready radial pulse. When you expose the patient, you find a single gunshot wound in the mid-abdomen. You see no exit wound on your rapid head-to-toe scan, which is done while your colleagues ready the stretcher for a rapid “load and go” transport to the designated trauma center.

You’ve already ”pre-alerted” the trauma team before you ever left the scene, and your partner is one of the best emergency vehicle operators in the system, but factoring distance and traffic, you’re still 20 minutes out. The patient’s blood pressure is now 80/40 mmHg, heart rate remains at 134 beats per minute, respirations are 22 per minute and his mental status indicates he’s “hanging on the cliff.” You understand the benefits of permissive hypotension in hemorrhagic shock and are titrating IV fluids to keep the systolic pressure from getting too high, concerned about “blowing out the clots” that this seriously traumatized patient is hopefully forming on his own.

Despite expert assessment, timely decisions and care, and your desire to save his life, this patient may not survive, even to arrival at the trauma center. You continue to think of what else can be done to promote hemostasis. Direct pressure? On what? Pressure points? Where? Elevation? Of the abdomen? Suddenly, all the “basics” of bleeding control you learned seem useless—and they functionally are, for this patient.

What about a topical hemostatic dressing? Not for this patient; his brisk and ongoing bleeding is all internal. What about a hemostatic powder? The single gunshot wound is small and essentially already sealed. Besides, his vascular wounds are most likely deep and inaccessible without exploratory surgery. What about a tourniquet? You have read about a promising clamp type tourniquet for some lower truncal wounds, but this is not one of them. Clearly, your extremity tourniquets won’t work either. Frustration mounts as the patient’s blood pressure continues to drop.

If only there was something more we could do in the field for patients like this. There is. Read on.

A Difference-Maker
Difference-makers: We like to be them and we like to use them in our practice of EMS medicine. We clearly can make meaningful impact through “difference-makers” for airway obstructions (Heimlich maneuver, foreign body airway removal), cardiac arrest (timely defibrillation, high-quality CPR), ST-segment acute myocardial infarctions (early recognition by 12-lead ECG and pre-arrival activation of the cardiac cath lab team), and even extremity arterial bleeding from trauma (tourniquets—once eschewed as instruments of the devil and now being added on all emergency apparatus).

Is there a difference-maker for the kind of patient described in our scenario? One besides the current trauma life support care and rapid, safe transport? We believe there is, and it’s a chemical that has been around for decades: tranexamic acid, or TXA.

You don’t have to spend much time studying acute myocardial infarctions or strokes to become aware of medications that work to break down clots, known as fibrinolytics—fibrin being a substance that forms the matrix of a clot and lysis or lytic being to break apart. TXA works in the opposite direction. TXA is an “antifibrinolytic,” an anti-clot buster. Another way to think of how TXA works is to picture it as a medication given to help stabilize the clots patients are trying to form on their own as it works to inhibit natural clot breakdown.

It sounds promising, but can, and should, EMS administer TXA? Like most considerations in medicine, the answer depends on many variables. In this article, we present some background information on TXA and discuss recent studies that promote EMS use of TXA for certain patients in systems in which TXA treatment can continue in the hospital setting.

Old Drug, New Studies
TXA has existed for decades. It was historically used in cardiovascular surgery and has been in the medical literature for more than 40 years. We shouldn’t be surprised that we’re finding new applications for older care capabilities—your supply list likely includes intraosseous access equipment and tourniquets.

The Federal Drug Administration has long approved TXA to decrease bleeding in hemophilia and prolonged uterine bleeding.

When summarizing the prior surgical literature of TXA, we can contemplate how the trauma wounds we work to stabilize are similar to some extent to wounds created by surgery. With surgical wounds, we heal through a process of hemostasis as well. Any blood loss can challenge coagulation and stimulate clot breakdown (fibrinolysis). Not surprisingly, hyperfibrinolysis is associated with very poor survival.

In more than 50 studies of TXA in the setting of elective surgery, although there was not a significant change in overall survival, the need for resuscitative blood transfusion was reduced by approximately 33%. Those studies are a helpful foundation, but two recent studies help us far better evaluate the role for TXA in EMS.

The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) study (published online at www.crash2.lshtm.ac.uk) is a landmark study for our consideration of TXA as an EMS difference-maker. This is a remarkably large study that enrolled more than 20,000 adult trauma patients at 274 hospitals in 40 countries (outside the US). Patients were identified as having significant bleeding, or at least at clinical risk for serious bleeding.

Significant bleeding was defined by tachycardia greater than 110 beats per minute, systolic blood pressure of less than 90 mmHg, or both. Patients were divided into the active treatment group and the placebo (no TXA) group within eight hours of injury. The active treatment group received TXA 1 g IV piggyback over 10 minutes, followed by a second dose of 1 g IV piggyback over eight hours.

CRASH-2 investigators evaluated patients for the following three outcomes:
1. Death in hospital within four weeks of injury (e.g., bleeding, vascular occlusion of myocardial infarct/stroke/
pulmonary embolism, multi-organ failure, head injury, etc.);
2. Vascular occlusive events; and
3. The need for blood transfusion or surgery.

All-cause mortality in CRASH-2 was 14.5% with TXA and 16.0% without TXA—a statistically significant reduction in mortality with TXA. In death due to bleeding, there was also a statistically significant reduction (a relative 15% reduction), with 4.9% mortality with TXA and 5.7% without TXA. TXA did not reduce the need for blood or surgery.

When all factors in this study are considered, the number of patients needed to treat (NNT) with TXA to save one life is 67 patients. We certainly do many things in medicine in which the NNT is far greater than 67. This is a promising study for TXA use, even started as early as in the field.

As discerning as you are, you’re likely thinking this all sounds great, but could an antifibrinolytic, TXA specifically, cause harm? Does it increase bad clotting, the kind in myocardial infarcts, strokes, deep venous thrombosis or pulmonary embolism? Theoretically, it could. However, in the CRASH-2 trial, there were no increases in any of these events when comparing the active treatment group and the placebo group.

The second major study that compels our discussion of TXA in EMS is the “Military Application of Tranexamic Acid in Trauma Emergency Resuscitation Study (MATTERs),” published in Archives of Surgery in 2012. This study was done by British physicians, treating casualties in military combat theater helicopters in southern Afghanistan. MATTERs investigators were aware of the CRASH-2 trial being simultaneously conducted, but they used a slightly different treatment protocol for TXA administration, with 1 g being given slow IV push and repeated in the same format if felt clinically indicated.

All patients in the study were identified by receiving a transfusion of at least one unit of packed red blood cells. A further subgroup comparison was conducted in patients requiring a massive transfusion, defined as at least 10 units of packed red blood cells and other blood products.

Nearly 900 patients were in the MATTERs study. This is an important point to consider in both CRASH-2 and MATTERs. Large numbers of study patients promote more reliable results when the research is done correctly. Both studies were carefully conducted.

In MATTERs, the three primary TXA effect study points were:
1. Total blood product use required;
2. Thromboembolic complications; and
3. Mortality at 24 hours, 48 hours and 30 days.

What we’re all most concerned with is meaningful survival in our patients, so let’s primarily discuss the mortality outcomes in MATTERs. Overall, mortality in the TXA group was lower than the placebo (no TXA) group, 17.4% as compared to 23.9%. These are not just impressive in raw numbers, but statistically significant as well. Particularly in the massive transfusion subgroup, the results with TXA were remarkable, with 14.4% mortality vs. 28.1% mortality without TXA, nearly a 50% reduction in mortality with TXA.

These results are statistically significant and the survival odds ratio (how much more likely to survive with TXA) was more than seven.

The NNT for MATTERs was seven patients. Very few things we do in medicine require such a low NNT. For comparison, to date, the NNT is six for post-cardiac arrest therapeutic hypothermia. When we consider how prevalent that is becoming in EMS, we should give serious thought to the role of TXA in the EMS drug box.

A Note of Caution
Before you talk with your medical director and trauma surgeons and order a batch of TXA, you should be aware of the thromboembolic complications seen in MATTERs and at least how some are interpreting those results.

Overall, there were statistically significant increases in deep venous thrombosis and pulmonary embolism (DVT/PE) with TXA, and here’s where statistics must be interpreted very carefully. The absolute number of patients affected was very small; thus, a statistical significance can be easily reached. One important factor to consider is that the patients treated with TXA in MATTERs actually had higher injury burdens and therefore had higher likelihood of DVT/PE in the first place.

The bottom line: Before TXA in instituted in your system, it is imperative that all involved EMS administrative and clinical leaders understand and discuss the evidence-based literature supporting TXA. Resources can be found at the end of this article.

A final interesting summary point of MATTERs is that the mortality benefit was not clearly seen until 48 hours, meaning that TXA is likely not just a clot-forming drug alone. There likely is some still-to-be-better-understood anti-inflammatory component of TXA as well. While these large trials are unlikely to be replicated, there still exists need for better clarifying the benefits of TXA in future investigations.

Considerations for Use in EMS
TXA is now a Class I recommendation in the U.S. military’s Tactical Combat Casualty Care guidelines. Few medical interventions warrant this strength of support, again speaking to how well CRASH-2 and MATTERs have been conducted and reported in peer-reviewed medical literature.

So where does an EMS leader go from here? The cost of TXA is not everything, but it must be considered. Current cost estimates of 1 g of TXA, typically supplied in a 10 mL ampule or vial, is between $45 and $55. Using the NNTs from MATTERs and CRASH-2, this would translate from $350 to $3,550 per life saved. The reality is likely not that isolated, but it gives a starting point for discussion in your EMS budget.

Another consideration: Clinically, TXA use in the field is a lot like prehospital therapeutic hypothermia—it doesn’t make sense for EMS to start a treatment that isn’t going to be continued in the hospital. You must ensure your trauma surgery community is on board and supportive of TXA. You may be surprised to find your hospital is already stocking TXA for use in its massive transfusion protocols. We found this to be true in both Oklahoma City and Tulsa.

Our discussions with our trauma surgeon leaders in both cities were surprisingly short. We anticipated a long review of the literature and having to assure our surgery community that our EMS clinicians were capable of identifying the right patients and administering TXA in the field. However, all our surgery partners were immediately supportive and congratulated us for keeping abreast of the surgery literature.

The Medical Control Board, which provides physician oversight to the EMS System for Metropolitan Oklahoma City and Tulsa, unanimously approved TXA for EMS use on Jan. 16, 2013, with implementation on April 1, 2013. We’ll watch these patients and their outcomes carefully and report back. For now, we encourage you to read the referenced studies (on TXA and other helpful hemostatic agents) and start similar discussions in your communities.

You already are the difference-maker in so many ways. Maybe TXA can help you do the same for certain patients that currently prove challenging and without a ready answer on the way to more definitive care.

Resources
1. Roberts I, Perel P, Prieto-Merino D, et al. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ. 2012;345:e5839.
2. 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.
3. Schwartz RB, Reynolds BZ, Shiver SA, et al. Comparison of two packable hemostatic Gauze dressings in a porcine hemorrhage model. Prehosp Emerg Care. 2011;15(4):477–482.
4. Littlejohn LF, Devlin JJ, Kircher SS, et al. Comparison of Celox-A, ChitoFlex, WoundStat, and combat gauze hemostatic agents versus standard gauze dressing in control of hemorrhage in a swine model of penetrating trauma. Acad Emerg Med. 2011;18(4):340–350.
5. Granville-Chapman J, Jacobs N, Midwinter MJ. Pre-hospital haemostatic dressings: a systematic review. Injury. 2011;42(5):447–459.
6. Shakur H, Roberts I, Bautista R, et al. 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(9734):23–32.
7. Achneck HE, Sileshi B, Jamiolkowski RM, et al. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use. Ann Surg. 2010;251(2):217–228.
8. Cox ED, Schreiber MA, McManus J,  et al. New hemostatic agents in the combat setting. Transfusion. 2009;49Suppl5:248S–255S.
9. Kheirabadi BS, Scherer MR, Estep JS, et al. Determination of efficacy of new hemostatic dressings in a model of extremity arterial hemorrhage in swine. J Trauma. 2009;67(3):450–459; discussion 459–460.
10. Sohn VY, Eckert MJ, Martin MJ, et al. Efficacy of three topical hemostatic agents applied by medics in a lethal groin injury model. J Surg Res. 2009;154(2):258–261.
11. Mabry R, McManus JG. Prehospital advances in the management of severe penetrating trauma. J Spec Oper Med. 2009;9(2):93–101.
12. Kheirabadi BS, Edens JW, Terrazas IB, et al. Comparison of new hemostatic granules/powders with currently deployed hemostatic products in a lethal model of extremity arterial hemorrhage in swine. J Trauma. 2009;66(2):316–326; discussion 327–328.

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Related Topics: Patient Care, Trauma, TXA, trauma care, trauma, tranexamic acid, MATTERs, internal bleeding, fibrinolytic, CRASH-2, clot-buster, clot, anti-fibrinolytic, Jems Features

 

David S. Howerton, NREMT-PDavid S. Howerton, NREMT-P, is director of Clinical Affairs - Western Division for the Office of the Medical Director in Oklahoma City. He’s the medical oversight liaison officer for all metropolitan Oklahoma City agencies working with the Medical Control Board. His EMS career spans nearly three decades and includes a multitude of clinical and administrative leadership roles. Contact him at howertond@emsa.net.

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Duffy McAnallen, NREMT-P

Duffy McAnallen, NREMT-P, is director of clinical affairs-eastern division for the Office of the Medical Director in Oklahoma City and Tulsa. He’s the medical oversight liaison for all metropolitan Tulsa agencies working with the Medical Control Board. His EMS career spans over three decades and includes clinical and administrative leadership roles in EMS, fire and law enforcement. Contact him at mcanallen@emsa.net.

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Howard Reed, NREMT-P

Howard Reed, NREMT-P, is director of research and clinical standards development for the Office of the Medical Director in Oklahoma City and Tulsa. His EMS career spans nearly three decades and includes clinical and administrative leadership roles. Contact him at reedh@emsa.net.

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Jeffrey M. Goodloe, MD, NREMT-P, FACEPJeffrey M. Goodloe, MD, NREMT-P, FACEP, is professor and director of the EMS Division of the Department of Emergency Medicine at The University of Oklahoma School of Community Medicine in Tulsa. He has the privilege of serving as medical director for the Medical Control Board in the EMS System for Metropolitan Oklahoma City and Tulsa, working with a multitude of agencies, including the Emergency Medical Services Authority (EMSA), the Oklahoma City Fire Department and the Tulsa Fire Department. He started in EMS in 1988 as an EMT-B and has never quit learning. Contact him at jeffrey-goodloe@ouhsc.edu.

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