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The Benefits of TXA
In the United States, trauma is the leading cause of death for patients under 45 and the fourth-leading cause of death for all ages. The CDC has reported that more than 140,000 patients die each year from traumatic injuries and 80,000 are permanently disabled.1,2,12 The annual number of U.S. in-hospital deaths due to bleeding is estimated to be 12,489.1,2 Rapid assessment and proper treatment of trauma patients begins in the prehospital environment with the arrival of trained emergency medical personnel and is essential in the presence of life-threatening injuries.8
Tranexamic acid (TXA) was originally developed for the treatment of hemophilia and to reduce bleeding in patients undergoing oral surgery. It has been shown effective as a preoperative drug that minimizes the need for large amounts of whole blood during general surgery procedures.4–6 TXA is now being used to treat severely injured trauma patients who have or are at risk for severe hemorrhage.1–4,6,7,10,11
Tranexamic acid is produced by Pfizer Injectables and distributed by the Pharmacia & Upjohn Company as Cyklokapron. TXA is a synthetic amino acid (lysine) that blocks plasminogen from being converted to the enzyme plasmin. Plasmin works to break down already-formed blood clots in the human body by attacking and breaking down fibrin, destroying clots in a process known as fibrinolysis.1 TXA is widely used by hospitals in Europe and other countries for severely injured trauma patients.1–4,6,7,10,11 TXA recently has been added to the trauma resuscitation protocols for U.S. Special Operations medics, role 3 echelon surgical hospitals outside the U.S., and Womack Army Medical Center at Ft. Bragg, NC, for U.S. soldiers wounded in Afghanistan and other combat theaters around the world.12,15,19,23
The Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) study, completed by researchers at the London School of Medicine, and Military Application of Tranexamic Acid in Trauma Emergency Resuscitation study (MATTERs) showed that when TXA can be administered within three hours of injury, the mortality of severely injured patients is reduced by up to 30%.1–3,6–8,11,13–18,20 With the introduction of TXA to the standard of care and trauma resuscitation protocols of providers in the prehospital setting (for patients who have experienced significant hemorrhage), survival rates should increase further, extrapolating the results garnered in CRASH-2 and MATTERs. We would expect at the least that an increased number of patients would meet the required three-hour treatment window. TXA use in both the CRASH-2 and MATTERs studies showed the greatest reduction in mortality when administration began within an hour of injury.1–3,6,18
Indications for Prehospital Administration
Unlike the chitosan-based HemCon dressings (see sidebar), QuikClot Combat Gauze, QuikClot Sponge and CAT tourniquet making their way into civilian prehospital medicine, tranexamic acid is not a hemostatic agent or tourniquet device.13 TXA is an antifibrinolytic agent that prevents plasminogen activators from attaching to the lysine binding site of the clot.1,2,9,14
During fibrinolysis, the process of blood clot breakdown begins when plasminogen is converted to plasmin, which then begins the destabilization of formed blood clots.1–3,6,9,14,15 This destabilization leads to increased bleeding and potentially patient death (at least in the severely injured trauma patient requiring surgical intervention).1–3,6,9,14–16 The administration of TXA prevents this clot destabilization cascade from developing. Large prospective randomized, controlled trials have shown that patient mortality is decreased when TXA is administered within three hours of injury.1,2,6,11,13,14 Mortality was shown to decrease even more when it’s given within one hour. 1,2,6,11,13,14 With the success of TXA during the clinical trials, its low cost, and its safety and side-effect profile, it is reasonable that TXA be introduced as a standard of care for ALS prehospital emergency medical services in the United States.
Any patient who has experienced trauma and is at risk for or has significant hemorrhage can benefit from TXA. Although transport times in urban settings can be short, TXA may not be beneficial if it greatly delays scene time to prepare and initiate the initial 1-gram dose and establish an IV. However, TXA would be ideal for situations including prolonged extrication, extended transport times due to heavy traffic or other conditions, and mass-casualty incidents. TXA should be administered at the incident site or as soon as an IV has been established, not as the unit pulls up to the trauma center, to meet the goal of giving the first dose within the first hour of injury. If TXA is administered after three hours, mortality rates have shown to increase.1–4,15,17 Patients receiving TXA should only be transported to trauma centers that are equipped to handle severely injured patients and can administer or follow patients who have received TXA.
Dr. Carl Bergren, a trauma surgeon at St. Francis Trauma Institute of Tulsa, OK, told the Tulsa World TXA has been used on the battlefield as well as on civilians and that using it on patients before they get to the hospital is a good measure. “For those who meet the criteria, it can show a definite benefit,” he said.25
The cost of tranexamic acid versus favorable outcomes in patient mortality is negligible. The current cost of TXA on the British National Formulary converted into international dollars is $5.70 per gram; in the United States the cost is approximately $10 per gram.4,19 Further, TXA is very easy to administer for paramedics, as they already have training to give intravenous medications in their scope of practice. The recommended procedure for administering TXA is 1 gram in 100 mL of 0.9% normal saline or Ringer’s lactate given by IV infusion over 10 minutes, followed by 1 gram in 500 mL of 0.9% NS or LR infused over eight hours.3,4,7–12,14,17 It is recommended that TXA not be mixed with colloid fluid, (e.g., Hextend or Hespan, plasma or any other blood components), nor with solutions containing penicillin, and/or piggybacked into any IV line delivering blood.2–5,9
The HemCon Dressing
The HemCon dressing is made from chitosan, a nontoxic complex carbohydrate derivative of chitin. It has been in use in the military for several years and when applied directly to the site of arterial hemorrhage and with direct pressure can quickly stop arterial and venous bleeding.13
Review of Current Literature
The CRASH-2 study, undertaken in 274 hospitals in 40 countries and published in 2010, showed that TXA, when administered within one hour of significant trauma, greatly reduced patient mortality (over 30%) when used in conjunction with blood transfusions.2,19–21 When TXA was used alone, patient mortality was reduced by over 20%.1,2,11,19–21
MATTERs was a retrospective observational study of 893 consecutive admissions of combat-injured persons in a role 3 surgical hospital (equivalent to a U.S. level 2 trauma center) in southern Afghanistan. In MATTERs 293 patients received TXA, while 603 did not. Authors measured patient mortality at 24 hours, 48 hours and 30 days, as well as the influence of TXA administration on postoperative coagulopathy and the rate of thromboembolic complications.6,7,11,20 The results of both the CRASH-2 and MATTERs studies showed a decrease in the unadjusted mortality of patients who received TXA (vs. placebo) within the first three hours of injury (17.4% vs. 23.9%).1,5–7,9,15,20,21 Patients who received TXA (vs. placebo) with associated blood transfusion within one hour of injury had an even greater decrease in mortality (14.4% vs. 28.1%).1,5–7,9,15,20–22 Both CRASH-2 and MATTERs showed that when TXA was used in conjunction with blood transfusions, mortality decreased further. 1–3,6,18 Overall, the MATTERs findings suggest that TXA is more beneficial in higher-severity traumatic injuries and is more effective when used with massive transfusion protocols covering, for example, blood transfusion, FFP, platelets and cryoprecipitate.
By developing local protocols and adding TXA to the paramedic formulary, the national trauma system as a whole could decrease the delay in the administration of TXA, resulting in more trauma patients meeting the three-hour window, but more so the optimal one-hour window from initial trauma. TXA administered more than three hours after injury, however, appears to increase the risk of death due to bleeding, to 4.4% compared with 3.1% for the placebo group. The researchers found no evidence that TXA’s effect on death due to bleeding varied on the basis of systolic pressure, Glasgow coma score or type of injury.26
The risk of death in the first year after trauma in the intervention group was calculated by multiplying the baseline cumulative hazard of the placebo group by the relative risk reduction of all-cause mortality as estimated in the CRASH-2 trial.12 Beyond 12 months the risk of death in the intervention arm was assumed to be equal to that estimated for the placebo arm.12 Since the CRASH-2 trial only recorded data up to 28 days or death, a parametric survival function was fitted to extrapolate mortality experience over the 12 months following injury.12 Using this model, research needs to be done in the United States to validate the increased (and standard) use of TXA in patients with or at risk of significant hemorrhage from trauma.12
The minor side effects recorded with the administration of TXA include giddiness, allergic dermatitis and gastrointestinal disturbances (nausea, vomiting, diarrhea). The most significant adverse reaction noted in the CRASH-2 trail was hypotension, observed only when the intravenous injection was too rapid, administered in under the 10-minute recommended time.2,5,7,9,14,15 The above data (in conjunction with the only contraindication to use being suspected subarachnoid hemorrhage) suggests the use of TXA is not only more cost-effective, but also more ethical when compared to not using TXA for appropriate patients.1–4,6,8,12
Conclusion
TXA as a standard of care would not be a cost burden. Research has shown that when used in Tanzania, India and the United Kingdom, TXA was cost-effective in reducing the risk of death in bleeding trauma patients.6,19 When used (compared to not being used), the cost per life-year saved in Tanzania, India and the U.K. was $48, $66 and $64 respectively.6,19 Life-years gained were estimated from a simple Markov model (i.e., patients were either alive or dead) by comparing the life-years experienced by a cohort given TXA with the cohort that did not receive TXA.6,19 The cumulative risk of death during the first year in the placebo arm was estimated using data from the CRASH-2 study. After the first year patients were assumed to experience the same probability of death as the general population of a similar age, using country-specific life tables from WHO.2,6,19
TXA is inexpensive, has minimal side effects, has a long shelf life and is easily administered via intravenous infusion. TXA’s efficacy, cost, ease of storage and practicality make it an obvious candidate for addition to the paramedic formulary as a standard of care for trauma patients who have or are at risk of significant hemorrhage.1–3,6,13,16,18,20
Currently TXA is not being widely used by civilian facilities or services in the United States in trauma resuscitation and treatment of patients suffering traumatic hemorrhage.24 Perhaps the use of TXA in the prehospital setting could improve these numbers too.
References
1. London School of Hygiene & Tropical Medicine, Clinical Trials Unit. Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage (CRASH 2). PowerPoint presentation of trial results, www.crash2.lshtm.ac.uk/.
2. Ker K, Kiriya J, Perel P, Edwards P, Shakur H, Roberts I. Avoidable mortality from giving tranexamic acid to bleeding trauma patients: an estimation based on WHO mortality data, a systematic literature review and data from the CRASH-2 trial. BMC Emergency Medicine, https://www.biomedcentral.com/1471-227X/12/3.
3. Hess JR. Update on trauma. ISBT Science Series, 2012; 7(1): 37–40.
4. Sepah YJ, Umer M, Ahmad T, Nasim F, Chaudhry MU, Umar M. Use of tranexamic acid is a cost effective method in preventing blood loss during and after total knee replacement. J Orthop Surg Res, 2011 May 21; 6: 22.
5. Cyklokapron package insert. New York, NY: Pfizer, Pharmacia & Upjohn Co., 2011.
6. 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 randomised controlled trial. Lancet, 2011; 377(9,771): 1,096–1,101.
7. Boling B, Moore K. Trauma notebook: Tranexamic acid (TXA) use in trauma. J Emerg Nurs, 2012; 38: 496–7.
8. Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: An exploratory analysis of the CRASH-2 randomised controlled trial. Lancet, 2011; 377(9,771): 1,096–1,101.
9. 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 randomised, placebo-controlled trial. Lancet, 2010 Jul 3; 376(9,734): 23–32.
10. McNab A, Burns B, Bhullar I, et al. Society of university surgeons: A prehospital shock index for trauma correlates with measures of hospital resource use and mortality. Surgery, 2011; 6(5):473–6.
11. Yeguiayan J, Rosencher N, Vivien B. Early administration of tranexamic acid in trauma patients. Lancet, 2011; 378(9,785): 27–8.
12. Schrager JJ, Branson RD, Johannigman JA. Lessons from the tip of the spear: Medical advancements from Iraq and Afghanistan. Respir Care, 2012; 57(8): 1,305–13.
13. Brown, MA, Daya, MR, Worley, JA. Experience with chitosan dressings in a civilian EMS system. J Emerg Med, 2009; 37(1): 1–7.
14. Gruen RL, Mitra B. Tranexamic acid for trauma. Lancet, 2011 Mar 26; 377(9,771): 1,052–4.
15. McCormack PL. Tranexamic acid: A review of its use in the treatment of hyperfibrinolysis. Drugs, 2012; 72(5): 585–617.
16. Mitra B, Fitzgerald M, Cameron PA, Gruen RL. Tranexamic acid for trauma. Lancet, 2010; 376(9,746): 1,049; author reply 1,050–1.
17. Moore KM. The four horsemen of the apocalypse of trauma. J Emerg Nurs, 2011;3 7(3): 294–5.
18. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg, 2012; 147(2): 113–9.
19. Roberts I, Lockey DJ, Weaver AE, Davies GE. Tranexamic acid: A recipe for saving lives in traumatic bleeding. Int J Occup Environ Med, 2013; 53(4): 189.
20. Guerriero C, Cairns J, Perel P, Shakur H, Roberts I. Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial. PLoS One, 2011; 6(5): e18987.
21. 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 randomised, placebo-controlled trial. Lancet, 2010 Jul 3; 376(9,734): 23–32.
22. Zunini-Fernandez G, Rando-Huluk K, Martínez-Pelayo FJ, Castillo-Trevizo A. [Massive transfusion and trauma patient management: Pathophysiological approach to treatment]. Circ, 2011; 79(5): 473–80.
23. Committee on Tactical Combat Casualty Care. Tranexamic Acid (TXA) in Tactical Combat Casualty Care. Guideline Revision Recommendation, 11 August 2011.
24. Clinical digest. Evidence supports wider use of tranexamic acid in traumatic bleeding. Nurs Stand, 2012; 27(6): 15.
25. Muchmore S. EMSA medics on the forefront of administering drug that helps stop bleeding before patient gets to hospital. Tulsa World, June 22, 2013.
26. Wells JC, Stevermer JJ. Trauma care—don’t delay with TXA. J Family Practice, 2013 May; 62(5): E4–E6.
Thank you to William J. Gephart, PA, RN, CEN, NRP, for the editing assistance.
Jon E. Thomas, BS, ATP, NREMT-P, has been in EMS since his honorable discharge from the U.S. Army in 1991. He has been a civilian instructor for the Special Operations Combat Medic Course at the Joint Special Operations Training Center in Fort Bragg, NC, since August 2004.
