Tranexamic Acid for Traumatic Hemorrhage

Published on October 24, 2014
Considering the available data, the early use of TXA should be strongly considered for any patient requiring blood products for trauma-related hemorrhage.

A 45-year-old healthy male arrives to your trauma bay via EMS as an unrestrained passenger in a high speed MVC. He is combative with a BP of 88/50 that improves transiently with two liters of normal saline. He has extensive ecchymosis over his right flank, but no evidence of active external bleeding; bedside FAST is positive for fluid in the RUQ and chest x-ray is normal.

Due to persistent hypotension and a positive FAST exam you activate your Mass Transfusion Protocol and begin administering uncross-matched pRBC’s and FFP. After initiating the resuscitation in the ED, the patient is taken to the OR for an exploratory laparotomy. As the dust settles, you ask yourself: “Is there more I could have done for this patient?” You recall a recent conference where tranexamic acid (TXA) was discussed, so you decide to investigate the literature of its use in trauma.

Initiating an effective resuscitation for a massive hemorrhage is an important and challenging task in the ED — after all, hemorrhage is responsible for 30% of in-hospital trauma deaths worldwide every year [1]. Naturally, the definitive treatment is the “bright lights and cold steel” of an OR, but we have to make sure the patient survives long enough to make it there. Aside from appropriate IV access, crystalloids, and blood products, our armamentarium is limited, though there is an increasing body of literature that supports a new role for an old drug.

TXA is an analog of the amino acid lysine that blocks the lysine binding site on plasminogen, preventing its conversion to plasmin, which in turn degrades fibrin. By preventing fibrin breakdown, TXA acts as a hemostatic agent and should therefore decrease blood loss in any bleeding condition [2]. Since the 1960’s, TXA has been shown to decrease blood loss in cardiopulmonary bypass [3] and other surgical procedures [4], menorrhagia [5] and upper GI bleeding [6]. Due to its efficacy in preventing blood loss without evidence of significant risk, the use of TXA in trauma has recently been under investigation. It is inexpensive, readily available, and commonly used for traumatic hemorrhage in other countries [7].

Due to its efficacy in preventing blood loss without evidence of significant risk, the use of TXA in trauma has recently been under investigation. It is inexpensive, readily available, and commonly used for traumatic hemorrhage in other countries.

CRASH-2 Study

The CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage) trial was conducted to assess the effects of early administration of TXA on survival from traumatic injuries [8]. This study enrolled patients predominately from low and middle income countries, where 90% of trauma deaths occur [9].

More than 20,000 patients from 274 hospitals in 40 countries were included based upon hemodynamic instability (SBP<90, HR>110) and “suspected hemorrhage.” Notably, there were no study sites in the United States. Researchers found a small but significant absolute reduction in the risk of death of 1.5% in those that received TXA, without an increase in vaso-occlusive events (ie, PE, DVT, AMI).

A subsequent subgroup analysis suggests that the difference in all-cause mortality can be explained by a reduction in bleeding deaths alone, although there was no difference in the amount of blood products given between the groups. When examining only deaths due to bleeding, the mortality benefit of TXA was only observed within the first three hours after a traumatic injury; after three hours, TXA actually increased mortality [10].

In the CRASH-2 trial, patients were enrolled based on “suspected hemorrhage.” Although not defined, patients in whom “a clear indication” for TXA existed were excluded, potentially eliminating the sickest patients from their study population. A secondary analysis of the data that assessed risk of death based on a validated prognostic model found that the highest risk group appeared to benefit the most from TXA [11].

MATTERs Study

To assess the application of TXA to a sicker population with increased access to advanced resources, we turn to the MATTERs [12](Military Application of Tranexamic acid in Trauma Emergency Resuscitation) study by Dr. Morrison and colleagues.

MATTERs is a retrospective analysis of patients treated at a military hospital in Afghanistan (NATO personnel and Afghan nationals) that suffered a combat injury and received at least one unit of blood. Although the groups were demographically similar, the injury severity score was significantly higher in the group that received TXA. Despite the higher injury score, there was an unadjusted absolute reduction in mortality in the TXA group of 6.5%. In a subgroup of patients that underwent a massive transfusion (>10 units pRBC’s within 24 hrs), there was a decrease in mortality of 13.5% in the TXA group. Patients who received TXA had a significant decrease in hypocoagulability (INR > 1.5; aPTT > 1.5x normal) from ED arrival to admission in the ICU, whereas there was no difference in the non-TXA group. The TXA group received more blood products than the control group, which the authors attributed to higher injury severity and survival bias. The authors proposed that the increased survival is more profound than the CRASH-2 trial due to the “beneficial effect of TXA [being] more prominent in those with higher injury severity.”

Distinct from the CRASH2 data, the rates of venous thromboembolism and pulmonary embolus, though rare and non-fatal, were increased in the TXA group. The authors attributed this potential increase of thromboembolic events to higher injury severity rather than to TXA. However, the degree of fibrinolysis was not reported, and as such it is difficult to discount the effects of TXA on these events.

Based on these studies, TXA appears to significantly decrease mortality for trauma in the developing world and in severely injured military patients, but it remains unclear if we can apply these data to the civilian trauma population in the US. To explore this topic, Valle et al performed a retrospective analysis that examined data from two trauma registries of consecutive patients that presented to an urban level 1 trauma center over a three-year period [13]. These registries identified trauma patients that 1) went directly from the ED to the OR, or 2) received emergency blood products in the ED or the OR.

They postulated that this would capture the most severely injured trauma patients that, as suggested by the MATTERs study, would likely realize a greater benefit from administration from TXA. TXA was given to 150 of 1217 patients enrolled in the database. Propensity matching was used to assign controls to these 150 patients from the remaining 1067 that did not receive TXA using seven variables including age, gender, mechanism of injury, systolic blood pressure and severity of injury. They found that patients who received TXA had a non-significant trend towards increased mortality (31% v 23%). After excluding patients who died within two hours of arrival, that increased mortality reached statistical significance (27% v 17%). Similar to the MATTERs study, blood product requirements were increased when compared to those who did not receive TXA. Importantly, TXA was not available until the middle of the study period and was administered at the surgeon’s discretion.

Now what?

Given the size and scope of CRASH-2, it is difficult to ignore its results, and at the very least it illustrates the mortality benefit of TXA in trauma patients that are hemodynamically unstable or suspected of having active hemorrhage. In sicker patients in whom the hemorrhage is obvious, we now have to decide whether to base our decisions on the lower quality retrospective data from Drs. Morrison or Valle. The MATTERs study population was more critically injured than in CRASH-2, had access to advanced trauma care, and revealed a decrease in mortality for patients treated with TXA.

The data from the Valle study seem to more accurately reflect the acuity and care of the trauma patients in a busy urban center, but its results conflict with the proposed scientific mechanisms and clinical studies examining TXA. While the Valle study was retrospective and the design was not ideal, the authors concluded that with access to advanced resources that may not have been available to patients in CRASH-2, TXA was associated with increased mortality.

We are thus reminded of the shortcomings of retrospective analyses and must not interpret association as causality. An important aspect of this study is that propensity matching cannot replace randomization and may not accurately reflect the acuity of patients. It was possible that patients who received TXA were sicker in a manner not reflected in the chosen parameters. This position is supported by the increase in blood product requirements and faster time to the OR in the TXA group. Additionally, the cause of death was not reported for this study. Were more deaths attributable to vaso-occlusive events (MI, CVA, PE) perhaps the results and conclusion would be more convincing.

The only prospective, randomized data that we have available demonstrates a small but significant survival benefit to TXA administration in trauma patients, without a significant increase in adverse events. This is supported by physiologic data that demonstrates normalization of coagulation panels [14] and decrease in pro-inflammatory factors with TXA [3], as well as clinical studies that show improvement in other bleeding conditions such as elective surgery [4], traumatic hyphema [15], upper GI bleeds [6], epistaxis [16] and menorrhagia [5]. Subsequent retrospective studies in trauma patients demonstrate conflicting results in severely injured patients, reinforcing the need for a randomized, prospective trial that is more applicable to trauma patients in the US. However, considering the available data, the early use of TXA within three hours of injury should be strongly considered for any patient requiring blood products for trauma-related hemorrhage and especially in patients requiring massive transfusion.

References

1 - Peden M, McGee K, Sharma G. The injury chart book: a graphical overview of the global burden of injuries. Geneva: World Health Organization, 2002

2 - Okamoto S, Hijikata-Okunomiya A, Wanaka K, et al. Enzyme controlling medicines: introduction. Semin Thromb Hemost. 1997;23:493-501.

3 - Jimenez JJ, Iribarren JL, Lorente L, Rodriguez JM, Hernandez D, Nassar I, Perez R, Brouard M, Milena A, Martinez R, Mora ML. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care. 2007;11(6).

4 - Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007;(4).

5 - Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding.Cochrane Database Syst Rev. 2000;(4).

6 - Biggs JC, Hugh TB, Dodds AJ. Tranexamic acid and upper gastrointestinal haemorrhage--a double-blind trial. Gut 1976;17:729-734

7 - Guerriero C, Cairns J, Perel P, Shakur H, Roberts I, et al. (2011) Cost-Effectiveness Analysis of Administering Tranexamic Acid to Bleeding Trauma Patients Using Evidence from the CRASH-2 Trial. PLoS ONE 6(5).

8 - CRASH-2 trial collaborators,Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, 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).

9 - Gosselin RA, Spiegel DA, Coughlin R, Zirkled LG. Injuries: the neglected burden in developing countries. Bull World Health Organ 2009; 87: 246.

10 - CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, Dewan Y, Gando S, Guyatt G, Hunt BJ, Morales C, 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(9771).

11 - 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.

12 - Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Appli- cation of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study. Arch Surg. 2012;147(2).

13 - Valle EJ, Allen CJ, Van Haren RM, Jouria JM, Li H, Livingstone AS, Namias N, Schulman CI, Proctor KG. Do All Trauma Patients Benefit from Tranexamic Acid? J Trauma Acute Care Surg. 2014;76

14 - Porta CR, Nelson D, McVay D, Salgar S, Eckert M, Izenberg S, Martin MJ. The effects of tranexamic acid and prothrombin complex concentrate on the coagulopathy of trauma: an in vitro analysis of the impact of severe acidosis. J Trauma Acute Care Surg. 2013 Dec;75(6):954-60.

15 - Rahmani B, Jahadi HR. Comparison of Tranexamic Acid and Prednisolone in the Treatment of Traumatic Hyphema. Ophthalmology 1999;106:375–379

16 - Zahed R, Moharamzadeh P, Alizadeharasi S, Ghasemi A, Saeedi M. Am J Emerg Med. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. 2013 Sep;31(9):1389-92. Epub 2013 Jul 30.

This article originally appeared in the October edition of Emergency Physicians Monthly and Issue 14 of Emergency Physicians International.

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