To the Editor
The US Department of Defense (US DoD) Hemorrhage and Resuscitation Research and Development Steering Committee review of tranexamic acid (TxA) in trauma, recently published in Shock (1), is balanced, circumspect, and, above all, timely. UK military guidelines that in 2011 recommended considering TxA early in massive transfusion (2) have recently changed to require mandatory administration if within 3 h of injury (3). While US military Joint Theater Trauma System 2013 guidelines remain more cautious, recommending only that TxA “should be considered strongly” (4), US Tactical Combat Casualty Care guidelines state that all casualties “anticipated to need significant blood transfusion” should “receive TxA as soon as possible” (5). Many civilian trauma systems have also protocolized TxA, no doubt swayed by emotive arguments that by doing so “more than 100,000 lives every year could be saved” (6) and promotional strategies such as the “Trauma Promise” (www.traumapromise.org). The TxA bandwagon is gaining momentum. However, like the US DoD committee, we agree there are substantial evidence gaps and that universally protocolizing TxA will prevent these gaps being filled.
Many of our concerns are articulated in the US DoD review (1). Less than 1.5% of more than 20,000 CRASH-2 (7) patients were treated in trauma systems in developed countries, raising three concerns. First, in CRASH-2, the effect of TxA was time-dependent, indicating harm if commenced more than 3 h after injury (1). We think the benefit-to-harm time threshold is likely affected by treatments commonly available to patients in advanced trauma systems but unavailable to many in the CRASH-2 study, such as blood component therapy, aggressive temperature management, and early surgery. Second, reported thrombotic complications in CRASH-2 were very rare (pulmonary embolus, 0.7%; deep venous thrombosis, 0.4%), probably because they were not actively sought in many participating hospitals. In contrast, pulmonary embolism (2.7%) and deep vein thrombosis (2.4%) rates were much higher in those receiving TxA in a military observational study (8). Third, in Victoria, Australia (for example), where adjusted odds of death have fallen by 50% in the decade following introduction of a comprehensive trauma system (9), the preventable death rate is likely to be much less than that in CRASH-2. The MATTERS (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation) observational study attempted to address whether the mortality benefit observed in CRASH-2 was applicable to military trauma systems, but its findings are limited by potential confounding, e.g., by mechanism of wounding, access to ongoing sophisticated medical care, and changes in practice during the study period.
The DoD committee identified as “priority 1 research requirements” addressing safety concerns, establishing TxA efficacy in patients treated to modern trauma standards, elucidation of mechanism of action, and better definition of which patients will benefit. These are the goals of our multicenter trial, the PATCH (Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage) study. However, despite securing multimillion dollar competitive grant funding, we are concerned that protocolized use of TxA in many hospitals may seriously compromise the opportunity to address these important questions. Premature incorporation of incomplete evidence into guidelines has stalled other critical care trials: for example, the CORTICUS trial of hydrocortisone in septic shock (10) was prematurely discontinued when investigators lost equipoise after steroids were included in consensus guidelines. The question is now being revisited a decade later (NCT01448109). We urge clinicians, especially those who write institutional protocols, to consider the concerns of the DoD committee and embrace the trials it recommends.
Michael C. Reade
Australian Defence Force and Burns
Trauma and Critical Care Research Centre
University of Queensland
Royal Brisbane and Women’s Hospital
National Trauma Research Institute, Monash University
Russell L. Gruen
The Alfred Hospital and National Trauma Research Institute
1. Pusateri AE, Weiskopf RB, Bebarta V, Butler F, Cestero RF, Chaudry IH, Deal V, Dorlac WC, Gerhardt RT, Given MB, et al. Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock
39 (2): 121–126, 2013.
2. Hodgetts T, Bland S, yers M, Davis P, Mahoney P, Russell R, Terrell A, Wilson D, Woolrich-Burt L, Green A, et al. JDP 4-03.1: Clinical Guidelines for Operations
. London: UK Ministry of Defence; 2011.
3. Russell R, Bess A: JSP 999: Clinical Guidelines for Operations
. London: UK Ministry of Defence; 2012.
5. Dickey NW, Jenkins D: Recommendations Regarding the Addition of Tranexamic Acid to the Tactical Combat Casualty Care Guidelines 2011-06
. Falls Church, VA: Defense Health Board; 2011.
6. 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 Emerg Med
12: 3, 2012.
7. 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
376 (9734): 23–32, 2010.
8. Morrison JJ, DuBose JJ, Rasmussen TE, Midwinter MJ: Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERS) study. Arch Surg
147 (2): 113–119, 2012.
9. Victorian State Trauma Registry 2008–2009 Summary Report
. Melbourne, Victoria, Australia: Victorian Government; 2010.
10. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med
358 (2): 111–124, 2008.