Crash 2 and Tranexamic Acid
One of the most exciting and underutilized therapies for trauma is tranexamic acid (txa). TXA inhibits the breakdown of clot–it is an anti-fibrinolytic. Is there evidence for using this in trauma patients?
First came the Crash 2 Trial (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: 23–32),
then the subgroup reanalysis (Lancet. 2011 Mar 26;377(9771):1096) showing the benefit of treatment as early as possible.
Recently, the MATTERS trial (Arch Surg. 2012; 147:113-119) was published demonstrating the benefits of TXA in military situations, particularly massive transfusion.
How about an incredible review from the J Trauma (2011; 71(1) Supplement S9)
Then there is this paper describing current military protocol rationale.
To discuss TXA in Trauma, I got to interview Dr. Tim Coats, one of the primary authors of Crash 2.
Here is a List of Resources from the Crash 2 Investigators
This is the official resource page from Crash 2
We also discussed the concept of the pragmatic trial…
Future Research in Emergency Medicine: Explanation or Pragmatism
Listen to the podcast excerpt on pragmatic trials (mp3–right click the link and choose save-as if you want to download)
In an amazing demonstration of synchronicity, Jeff Guy of the ICU Rounds Podcast put out a tranexamic acid episode on the same day.
Minh Le Cong provided this prehospital protocol for TXA use.
An incredible review article can be found at this citation (Journal of TRAUMA 2011;71(1) July Supplement)
This article published in J Trauma (74(6), May 2013, p 1587–1598) gives an excellent summary of the current evidence as of 5/2013
Meta-Analysis shows NO Assoc with Thrombotic Event Increase [Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality A Systematic Review, Meta-analysis, and Meta-regression. JAMA Surgery 156(6):3210884, 2021]
Summary: What Do We Know?
- TXA is associated with a 1.5% reduction in 28-day all-cause mortality in adult trauma patients with signs of bleeding (SBP < 90 mm Hg, heart rate > 110 beats per minute, or both, within 8 hours of injury) in a large pragmatic prospective randomized placebo-controlled trial.
- What is critical is the modest effect on the overall population: All-cause mortality was “significantly” reduced from 16.0% to 14·5% (NNT, 67). The risk of death caused by bleeding overall was “significantly” reduced from 5.7% to 4·9% (NNT, 121).
- TXA signal for benefit was in the most severe shock group (admission SBP <= 75 mm Hg), 28-day all-cause mortality of 30.6% for the TXA group versus 35.1% for the placebo group (RR, 0.87; 99% CI 0.76–0.99).
- 1,063 deaths (35%) were caused by bleeding in the CRASH-2 Trial.
- TXA had greatest impact on reduction of death caused by bleeding in the severe shock group (SBP <= 75 mm Hg) (14.9% vs. 18.4%; RR, 0.81; 95% CI, 0.69–0.95).
- Early TXA (<=1 hour from injury) was associated with the greatest reduction (32% reduction) in deaths caused by bleeding (5.3% vs. 7.7%; RR, 0.68; 95% CI, 0.57–0.82; p < 0.0001).
- TXA given between 1 hour and 3 hours after injury also reduced the risk of death caused by bleeding (4.8% vs. 6.1%; RR, 0.79; 95% CI, 0.64–0.97; p = 0.03).
- TXA given after 3 hours after injury was associated with an increased risk of death caused by bleeding (4.4% vs. 3.1%; RR, 1.44; 95% CI, 1.12–1.84; p = 0.004).
- TXA had no impact on TBI outcomes, but the study was limited by small sample size.
- TXA treatment is not associated with an increased risk of vascular occlusive events.
What Is Still Unknown?
- Whether TXA has any impact on trauma outcomes when damage-control resuscitation or MT protocols are used;
- The mechanism by which TXA reduced mortality in trauma in the CRASH-2 Trial. Fibrinolysis assessment and coagulation testing were not part of the study design, and determination of time to cessation of hemorrhage was not required in the study;
- Whether fibrinolysis testing should be performed before consideration of TXA treatment;
- What is the optimal dose and timing of TXA in trauma;
- Whether other antifibrinolytic agents could be substituted for TXA use in trauma;
- Whether TXA is associated with higher seizure rates in trauma or TBI patients. Increased postoperative seizures have been reported in cardiac surgery with TXA doses that are 2-fold to 10-fold higher than those used in CRASH-2.75–80 These seizures have been associated with an increased incidence of neurologic complications (delirium and stroke), prolonged recovery, and higher mortality rates. A proposed mechanism for seizures is TXA-mediated inhibition of glycine receptors as a potential cause of neurotoxicity.81,82 A recent warning has been added to the FDA drug label: “Convulsions have been reported in association with tranexamic acid treatment.”83
A Rational Approach for TXA use in Trauma
- In adult trauma patients with severe hemorrhagic shock (SBP <= 75 mm Hg), with known predictors of fibrinolysis, or with known fibrinolysis by TEG (LY30 > 3%);
- Only administer TXA if less than 3 hours from time of injury;
- TXA administration: 1 g intravenously administered over 10 minutes, then 1 g intravenously administered over 8 hours.
Also, MATTERS II was published, here is the summary from the same J Trauma review
MATTERs II Study excerpted from the same article
The MATTERs II study expanded the sample size of the MATTERs I study to further evaluate TXA and trauma outcomes. A review of 1,332 patients (identified from prospectively collected UK and US trauma registries) who required one or more RBC unit transfusion were analyzed to examine the impact of cryoprecipitate (CRYO) in addition to TXA on survival in combat injured patients.
Despite greater ISSs and RBC transfusion requirements, mortality was lowest in patients who received TXA (18.2%) or TXA/CRYO (11.6%) compared with CRYO alone (21.4%) or no-TXA/CRYO (23.6%). Logistic regression analysis confirmed that TXA and CRYO were independently associated with a similarly reduced mortality (OR, 0.61; 95% CI, 0.42–0.89; p = 0.01 and OR, 0.61; 95% CI, 0.40–0.94; p = 0.02, respectively). The combined TXA and CRYO effect versus neither in a synergy model had an OR of 0.34 (95% CI 0.20–0.58; p < 0.001), reflecting nonsignificant interaction (p = 0.21).
Additional Resources and Studies
- Tranexamic acid in trauma: How should we use it?
- Tranexamic Acid for Trauma Patients: A Critical Review of the Literature
- Progressive intracranial haemorrhage was present in 21 (18%) of 120 patients allocated to TXA and in 32 (27%) of 118 patients allocated to placebo. The difference was not statistically significant [RR?=?0.65 (95% CI 0.40 to 1.05)]. (Tranexamic Acid for Patients With Traumatic Brain Injury A Randomized, Double-Blinded, Placebo-Controlled Trial BMC Emerg Med. 2013;13)
- Annals of Surgery 2015;261(2):390 Tranexamic Acid Use in Severely Injured Civilian Patients and the Effects on Outcomes: A Prospective Cohort Study Cole, Elaine MSc*; Davenport, Ross PhD*; Willett, Keith FRCS†; Brohi, Karim FRCS, FRCA* Abstract Objective: To characterize the relationship between tranexamic acid (TXA) use and patient outcomes in a severely injured civilian cohort, and to determine any differential effect between patients who presented with and without shock. Background: TXA has demonstrated survival benefits in trauma patients in an international randomized control trial and the military setting. The uptake of TXA into civilian major hemorrhage protocols (MHPs) has been variable. The evidence gap in mature civilian trauma systems is limiting the widespread use of TXA and its potential benefits on survival. Methods: Prospective cohort study of severely injured adult patients (Injury severity score > 15) admitted to a civilian trauma system during the adoption phase of TXA into the hospital's MHP. Outcomes measured were mortality, multiple organ failure (MOF), venous thromboembolism, infection, stroke, ventilator-free days (VFD), and length of stay. Results: Patients receiving TXA (n = 160, 42%) were more severely injured, shocked, and coagulopathic on arrival. TXA was not independently associated with any change in outcome for either the overall or nonshocked cohorts. In multivariate analysis, TXA was independently associated with a reduction in MOF [odds ratio (OR) = 0.27, confidence interval (CI): 0.10–0.73, P = 0.01] and was protective for adjusted all-cause mortality (OR = 0.16 CI: 0.03–0.86, P = 0.03) in shocked patients. Conclusions: TXA as part of a major hemorrhage protocol within a mature civilian trauma system provides outcome benefits specifically for severely injured shocked patients.
- Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40?138 bleeding patients
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