MATTERs

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Morrison JJ, et al. "Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study". Arch Surg. 2012. 147(2):113-119.
PubMed

Clinical Question

In patients that that experience a combat related injury in theatre requiring transfusion, what affect does tranexamic acid administration have on mortality and blood product administration.

Bottom Line

Administration of tranexamic acid in conjunction with blood products for resuscitation following combat injury show improvement in mortality and coagulopathy.

Major Points

Hemorrhage is a leading cause of death among both military and civilian patients with major trauma. Tranexamic acid (TXA), a synthetic derivative of lysine, after forming a reversible complex displaces plasminogen from fibrin, stabilizing formed clots. It has indication for dental extraction in patients with hemophilia and cyclic menstrual bleeding, and has been for other conditions including TXA for Epistaxis[1]<refZahed R et al. Topical Tranexamic Acid Compared With Anterior Nasal Packing for Treatment of Epistaxis in Patients Taking Antiplatelet Drugs: Randomized Controlled Trial. Acad Emerg Med 2018. 25:261-266.</ref>. In trauma, TXA appears to interfere with hyperfibrinolysis be an unclear mechanism. Trauma leads to hemorrhage both from primary injury to organs and blood vessels, but also to transient hyperfibrinolysis that is incompletely understood. In trauma TXA appears to interfere with hyperfibrinolysis by an unclear mechanism.

The Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study included 896 combat injuries treated in a single coalition hospital in southern Afghanistan and included patients that were actively bleeding. The trial was a retrospective, observational, registry trial where patients were given TXA 1g bolus by discretion of the attending physicians or by clinical guidelines after they were developed. Overall it showed no difference in 24 hour mortality, but had a mortality risk reduction of 7.6% (P = 0.004) at 48 hours and 14.4% (P= 0.006) reduction at 30 days.

This trial is concordant with the CRASH-2[2] published in 2010. That large trial randomized patients to receive a 1g bolus of TXA followed by a second 1g infusion over 8 hours, given within 8 hours of presentation. CRASH-2 with over 20 000 trauma patients showed a 1.5% reduction in mortality at 4 weeks. A sub-group analysis looking at patients that received the TXA within 1 and 1-3 hour strata showed a decrease in all-cause mortality.[3]

An important consideration is whether the reduction in hemorrhage comes at the expense of an increased risk of vascular occlusion such as MI, stroke, DVT, or PE. The MATTERs did show an increased risk in the overall population but not in the patient that required Massive Transfusion. Other studies have demonstrated that TXA may elevate the risk of VTE however CRASH-2 did not demonstrate this. Following publication of this and CRASH-2, TXA for trauma has become the standard of care.[4]

Guidelines

Tactical Combat Casualty Care (US Military) 2011[5]

  • Early administration of 1 gram of tranexamic acid to casualties expected to receive blood transfusions as soon as possible (class I, level B).
  • Administration should be no more than 3 hours after initial trauma.

Design

  • Single centre, retrospective, registry, cohort trial
  • Overall N=896
    • Tranexamic Acid (n=293)
    • No Tranexamic (n=603)
  • Setting: Single American surgical centre in southern Afganistan
  • Enrollment: 1 January 2009 until 31 December 2010
  • Mean follow-up: 16 days
  • Analysis:
  • Primary Outcome: 24 and 48 hour in-hosptial mortality

Population

Inclusion Criteria

  • at least 1 unit packed red blood cell (pRBC) within 24 hours of admission
  • NATO military personnel, Afghan police, military, and civilians (designated host nationals)

Exclusion Criteria

  • non-combat injury
  • not receiving transfusion

Baseline Characteristics

‘’Overall Tranexamic Acid group displayed

  • Demographics: mean age 24.9 years, Male 97%, NATO personnel 60.4%, Host national 39.6%
  • Injury: Gun-Show-Wound 25.3%, Explosion 74.7%, mean Injury Severity Score 25.2, mean Revised Trauma Score 5.53
  • Physiologic parameters: Glasgow-Coma-Score ≤8 63.3%, SBP ≤90 mmHg 22.8%

Interventions

  • Intravenous 1g bolus, repeated at the discretion of the managing clinician
    • Prior to 2010, administered at the discretion of surgeon or anesthetist from clinical judgement
    • After 2010, as part of a major hemorrhage protocol or clinical practice guideline

Outcomes

Comparisons are Tranexamic Acid vs. No Tranexamic Acid.

Primary Outcomes

Mortality < 24 hours
9.6% vs. 12.4% (P = 0.20)
Mortality < 48 hours
11.3% vs. 18.9% (P = 0.004)
In-hospital mortality
17.4% vs. 23.9% (P = 0.03)

Secondary Outcomes

mean dose TXA
2.3 g
30-day survival
50.5% vs. 36.1% (P = 0.006)
24 hour mean Transfusion pRBC
11.8 vs. 9.8 (P < 0.001)
24 hour mean Transfusion FFP
10.3 vs. 8.6 (P < 0.001)
24 hour mean Transfusion Platelets
1.6 vs. 1.4 (P = 0.001)
24 hour mean Transfusion Cryoprecipitate
1.6 vs. 0.5 (P < 0.001)
Time in Emerg, mean, min
36 vs. 56 (P < 0.001)
Time in OR, mean, min
170 vs. 115 (P < 0.001)
Multivariate Analysis
GCS score ≤8 - Odds Ratio 0.304 (95% CI 0.108-0.860) P = 0.02
Hypotension - Odds Ratio 0.303 (95% CI 0.107-0.855) P = 0.02
Coagulopathy at admission - Odds Ratio 0.291 (95% CI 0.113-0.749) P = 0.01

Subgroup Analysis

'Massive Transfusion, ≥ 10 units pRBC within 24 hours’

  • Massive Transfusion Protocol N=231
    • Tranexamic Acid (n=125)
    • No Tranexamic (n=196)
Mortality < 24 hours
9.6% vs. 14.8% (P = 0.17)
Mortality < 48 hours
10.4% vs. 23.5% (P = 0.003)
In-hospital mortality
14.4% vs. 28.1% (P = 0.004)
30-day survival
56.8% vs. 42.0% (P = 0.004)
24 hour mean Transfusion pRBC
21.0 vs. 22.5 (P = 0.47)
24 hour mean Transfusion FFP
Massive Transfusion 18.4 vs. 19.6 (P = 0.67)
24 hour mean Transfusion Platelets
3.2 vs. 3.6 (P = 0.84)
24 hour mean Transfusion Cryoprecipitate
1.6 vs. 0.7 (P < 0.001)
Time in Emerg, mean, min
39 vs. 52 (P = 0.39)
Time in OR, mean, min
180 vs. 113 (P < 0.001)
Multivariate Analysis
GCS score ≤ 8 - Odds Ratio 0.027 (95% CI 0.008-0.085) P < 0.001
Injury Severity Score > 15 - Odds Ratio 0.359 (95% CI 0.123-1.053) P = 0.06
TXA - Odds Ratio 7.228 (95% CI 3.016-17.322) P < 0.001

Adverse Events

Pulmonary Embolism
Overall 2.7% vs. 0.3% (P = 0.001)
Masive Transfusion 3.2% vs. 0% (P = 0.01)

Deep Vein Thrombosis

Overall 2.4% vs. 0.2% (P = 0.001)
Massive Transfusion

Criticisms

  • Registry trial
  • Tranexamic Acid was added to the practice guidelines half-way through the trial period
  • Retrospective trial limits characterizing adverse thrombotic events (identified through diagnostic code
  • Bias may have been introduced with patients mortality early in admission not have time to benefit of intervention
  • Inclusion of Host Nationals may affect 30 day mortality as commonly discharged prior to that date
  • did not quantify degree of hyperfibrinolysis or response to treatment but this may not have been included in the registry

Funding

  • Office of US Air Force Surgeon General
  • Air Force Medical Support Agency

Further Reading

  1. Zahed R et al. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med 2013. 31:1389-92.
  2. Shakur H 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. 376:23-32.
  3. Roberts I 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. 377:1096-101, 1101.e1-2.
  4. Luehr E et al. Administration of tranexamic acid in trauma patients under stricter inclusion criteria increases the treatment window for stabilization from 24 to 48 hours-a retrospective review. Int J Burns Trauma 2017. 7:115-119.
  5. Defense Health Board. "Executive summary: Recommendations regarding the addition of tranexamic acid to the tactical combat casualty care guidelines 2011-06." Letter to Jonathan Woodson MD: 2011-09-23. Accessed 2013-07-03.