Does TXA MATTER When Your Patients CRASH?

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A Summary of 2 Seminal Studies of Tranexamic Acid in Trauma

The past decade has ushered in significant advances in the care of patients with traumatic injuries due, in part, to a war that continues to smolder in the Middle East. Among these are extensive innovations in hemostatic dressings and the reinvigoration of the tourniquet as a viable first-line option for severe hemorrhage in the prehospital setting. On the cutting edge of EMS trauma management is the rediscovery of a drug that has existed for decades: tranexamic acid (TXA). Despite first approval in 1986 as an antifibrinolytic, and subsequent approval for cyclic heavy menstrual bleeding (as Lysteda, an oral medication, in 2009), and dental hemorrhage in hemophiliacs (as Cyklokapron, an injectable or topical medication), it continues to be investigated as an adjunct for reducing intraoperative hemorrhage and improving trauma outcomes. Level I evidence in the form of double-blinded placebo-controlled trials supports the use of tranexamic acid in these FDA-approved instances. When used for heavy menstrual bleeding, oral TXA has been tolerated well, and has been associated with significant improvements in both menstrual blood loss and health-related quality of life.1,2 Likewise, when used in hemophiliacs undergoing dental procedures, TXA was found to improve control of gingival hemorrhage.3 Considering the safety and efficacy demonstrated in these instances, it seems reasonable that the drug’s utility could be extrapolated towards trauma.

In contemporary literature, the most talked-about trials regarding the use of TXA in trauma patients include the CRASH-2 trial and the MATTERs study.

CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2)

Published in 2010 in The Lancet, the CRASH-2 trial4,5 (Table 1) aimed to determine the effect of the early administration of TXA on death, vascular occlusive events, and blood transfusion requirements in bleeding trauma patients. Primary outcome data were available for 20,127 (99.6%) of the randomized patients. 99.1% of patients were known to have completed the loading dose and 94.2% of patients completed the maintenance dose.

Table 1. Study Parameters of the CRASH-2 Trial
CRASH-2: Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2
Design Double-blinded, randomized, placebo-controlled trial
Population n=20,211 (civilians; average age= 35, 85% male)
Pt Inclusion Adult trauma patients with significant hemorrhage [SBP<90mmHg, HR > 100 BPM or both] or considered to be at risk of significant hemorrhage. Within 8 hours of injury.
Sites 274 hospitals in 40 countries
Site Inclusion Definitive trauma care for a sufficiently large number of trauma patients; hospital doctors substantially uncertain regarding the effect of TXA in the management of bleeding trauma patients; necessary research infrastructure to conduct the trail.
Protocol Experimental: 1g TXA over 10 minutes + 1 g over 8 hour infusion
Control: Matching placebo (0.9% saline)
Outcome Primary: Death in hospital within 4 weeks of injury, subdivided by baseline characteristics: estimated hours since injury, SBP, GCS, type of injury.
  Secondary: Vascular occlusive events, surgical intervention, blood transfusion requirements while the patient was hospitalized, within 28 days of randomization
Analyses Intention-to-treat. Primary outcomes reported as RRs with 99% Cis, and two-sided p-values. Binary outcomes reported as RRs with 95% Cis, and two-sided p-values. Heterogeneity ion treatment effects across subgroups assessed with chi-squared tests.
Funding Publicly funded using generic drug.
Criticisms Management of trauma patients at participating hospitals was not stipulated. Simple entry criteria allowed participating doctors to use clinical judgment when deciding whether or not to enroll patients into the trial. Risk of non-fatal vascular occlusive events with TXA may be under-reported, as specificity was emphasized over sensitivity in reporting. External validity unclear as many of the patients arose from middle-income and low-income countries. Additionally, only half of the patients actually received a transfusion, with a similarly low percentage requiring an operation.

All-cause mortality was significantly reduced with TXA; relative risk of death was 0.91 (p=0.0035). Deaths from multiorgan failure, head injury, or other causes did not significantly differ between treatment groups. Vascular occlusive events (fatal or non-fatal) did not differ significantly (TXA 1.7%; Placebo 2.0%). Mortality differences between geographic regions of the test sites were not found to be statistically different (Χ2=1.445; p=0.70).

Subgroup analyses on death due to bleeding were also performed. The risk of death due to bleeding on Day 0 was significantly reduced with TXA (RR 0.80, p=0.003). The effect of TXA on death due to bleeding varies according to time from injury to treatment (p<0.0001), even after adjustment for interactions between other baseline characteristics and treatment (Table 2). No substantial reduction in blood transfusion requirements was identified.

Table 2. Results of CRASH-2 trial
(Relative risk (RR) of bleeding mortality with TXA. Benefit is greatest when TXA is administered within the first hour of injury.)
Results: RR of Bleeding Mortality with TXA
   Overall (Day 0): RR 0.80 (p=0.003)
   Overall (Total): RR 0.85 (p=0.0077)
Time Elapsed from Injury to TXA
   <1 hr: RR 0.68 (p=0.0001)
   1–3 hrs: RR 0.79 (p=0.03)
   >3 hrs: RR 1.44 (p=0.004)

MATTERs (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation)

Published in 2012 in Archives of Surgery, the MATTERs trial6 (Table 3) aimed to characterize contemporary use of TXA in combat injury and to assess the effect of its administration on total blood product use, thromboembolic complications, and mortality. While the UK Defence Medical Service has used TXA since 2009 as part of a massive transfusion protocol, the US Combat Casualty Care program had previously deferred its use altogether.

Table 3. Study Parameters of the MATTER Study
MATTERs: Military Application of TXA in Trauma Emergency Resuscitation
Design Retrospective observational cohort study
Population n=896 (military combat injuries)
Pt Inclusion Adult coalition military personnel and host national who received at least 1 unit of PRBCs within 24 hours of admission following combat-related injury from 1/6/09–12/31/10.
Site Role 3 Echelon surgical hospital in southern Afghanistan
Protocol TXA was administered to patients requiring emergency blood products or patients with evidence of hyperfibrinolysis. Standard dosing regimen consisted of 1g IV bolus, repeated as felt indicated by the managing clinician.
Outcome Primary: 24 hour, 48 hour, and in-hospital mortality (within 30 days at the hospital in Afghanistan or any point throughout the aeromedical evacuation chain).
  Secondary: Transfusion requirements and coagulation parameters (PT, aPTT). Incidence of thrombotic events.
Analyses Comparison performed by chi-square test. Differences in means by t-test. Continuous variables dichotomized at the time of admission. Thrombotic risk analysis by adjusted OR with 95% CI and p<.05. Mantel-Cox log-rank test and Kaplan-Meier life table analysis to report survival in treatment and nontreatment groups. Subgroup analysis of massive transfusion recipients (patients receiving >10 units PRBCs in 24 hours).
Funding Office of the US Air Force Surgeon General. No financial disclosures reported.
Criticisms The number of venous thrombotic events in the study is too small to assess any independent risk of TXA. Furthermore, the retrospective nature of the study impeded data collection regarding venous thrombotic events. Clinical practice guidelines for TXA use were not introduced until the later part of the study period, so variations may exist in the use of the medication throughout the study. An immediate mortality bias may exist. Inclusion of host national patients (with hospital courses shorter than 30-days) limits this outcome data.

 

Of the 896 patients with a combat injury requiring transfusion, 32.7% received IV TXA within one hour of the injury. Statistically significant reduction in 48-hour (p=.004) and in-hospital mortality (p = .03), but not 24-hour mortality, was found with TXA administration. In the massive transfusion group, this correlation was even stronger (48-hour mortality p=.003; in-hospital mortality p=.004). At 30-days, survival in the TXA group was also better than the no-TXA group (p=.006). In the massive transfusion group, this relationship persisted with even greater absolute risk reductions (p=.004) (Table 4).

Table 4. Results of MATTER Study
(Absolute risk reduction (ARR) in all-cause mortality with TXA. Benefit is greatest in subgroup of patients receiving massive transfusion (>10 units PRBC per 24 hours.)
Results: ARR in All-Cause Mortality with TXA
Overall
      <24h ARR 2.8% (p=.20)
      <48h ARR 7.6% (p=.004)
      In-Hospital ARR 6.5% (p=0.3)
Massive Transfusion Subgroup
      <24h ARR 5.2% (p=.17)
      <48h ARR 13.1% (p=.003)
      In-Hospital ARR 13.7% (p=.004)

In the overall cohort, a GCS score of 8 or lower, hypotension, and the presence of coagulopathy were independently associated with mortality. In the massive transfusion group, a GCS score of 8 or lower and an injury severity score of 15 or higher were associated with mortality, while TXA use was independently associated with survival (OR 7.228, p<.001).

The percentage of patients with hypocoagulopathy on admission to the ICU following TXA administration was reduced as compared to no-TXA in both the overall cohort and massive transfusion subgroup (p<.05). The combination of this finding along with the highest mortality benefits observed after 48 hours suggests that TXA likely functions not only as an antifibrinolytic, but perhaps also as an anti-inflammatory, due to its non-immediate effects.

What does this mean for the use of TXA in the prehospital setting?

These studies have appreciable shortcomings, but it is generally agreed that their primary outcomes hold internal validity. Additionally, while the generalizability of these studies may be contended, the data remains compelling. In short, the following conclusions can be drawn from these two trials.

CRASH-2 demonstrated a reduction in all-cause mortality, but especially in death due to bleeding. When considering the impact of TXA, the greatest benefits were associated with early administration of the drug (< 1 hour). Vascular occlusive events did not differ in incidence between treatment and control groups.4,5 In this trial, the number needed to treat (NNT) with TXA was 67 patients.

MATTERs also revealed a reduction in all-cause mortality past 48 hours in patients receiving TXA. The greatest benefit from TXA was identified in patients with severe injuries requiring massive transfusion.6 In this study, with patients of a reportedly higher acuity than the CRASH-2 trial, the NNT was 7.

Taken in concert, these findings suggest that the greatest benefit of this drug might be in its use as an adjunct for severely injured and bleeding patients, especially when administered early. As EMTs and paramedics are frequently the first healthcare providers to make contact with civilian trauma patients, the use of TXA may have a reasonable niche in the world of EMS.

While these studies have failed to demonstrate an increased risk of thromboembolic events, both have limitations to this data. Consequently, a reasonable approach to implementation of TXA might include an assessment of a patient’s thrombotic risk factors.

At this time, TXA has become a Class I recommendation in the U.S. military’s Tactical Combat Casualty Care guidelines,7 indicating that there is evidence (currently Level B) and/or general agreement that a given procedure or treatment is useful and effective. Additionally, multiple EMS agencies in the U.S. have begun to implement TXA in their treatment protocols.

As trauma management continues to evolve, the role of TXA may yet blossom. Ongoing surveillance of trauma outcomes by EMS systems employing this medication will be integral in defining the role that TXA should or should not play in the future of prehospital trauma care.

References

  1. Lukes AS, Moore KA, Muse KN, et al. Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol. 2010;116(4):865-75.
  2. Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Committee Opinion No. 557. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:891–6.
  3. Anderson JA, Brewer D, Creagh S, et al. Guidance on the dental management of patients with haemophilia and congenital bleeding disorders. British Dental journal. 2013;215:497-504.
  4. Shakur H, Roberts I, Bautista R, et al; CRASH-2 Trial Collaborators. 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):23-32.
  5. Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess 2013;17(10).
  6. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113-119.
  7. Bayless, L. ed. Prehospital Trauma Life Support: Military Version, Eighth Edition. St. Louis, MO: Mosby Jems Elsevier; 2014.
Michael Spigner, EMT-CC, MSIII

Michael Spigner, EMT-CC, MSIII

Hofstra North Shore, LIJ School of Medicine, Uniondale, NY
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