Article
Guyette FX, Brown JB, Zenati MS, et al. Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial. JAMA Surg. 2020 Oct 5;e204350. doi:10.1001/jamasurg.2020.4350
OBJECTIVE
To assess the effectiveness and safety of tranexamic acid (TXA) administered before hospitalization compared with placebo in injured patients at risk for hemorrhage
BACKGROUND
Tranexamic acid (TXA) is one of the current darlings for anything that bleeds from trauma to epistaxis and GI bleeds to postpartum hemorrhage. A brief history of how we got to our current infatuation with TXA: In 2010, the CRASH-2 investigators found a 1.5% absolute reduction in mortality in trauma patients who were bleeding or at risk of bleeding.1 The MATTERs trial came shortly after in 2012 that demonstrated the use of TXA reduced overall mortality in patients with penetrating combat injuries who required blood transfusions within 1hr of presentation.2 In 2017, the WOMAN trial examined the effect of TXA on women with postpartum hemorrhage and found a reduction in deaths from bleeding due to postpartum hemorrhage.3 Tranexamic Acid for Hyperacute Primary Intracerebral Hemorrhage (TICH-2) published in 2018 demonstrated no significant effect on functional outcomes at 90 days when comparing TXA to placebo.4 Lastly, CRASH-3, published in 2019, examined the effect of TXA versus placebo in patients with traumatic brain injury in regards to head injury related death.5 There was also no demonstrated mortality benefit in CRASH-3.5
Examination of all of these studies brought a significant caveat to the forefront when examining the potential benefits of TXA, the time to administration of TXA is important. As time from injury increases, the beneficial effects of TXA administration gradually diminish leading many to the conclusion that if you’re going to give TXA, it should be initiated as soon as possible, ideally within one hour from injury. All of this history leads us to our newest study in the TXA saga, Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury, otherwise known as the STAAMP Trial.6
DESIGN
Pragmatic, phase 3, multi-center, double blind, placebo-controlled, superiority randomized clinical trial
POPULATION
Inclusion Criteria
- Injured patients at risk for hemorrhage
- Transported from scene or outside hospital
- Arriving to participating site within 2 hrs from time of injury
- With either hypotension (SBP <90 mm Hg) or tachycardia (>110 bpm) prior to arrival
Exclusion Criteria
- Age >90 or <18
- Lack of IV or IO access
- Isolated fall from standing
- Cervical cord injury
- Prisoner
- Pregnant
- Traumatic arrest > 5 min
- Penetrating brain injury
- Isolated drowning or hanging
- Objection to study voiced or wearing STAAMP opt-out bracelet
INTERVENTION
Pre-hospital
- Intervention group: Received 1 gram of TXA (in 10 mL of solution) added to 100 mL bag of 0.9 Normal Saline and infused over 10 min
- Control group: Received 10 mL of placebo solution added to 100 mL bag of 0.9 Normal Saline and infused over 10 min
In-Hospital
- Intervention groups
- Group 1: Received placebo bolus then placebo infusion over 8 hrs
- Group 2: Received placebo bolus then 1 g TXA infusion over 8 hrs
- Group 3: Received additional 1 g TXA bolus over 10 mins then 1 g TXA infusion over 8 hrs
- Control group: All patients received bolus and infusions of placebo
OUTCOMES
Primary
- 30 day mortality
Secondary
- 24 hour and in-hospital mortality
- Blood component resuscitation volumes at 6 and 24 hrs
- Incidence of multi-organ failure
- Incidence of Acute Respiratory Distress Syndrome
- Incidence of nosocomial infection
- Incidence of pulmonary embolism and deep vein thrombosis
- Crystalloid resuscitation over 24 hrs from admission
- Incidence of coagulopathy and hyperfibrinolysis
Pre-Specified Subgroup Analyses for 30-day Mortality
- Patients who did or did not require blood transfusion
- Significant traumatic brain injury
- Patients enrolled from scene of injury vs a referral hospital
- History of vitamin K antagonist medication
- History of anti-platelet medication
- Patients who required massive transfusion (>10 units of blood in first 24 hrs)
KEY RESULTS
- No significant difference in 30-day mortality in TXA versus placebo (8.1% vs 9.9%, 95% CI [-5.6% to 1.9%], p=0.17)
- No significant differences in incidence of:
- Pulmonary embolism (2.9% vs 1.5%, difference of 1.4%, [95% CI, -3.3 to 0.5], p = 0.16)
- Deep vein thrombosis (2.7% vs 1.5%, difference of 1.2%, [95% CI, -3.3 to 0.5], p = 0.23)
- Post-hoc analyses
- Repeat bolus regimen (1g of TXA bolus, 1g of TXA bolus, then 1 g infused over 8 hours) demonstrated a lower 30 day mortality compared to placebo (7.3% vs 10.0%, difference of 2.7%, [95% CI, -5.0 to -0.4], p = 0.04)
- TXA administered within 1 hour of injury in qualified shock severity patients demonstrated lower 30 day mortality compared to placebo (4.6% vs 7.6%, differences of -3.0%, [95% CI, -5.7 to -0.3], p <0.002)
- TXA in patients with pre-hospital severe shock (systolic blood pressure <70 mm Hg) had lower 30 day mortality compared to placebo (18.5% vs 35.5%, difference -17%, [95% CI, -25.8% to -8.1%], p < 0.003)
STRENGTHS
- Pragmatic and blinded
- Broad inclusion criteria with limited exclusion criteria
- Wide spectrum of injury types and wide spectrum of shock severity
- Builds on prior TXA trials
- Examined the benefit/effect of additional TXA dosing in bolus and infusion forms with a 1 g total group, 2 g total group, and a 3 g total group
- Minimal loss of follow up information
LIMITATIONS
- Low injury severity
- Low blood transfusion requirement
- Overall low mortality rate
- Not fully generalizable to hospitals with less robust pre-hospital trauma systems
- Study stopped early due to slowing enrollment and financial limitations
- Underpowered subgroup analyses
EM TAKE-AWAYS
The literature on TXA is far from clear; however, one concept is becoming more certain: The time to administration of TXA from injury is one of the most important factors in whether patients will benefit. The STAAMP Trial provides another caveat for the consideration of TXA administration in that the patient’s degree of shock may be a factor, and those in more severe shock may have more to gain from TXA administration. Potential adverse effects of TXA are also a hotly examined aspect, and the STAAMP trial provides further evidence that the adverse effect rate with TXA administration is low in terms of arterial and venous thrombotic complications.
The conclusion: TXA, with a thus far demonstrated low adverse event rate, should be considered in all trauma patients as early as feasibly possible, and those with more severe forms of shock may have a larger benefit from administration.
Recommended Reading
- Salim Rezaie’s "Tranexamic Acid (TXA) for Everything that Bleeds?" REBEL EM blog, March 25, 2019. Available at: https://rebelem.com/tranexamic-acid-txa-for-everything-that-bleeds/.
- Justin Morgenstern’s "The CRASH-2 trial (a review)". First10EM blog, February 17, 2020. Available at: https://first10em.com/the-crash-2-trial/.
- Justin Morgenstern’s "CRASH 3: TXA is no wonder drug". First10EM blog, October 28, 2019. Available at: https://first10em.com/crash-3/.
References
- CRASH-2 trial collaborators, Shakur H, Roberts I, 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):23-32.
- 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.
- WOMAN Trial Collaborators. Effect of Early Tranexamic Acid Administration on Mortality, Hysterectomy, and Other Morbidities in Women with Post-Partum Haemorrhage (WOMAN): An International, Randomised, Double-Blind, Placebo-Controlled Trial. Lancet. 2017;389(10084):2105-2116.
- Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic Acid for Hyperacute Primary IntraCerebral Haemorrhage (TICH-2): An International Randomised, Placebo-Controlled, Phase 3 Superiority Trial. Lancet. 2018;391(10135):2107-2115.
- The CRASH 3 Trial Collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH 3): a randomised, placebo-controlled trial. Lancet. 2019;394(10210):1713-1723.
- Guyette FX, Brown JB, Zenati MS, et al. Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial. JAMA Surg. 2020;Oct 5:e204350. doi:10.1001/jamasurg.2020.4350.
- Rezaie S. Tranexamic Acid (TXA) for Everything that Bleeds? Rebel EM blog. March 25, 2019.
- Morgenstern J. The CRASH-2 trial (a review). First10EM blog. February 17, 2020.
- Morgenstern J. CRASH 3: TXA is no wonder drug. First10EM blog. October 28, 2019.