Does administration of tranexamic acid reduce the risk of death if administered early in severe trauma?
Tranexamic acid improves survival when administered in less than 3 hrs after injury in patients with significant hemorrhage.
Tranexamic acid is a synthetic derivative of the aminoacid lysine that inhibits fibrinolysis by blocking the lysine binding sites on plasminogen. Prior systemic review showed a third decrease in blood transfusions but no mortality benefit. In this study, however, the risk of death due to bleeding was significantly reduced (489 [4·9%] vs 574 [5·7%] as well as all-cause mortality (1463 [14.5%] tranexamic acid group vs 1613 [16.0%] placebo group).
CRASH-2 was the second part of the Corticosteroid Randomization After Significant Head Injury(CRASH) Trial. which showed that corticosteroids should not be used routinely in the treatment of head injury
- Multicenter, randomized, placebo-controlled trial involving 274 hospitals in 40 countries
- 20,207 trauma patients with or at risk of significant hemorrhage
- Tranexamic acid (n=10,093)
- Placebo (n=10,114)
- Intention-to-treat analysis with 4 week followup
- Adult trauma patients with significant hemorrhage defined as:
- systolic blood pressure <90 mm Hg
- heart rate >110 beats per min
- or both of the above
- Trauma patients considered to be at risk for significant hemorrhage and within 8 h of injury
- Clear contraindication to tranexamic acid
- Male: 84%
- Mean age: 35 years
- Mean time since injury: 3h
- Blunt trauma: 68%
- Systolic BP <90: 32%
- HR >91: 74%
- GCS: 3-8 (18%), 9-12 (13%), 13-15 (68%)
- Loading dose of 1 g of tranexamic acid infused over 10 min, followed by an intravenous infusion of 1 g over 8 h, or placebo (0·9% saline).
- Primary outcome was death in hospital within 4 weeks of injury
- TXA Group (n=10060) 1463 -- 14.5%
- Placebo Group (n=1613) -- 16.0%
- RR (95%CI) 0.91 (0.85–0.97) pvalue - 0.0035
Vascular occlusive events (MI, CVA, PE, DVT)
- TXA: 1.7%
- Placebo: 2.0% (P=0.084)
- TXA: 47.9%
- Placebo: 48.0% (P=0.79)
- TXA: 50.4%
- Placebo: 51.3% (P=0.21)
Criticisms & Further Discussion
- In 2012 the MATTERS Trial demonstrated the benefits of TXA in military trauma, particularly massive transfusion outcomes.
- Significant criticism exists regarding the randomization scheme where doctors could choose to randomize or not randomize based on treatment certainty. Also only approximately 5% of patients had bleeding as a cause of death and the was no data regarding the severity of hemorrhagic shock. There was also no decrease in blood transfusions and the majority of he population in the study had traumatic brain injury.
- TXA was not included in any protocol associated with massive transfusion which is where the drug is often administered and most patients with acute traumatic coagulopathy were denied the drug in the study. 
- Approximately half of the patients in the trial did not even require a transfusion.
- The fact that less blood was transfused in TXA administered groups raises questions regarding questions regarding the mechanism of action of antifibrinolysis as beneficial to mortality as well as the difficulty in parsing out survivor bias
- The MATTERs study showed that rates of PE and DVTamong patients who received TXA were, respectively, 9 and 12 times the rates among those who did not
UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation
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- MATTERs Study