EBQ:CRASH-2 Trial

Complete Journal Club Article
Shakur H, et al. "Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage". The Lancet. 2010. 376(9734):23-32.
PubMed Full text PDF

Clinical Question

Does administration of tranexamic acid reduce the risk of death if administered early in severe trauma?

Conclusion

Tranexamic acid improves survival when administered in less than 3 hrs after injury in patients with significant hemorrhage.

Major Points

Tranexamic acid is a synthetic derivative of the aminoacid lysine that inhibits fibrinolysis by blocking the lysine binding sites on plasminogen.[1] Prior systemic review showed a third decrease in blood transfusions but no mortality benefit.[2] 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.[3] which showed that corticosteroids should not be used routinely in the treatment of head injury

Study Design

  • Multicenter, randomized, placebo-controlled trial involving 274 hospitals in 40 countries
  • 20,207 trauma patients with or at risk of significant hemorrhage
  • Intention-to-treat analysis with 4 week followup

Population

Inclusion Criteria

  1. Adult trauma patients with significant hemorrhage defined as:
    1. systolic blood pressure <90 mm Hg
    2. heart rate >110 beats per min
    3. or both of the above
  2. Trauma patients considered to be at risk for significant hemorrhage and within 8 h of injury

Exclusion Criteria

  1. Clear contraindication to tranexamic acid

Patient Characteristics

  • 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%)

Interventions

  1. 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).

Outcome

Primary Outcomes

  • 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

Secondary Outcomes

Vascular occlusive events (MI, CVA, PE, DVT)

TXA: 1.7%
Placebo: 2.0% (P=0.084)

Surgical intervention

TXA: 47.9%
Placebo: 48.0% (P=0.79)

Blood transfusion

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.[4]
  • 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.[5]
  • 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. [6]
  • 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[7]
  • 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[8]

Funding

UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation

Further Reading

MATTERs Study

References

  1. Okamoto S, Hijikata-Okunomiya A, Wanaka K, Okada Y,Okamoto U. Enzyme controlling medicines: introduction. Semin Thromb Hemost1997;23: 493–501
  2. Henry DA, Carless PA, Moxey AJ, et al. Anti-fi brinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007; 4: CD001886.
  3. Edwards P, Arango M, Balica L, Cottingham R, El-Sayed H, Farrell B, Fernandes J, Gogichaisvili T, Golden N, Hartzenberg B, Husain M, Ulloa MI, Jerbi Z, Khamis H, Komolafe E, Laloe V, Lomas G, Ludwig S, Mazairac G, Munoz Sanchez Mde L, Nasi L, Olldashi F, Plunkett P, Roberts I, Sandercock P, Shakur H, Soler C, Stocker R, Svoboda P, Trenkler S, Venkataramana NK, Wasserberg J, Yates D, Yutthakasemsunt S, et al. Final results of MRC CRASH, a randomized placebo-controlled trial of intravenous corticosteroids in adults with head injury-outcomes at 6 months. Lancet. 2005:365:1957-1959.
  4. Morrison JJ, et al. "Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study." Arch Surg. 2012;147(2):113-9.
  5. Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE. Tranexamic acid in trauma: how should we use it? JTrauma Acute Care Surg. 2013; 74:1575-1586.
  6. Gruen RJ, Jacobs IG, Reade MC. Trauma and Tranexamic Acid. Med J Aus. 2013; 199:310-311.
  7. Kenji Inaba. Antifibrinolytics in Trauma Patients: Does It MATTER? Comment on “Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study” Arch Surg. 2012;147(2):119
  8. MATTERs Study