CRASH-2

Published

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 tranexamic acid, when given within 8 hours to patients with or at risk of significant bleeding reduce death within 4 weeks of injury?

Bottom Line

Tranexamic acid improves survival when administered early in trauma with known or suspected significant hemorrhage.

Major Points

Hemorrhage is a leading cause of death among patients with major trauma. Trauma leads to hemorrhage both from primary injury to organs and blood vessels, but also to transient hyperfibrinolysis that is incompletely understood. Tranexamic acid, a synthetic derivative of the amino acid lysine, appears to interfere with this hyperfibrinolysis, prompting investigators to study whether the agent may reduce the morbidity and mortality of traumatic hemorrhage. It has previously been used in controlling bleeding complications in those with hemophilia, those undergoing cardiopulmonary bypass, and those with menorrhagia.

The 2010 Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) was an international study of 20,207 trauma patients with or at risk of significant hemorrhage, defined based on hemodynamic instability. Patients were randomized to double-blind treatment with either tranexamic acid or matching placebo, given within 8 hours of presentation. At 4 weeks of follow-up, tranexamic acid was associated with a 1.5% absolute reduction in mortality (14.5% vs. 16%) compared to placebo. A separately published but prespecified subgroup analysis demonstrated that early administration of tranexamic acid (within one hour of injury) was associated with greater reductions in death due to bleeding, while delayed administration (>3 hours from injury) was associated with increased bleeding deaths. All-cause mortality was reduced in the <1 hour and 1-3 hour strata, but not in the >3 hour stratum.

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. Prior studies have demonstrated that tranexamic acid may elevate the risk of VTE, particularly among those with factor IX deficiency. However, in CRASH-2, there were no differences in the rate of vascular occlusive events (1.7% vs. 2.0%).

The results of CRASH-2 were concordant with those of the subsequent MATTERs trial (2012).

Guidelines

Tactical Combat Casualty Care (US Military) 2011

• 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

• Multicenter, randomized, placebo-controlled trial
• N=20,207 trauma patients with or at risk of significant hemorrhage
  • Tranexamic acid (n=10,093)
  • Placebo (n=10,114)
• Setting: 274 hospitals in 40 countries
• Enrollment: Began in 2005
• Follow-up: 4 weeks
• Analysis: Intention-to-treat
• Primary outcome: In-hospital death at 4 weeks

Population

Inclusion Criteria

• Adult trauma patients
• Hemorrhagic shock or at risk of significant hemorrhage (systolic BP <90 or HR >110, or both)
• Within 8 hours of injury

Exclusion Criteria

• Clear indication for tranexamic acid
• Clear contraindication to tranexamic acid

Baseline 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

• Randomized to tranexamic acid or placebo
• Tranexamic acid loading dose 1g over 10 minutes, followed by 1g/8h infusion

Outcomes

Comparisons are tranexamic acid vs. placebo.

Primary Outcomes

Death in hospital within 4 weeks of injury

14.5% vs. 16.0% (RR 0.91, 95% CI 0.85–0.97; P=0.0035)

Secondary Outcomes

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

1.7% vs. 2.0% (P=0.084)

Surgical intervention

47.9% vs. 48.0% (P=0.79)

Blood transfusion

50.4% vs. 51.3% (P=0.21)

Death by cause

Bleeding: 4.9% vs. 5.7%

Vascular occlusive event: 0.3% vs. 0.5%

Multiorgan failure: 2.1% vs. 2.3%

Head injury: 6.0% vs. 6.2%

Other: 1.3% vs. 1.4%

Subgroup Analysis

Published separately.

Death due to bleeding

≤1h from injury: 5.3% vs. 7.7% (RR 0.68, 95% CI 0.57-0.82; P<0.0001)

1-3h: 4.8% vs. 6.1% (RR 0.79, 95% CI 0.64-0.97; P<0.00001)

>3h: 4.4% vs. 3.1% (RR 1.44, 95% CI 1.12-1.84; P<0.0001)

All-cause mortality

≤1h from injury: RR 0.87, 95% CI 0.76-0.97

1-3h: RR 0.87, 95% CI 0.77-0.97

>3h: RR 1.00, 95% CI 0.90-1.13

Criticisms

• Did not measure fibrinolytic activity of participants
• Did not provide full data in subroup analysis of all-cause mortality

Funding

Both public (eg, UK NIHR) and private (eg, Pfizer) sources.