1. CRASH 2
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

2. CLINICAL QUESTION
In trauma patients with or at risk of significant haemorrhage, does the early administration of a short course of tranexamic acid (TXA) affect the mortality, incidence of occlusive events and the amount of blood transfused?

3. Tranexamic acid Anti-fibrinolytic derivative of lysine
Mechanism of action
interferes with the normal fibrinolysis process
competitive inhibits activation of plasminogen through reversible interactions with lysine- binding sites on the enzyme
non-competitively inhibits plasmin at higher concentrations
10-fold greater potency than aminocaproic acid in vitro

4. DESIGN
Randomised using 24hr free call service balanced by centreMulti-centre
Double-blinded, placebo-controlled with identical treatment packs
With 20,000 patients, study powered to detect a 2% survival advantage from a baseline of 20% at either:
85% power with α-error = 0.01, or
95% power with α-error = 0.05
274 hospitals in 40 countries
20,207 trauma patients randomised and 20,127 analysed under intention-to-treat basis

5. POPULATION Inclusion: Exclusion: clear contra-indication to TXA
adults (age > 18) with trauma;
present within 8 hours of incident;
either significant haemorrhage, or who are considered to be at risk of significant haemorrhage (systolic blood pressure < 90 mmHg and / or heart rate > 110 bpm);
responsible doctor was substantially uncertain about whether or not to treat with TXA
Exclusion: clear contra-indication to TXA
patients were allocated to tranexamic acid and to placebo, of whom and , respectively, were analysed

6. INTERVENTION vs placebo
Loading dose of 1 g of TXA infused over 10 min
Followed by an intravenous infusion of 1 g over 8 h
VERSUS
Placebo (0.9% saline)

7. outcome Primary outcome: death in hospital within 4 weeks of injury
Significant reduction in intervention group
Secondary outcomes: no significant difference in intervention and control groups
Receipt of a blood-products transfusion
Unit of blood products transfused
Surgical intervention
Occurrence of vascular occlusive episodes (stroke, myocardial infarction, pulmonary embolism, clinical evidence of deep vein thrombosis)
Dependency at hospital discharge or at day 28 if still in hospital

9. weaknesses
Randomisation based on subjective opinion of treating physician; no standardised criteria for the definite use of TXA → selection bias
No stratification of injury severity
Follow up period only 28 days and was incomplete
Non-standardisation on the use of fluids/blood products in groups. TXA did not reduce transfusion rates
Only 5% of patients in both groups actually died of haemorrhage

10. conclusion Tranexamic acid is cheap and it saves lives.
Associated with a 1.5% reduction in 28-day all-cause mortality
TXA had greatest impact on reduction of death caused by bleeding in the severe shock group (SBP <= 75 mm Hg)
TXA given after 3 hours after injury was associated with an increased risk of death caused by bleeding 
Not associated with an increased risk of vascular occlusive events