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

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?

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

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

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 10 096 patients were allocated to tranexamic acid and 10 115 to placebo, of whom 10 060 and 10 067, respectively, were analysed

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)

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

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

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