Effects of tranexamic acid on death, vascular occlusive events, & blood
transfusion in trauma patients with significant haemorrhage (CRASH-2): a
randomised, placebo-controlled trial
(A) Are the results of the review valid
1. Did the trial address a clearly focused issue? Yes
-Population: 20 211 trauma patients with or at risk of significant bleeding over 40 countries & 274 hospitals
-Intervention: Tranexamic acid 1g over 10 mins then 1g over 8hr IV
-Comparator: placebo
-Primary outcome:
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All-cause mortality within 4 weeks of injury (bleeding, vascular occlusion – (MI, CVA, PE), multiorgan failure, head injury & other)
-Secondary outcomes:
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Vascular occlusive events (MI, CVA, PE, DVT)
Surgical intervention (neurosurgery, thoracic, abdominal, pelvic)
Receipt of blood transfusion, units of blood transfused
Degree of dependency
FVIIa use
GI bleeding
2. Was the assignment of patients to treatments randomised? Yes
-After patients were found to be eligible & consent obtained the patients were randomised. Randomisation
was balanced by centre, with an allocation sequence based on a block size of 8, generated with a computer
random number generator. In hospitals where telephone randomisation was not practical they used a local
pack system that allowed for randomisation. The telephone randomisation service used an algorithm that
balanced for sex, age, time since injury, type of injury, GCS, systolic BP, respiratory rate, central capillary
refill time & country.
-Patients were randomly allocated to receive a loading dose of 1g of TXA infused over 10 minutes followed
by an IV infusion of 1g over 8 hrs or matching placebo (0.9% saline)
-The allocation sequence was concealed from both the patients & staff
3. Were all of the patients who entered the trial properly accounted for at its conclusion? Yes
-See figure 1
4. Were the patients, health workers & study personnel ‘blind’ to treatment? Yes
-“Both participants and study staff (site investigators and trial coordinating centre staff ) were masked to
treatment allocation”
5. Were the groups similar at the start of the trial? Yes
-See table 1
6. Aside from the experimental intervention, were the groups treated equally? Yes
-Due to blinding, apart from the tranexamic acid both groups were treated equally
(B) What are the results?
7. How large was the treatment effect?
Findings in this study:
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All cause mortality at 4 weeks was significantly lower in the TXA group compared to placebo:
14.5% (1463) vs 16% (1613) (Relative risk 0.91 confidence interval (0.85-0.97) p value 0.0035
The risk of death due to bleeding was significantly reduced 4.9% (489) vs 5.7% (574) RR 0.85, 95%
CI (0.76-0.96) p value 0.0077
Trend towards more vascular occlusive events in the placebo group
No difference in transfusion & need for surgery
Trend towards early treatment being more effective
-As shown above all the evidence points towards an overall survival benefit with using TXA.
8. How precise was the estimate of the treatment effect?
-Primary outcome: all-cause mortality within 4 weeks of injury (bleeding, vascular occlusion – (MI, CVA,
PE), multi-organ failure, head injury & other)
Secondary outcomes: vascular occlusive events (MI, CVA, PE, DVT)
Secondary outcomes: receipt of blood transfusion, units of blood transfused & surgical intervention
(neurosurgery, thoracic, abdominal, pelvic)
Secondary outcomes: degree of dependency
Secondary outcomes: FVIIa use
-13 (0.13%) patients in the TXA group received FVIIa & 4 (0.04%) received FVIIa in the placebo group.
Secondary outcomes: GI bleeding
-132 patients in each group had GI bleeding.
(C) Will the results help locally?
9. Can the results be applied in your context? Yes
-We can apply this to our trauma patient population
10. Were all clinically important outcomes considered? Yes
Yes I think the outcomes were adequate. If they had looked at more outcomes it would have become too
complicated.
11. Are the benefits worth the harms & costs? Yes
Criticisms/Issues/Comments
-Higher percentage of blunt trauma
-? The modest injury profile may have introduced a conservative bias against TXA
-A high percentage of patients were treated in developing countries: less than 2% of the patients in CRASH2 were treated in countries that routinely provide rapid access to blood products, damage control surgery &
angiography, & advanced critical care
-Re-examination of the 1063 deaths resulting from bleeding (35%) found that benefit from TXA was
greatest when given early (at ≥ 1 hr, RR 0.68; at 1-3 hrs, RR 0.79). When given > 3 hrs after injury, an
unexpected & unexplained increase in deaths due to bleeding was found (RR 1.44) 95% CI (1.12 - 1.84) p
value 0.004
-Low thromboembolic rates may reflect the participating hospitals not actively investigating/ruling out.
(Roberts et al The importance of early treatment with TXA in bleeding trauma patients: an exploratory
analysis of the CRASH-2 randomised controlled trial)