Applying CRASH-2 (Clinical Randomisation of an
Antifibrinolytic in Significant Haemorrhage 2) in a PreHospital Wilderness Context
Paul B. Jones
PGY1 McMaster Family Medicine
My question?
Does the administration of
tranexamic acid (TXA)
among adult trauma
patients with, or at risk of
significant hemorrhage
have an impact on death?
Why do I care?
 Wilderness medicine, including the application of
first-aid, includes any context that involves
patient care in extreme environments, when
resources may be limited or non-existent, and
evacuation to greater medical care may be
hours, days or longer.
 Applications of wilderness medicine may be in a
remote corner of the planet, but also include
environments such as urban disasters, severe
weather conditions, multiple patients, police and
military interventions or any situation that creates
a context with minimal resources or extended
scene patient management.
 A large randomised placebo controlled trial
among trauma patients with, or at risk of,
significant haemorrhage, of the effects of
antifibrinolytic treatment on death and
transfusion requirement
 Double blind RCT, London School of Hygiene and
Tropical Medicine
 274 Hospitals, 40 Countries,
 20 211 adult trauma patients
Adult trauma patients with
significant haemorrhage
 Systolic blood pressure < 90 mm Hg
 or heart rate >110 beats per min,
 or both,
 or who were considered to be at risk of
significant haemorrhage,
 and who were within 8 hours of injury.
“Uncertainty principle”
 Patients with clear indication for tranexamic acid
were not randomly assigned
 Patients with a clear contraindication for
tranexamic acid were not randomly assigned
 “When the responsible doctor was substantially
uncertain as to whether or not to treat with this
agent these patients were eligible for
randomization”
Intervention
 Patients were randomly allocated to either:
 Treatment - receive a loading dose of 1 g
tranexamic infuse over 10 min, followed by IV
infusion of 1 g over 8 h.
 Placebo - matching (0.9% saline).
Primary Outcome
 Death in hospital within 4 weeks of injury
 Cause of death categories:
 Bleeding
 Vascular occlusion (MI, CVA, and PE
 Multiorgan failure
 Head injury
 Other
Secondary Outcomes
 Vascular occlusive events (MI, CVA, PE or DVT)
 Surgical intervention
 Receipt of blood transfusion and units of blood
products transfused
 Dependency (dead, fully dependent day &
night, or dependent but not needing constant
attention)
Baseline characteristics
1. Estimated hours since injury (<1, 1-3, 3-8h)
2. Systolic blood pressure (≤ 75, 76-89, 90 ≥ mm
Hg)
3. GCS (severe 3-8, moderate 9-12, mild 13-15)
4. Type of injury (penetrating only or blunt, which
included blunt and penetrating)
Table 1
TXA vs. Placebo
Table 2
Death by Cause
2x2 – Any Death
Any Death
No Death
TXA
1463 (a)
8597 (b)
Placebo
1613 (c)
8454 (d)
CER = 0.16023
EER = 0.14543
RR = 0.90763
RRR = 0.09237 = 9.24%
ARR = 0.0148 = 1.48%
NNT = 67.57
2x2 – Bleeding Death
Bleeding Death
No Death
TXA
489 (a)
9571 (b)
Placebo
574 (c)
9493 (d)
CER = 0.05702
EER = 0.04861
RR = 0.85251
RRR = 0.14749 = 14.75%
ARR = 0.00841 = 0.84%
NNT = 118.91
All-cause mortality by
subgroups
All-cause mortality by subgroup
Cochrane Review
 “Each year, world-wide, about four million
people die as a result of traumatic injuries and
violence. Approximately 1.6 million of these
deaths occur in hospital and about one third of
these deaths (480,000) are from haemorrhage.
The CRASH-2 2010 trial has shown that TXA
reduces mortality from haemorrhage by about
one sixth. If this widely practicable intervention
was used world- wide in the treatment of
bleeding trauma patients, it could prevent over
70,000 deaths each year.”
(Antifibrinolytic drugs for acute traumatic injury. Cochrane Database of
Systematic Reviews 2011)
Cochrane Review
 Tranexamic acid (TXA) safely reduces mortality in
bleeding trauma patients. Because most deaths
from traumatic haemorrhage occur in the first
few hours after injury, every effort should be
made to treat patients as soon as possible.
 More research on mortality and morbidity is
required on the use of TXA in TBI patients before it
can be recommended in this population.
(Antifibrinolytic drugs for acute traumatic injury. Cochrane Database of
Systematic Reviews 2011)
References
 CRASH-2 trial collaborators (2010) Effects of tranexamic acid on death,
vascular occlusive events, and blood transfusion in trauma patients
with significant haemorrhage (CRASH-2): a randomised, placebocontrolled trial. Lancet Jul 3;376(9734): 23–32.
 Guerriero C, Cairns J, Perel P, Shakur H, Roberts I, et al. (2011) CostEffectiveness Analysis of Administering Tranexamic Acid to Bleeding
Trauma Patients Using Evidence from the CRASH-2 Trial. PLoS ONE 6(5):
e18987. doi:10.1371/journal.pone.0018987
 The CRASH-2 Trial Collaborators (2006) Improving the evidence base
for trauma care: Progress in the international CRASH-2 trial. PLoS Clin
Trials 1(6): e30. DOI: 10.1371/journal.pctr.0010030
 Roberts I, Shakur H, Ker K, Coats T, on behalf of the CRASH-2 Trial
collaborators. Antifibrinolytic drugs for acute traumatic injury.
Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.:
CD004896. DOI: 10.1002/14651858.CD004896.pub3.
 Gruen RL, Biswadev M. Tranexamic acid for trauma. Lancet. Published
Online March 24, 2011 DOI:10.1016/S0140- 6736(11)60396-6