special editorial on trauma:
A large scale randomised
controlled trial is needed.
Editor, Cochrane Injuries Group and
Clinical Co-ordinator CRASH-2 trial
Address for correspondence
CRASH-2 trial co-ordinating centre
London School of Hygiene & Tropical Medicine,
Keppel Street, London WC1E 7HT
Phone 0207 958 8128
Fax: 0207 299 4663
For people at ages 5 to 45
years, trauma is second only to HIV/AIDS as a cause of death.
Each year, worldwide, over three million people die as a result
of trauma, many after reaching hospital.1 Among trauma patients
who do survive to reach hospital, exsanguination is a common
cause of death, accounting for nearly half of in-hospital
trauma deaths.2 Central nervous system injury and multi-organ
failure account for most of the remainder, both of which can
be exacerbated by severe bleeding.3
The haemostatic system helps to maintain the
integrity of the circulatory system after severe vascular
injury, whether traumatic or surgical in origin.4 Major surgery
and trauma trigger similar haemostatic responses and any consequent
massive blood loss presents an extreme challenge to the coagulation
system. Part of the response to surgery and trauma, in any
patient, is stimulation of clot breakdown (fibrinolysis) which
may become pathological (hyper-fibrinolysis) in some.4 Anti-fibrinolytic
agents have been shown to reduce blood loss in patients with
both normal and exaggerated fibrinolytic responses to surgery,
and do so without apparently increasing the risk of post-operative
complications, most notably there is no increased risk of
Systemic anti-fibrinolytic agents are widely
used in major surgery to prevent fibrinolysis and thus reduce
surgical blood loss. A recent systematic review6 of randomised
controlled trials of anti-fibrinolytic agents (mainly aprotinin
or tranexamic acid) in elective surgical patients identified
89 trials including 8,580 randomised patients (74 trials in
cardiac, eight in orthopaedic, four in liver, and three in
vascular surgery). The results showed that these treatments
reduced the numbers needing transfusion by one third, reduced
the volume needed per transfusion by one unit, and halved
the need for further surgery to control bleeding. These differences
were all highly statistically significant. There was also
a statistically non-significant reduction in the risk of death
(RR=0.85: 95%CI 0.63 to 1.14) in the anti-fibrinolytic treated
Because the haemostatic abnormalities that occur
after injury are similar to those after surgery, it is possible
that anti-fibrinolytic agents might also reduce blood loss,
the need for transfusion and mortality following trauma. However,
to date there has been only one small randomised controlled
trial (70 randomised patients, drug versus placebo: 0 versus
3 deaths) of the effect of anti-fibrinolytic agents in major
trauma.7 As a result, there is insufficient evidence to either
support or refute a clinically important treatment effect.
Systemic anti-fibrinolytic agents have been used in the management
of eye injuries where there is some evidence that they reduce
the rate of secondary haemorrhage.8
A simple and widely practicable treatment
that reduces blood loss following trauma might prevent thousands
of premature trauma deaths each year and secondly could reduce
exposure to the risks of blood transfusion. Blood is a scarce
and expensive resource and major concerns remain about the
risk of transfusion-transmitted infection. Trauma is common
in parts of the world where the safety of blood transfusion
is not assured. A recent study in Uganda estimated the population-attributable
fraction of HIV acquisition as a result of blood transfusion
to be around 2%, although some estimates are much higher.9,10
Only 43% of the 191 WHO member states test blood for HIV,
hepatitis C and B viruses. Every year, unsafe transfusion
and injection practices are estimated to account for 8-16
million Hepatitis B infections, 2.3-4.7 million Hepatitis
C infections and 80,000-160,000 HIV infections.11 A large
randomised trial is therefore needed of the use of a simple,
inexpensive, widely practicable anti-fibrinolytic treatment
such as tranexamic acid (aprotinin is considerably more expensive
and is a bovine product with consequent risk of allergic reaction
and hypothetically transmission of disease), in a wide range
of trauma patients, who when they reach hospital are thought
to be at risk of major haemorrhage that could significantly
affect their chances of survival.
The CRASH 2 trial will be a large international, placebo controlled
trial of the effects of the early administration of the anti-fibrinolytic
agent tranexamic acid on death, vascular events and transfusion
requirements.12 The trial aims to recruit some 20,000 patients
with trauma and will be one of the largest trauma trials ever
conducted. However, it will only be possible to conduct such
a trial if hundreds of healthcare professionals worldwide
work together to recruit patients to the trial in order to
make it a success.
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