Tranexamic acid for trauma
After its publication in July, 2010, the CRASH-2 study1
generated widespread interest in the early administration
of the antifi brinolytic agent tranexamic acid to
patients with traumatic bleeding. Tranexamic acid is an
inexpensive, easily used, and relatively safe drug, and it
seemed to have saved lives. However, how it did so was
unclear—the blood-transfusion requirements of the
tranexamic acid and placebo groups were similar and,
survival bias notwithstanding, the mortality benefi t might
have been attributable to an eff ect of tranexamic acid on
something other than acute traumatic coagulopathy.2
This issue is partly addressed with the publication in
The Lancet of a follow-up analysis that used the outcome
of death due to bleeding rather than all-cause mortality.3
The CRASH-2 collaborators3
report a 32% reduction in
death due to bleeding when tranexamic acid is given
within 1 h of injury. Although markers of coagulopathy
were not measured, the mortality benefi t is probably
mediated through antifi brinolytic eff ects on clot
stabilisation.4 While it will not prevent the massive
haemorrhage from disrupted vessels or organs that needs
surgical intervention, tranexamic acid appears to improve
survival through its eff ect on mild to moderate bleeding.
Early administration is necessary, however, and benefi t
was only seen in CRASH-2 when tranexamic acid was
administered within 3 h of injury. Unlike coagulopathy
that is secondary to haemodilution, hypothermia, or
acidosis, acute traumatic coagulopathy is a hyperacute
process in which systemic fi brinolysis releases D-dimers
that are detectable within 30 min of injury.5 While the
mechanisms are poorly understood, shock and tissue
injury seem to be important initiators.6 Not all severely
injured patients develop acute coagulopathy, but those
who do are much more likely to die and to die early.7 The
earlier that tranexamic acid is administered, the more
likely it might be to prevent full activation of fi brinolysis.
Once fully activated, fi brinolysis has been shown to
continue unabated until endogenous antifi brinolytic
elements are restored.8
Importantly, the CRASH-2 collaborators3
report
increased mortality due to bleeding in patients receiving
tranexamic acid when it is given more than 3 h after
injury. The cause of these deaths is unclear. Reports exist
of prothrombotic eff ects of each of the anti-fi brinolytic
drugs. Alternatively, it might refl ect some factor of the
patients who received it late. Whatever the mechanism,
the CRASH-2 collaborators3
have cautioned against the
use of tranexamic acid when more than 3 h have expired
after injury.
Who, then, should be treated with tranexamic
acid? Most of the 274 study sites in CRASH-2 were
in low-income and middle-income countries, where
other treatments directed at coagulopathy, such as
fresh frozen plasma, platelets, and cryoprecipitate,
are less available. Although many patients with
acute coagulopathy will die before reaching hospital,
tranexamic acid is a practical, aff ordable, and eff ective
treatment for bleeding trauma patients in such centres,
provided they receive it within 3 h of injury.
Far less clear is the place for tranexamic acid in high
income countries where massive transfusion protocols
incorporate fresh-frozen plasma that contains all the
endogenous antifi brinolytic elements in plasma.9
Plasma can cause harm as well as benefi t, and there
is little prospective evidence regarding its effi cacy.
However, because it is in widespread use, and because
late administration of tranexamic acid can be harmful, it
is unlikely that many clinicians in major trauma centres
will choose tranexamic acid as fi rst-line treatment.
The best place for tranexamic acid in developed
trauma systems might actually be in the prehospital
environment. Helicopter and road transport direct
to major trauma centres has reduced overall injury
mortality, but has extended the time before patients
reach hospital.10
Prehospital administration of blood
products, especially plasma, is uncommon in civilian
settings, resulting in little directed management of
coagulopathy. By contrast, tranexamic acid can be safely
stored in vehicles and simply administered. In view of the
new fi ndings from CRASH-2, the best outcomes might
be achieved with simple measures for haemorrhage
control and early inhibition of coagulopathy with
tranexamic acid, followed by rapid transport for
surgery or angiography and tailored management of
coagulopathy in hospital.
CRASH-2 was an extraordinary achievement, with
randomisation of more than 20 000 patients in
40 countries. It has established tranexamic acid as
an eff ective hospital-based treatment for traumatic
haemorrhage, provided that the drug is given within 3 h of
injury. In trauma systems that have advanced prehospital
services and that use other hospital-based treatments for
coagulopathy, CRASH-2 raises more questions—and more
possibilities—that are worth investigating.
http://download.thelancet.com/flatcontentassets/pdfs/S0140673611603966.pdf