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Mon Oct 11 17:32:51 BST 2004

Actually, 'Equipoise' as defined by clinical trials (FDA/EMEA) does not mean
that you believe that the two possibilities are equal - but that the outcome
for the treatment arm is not thought to be worse than the control arm.  

At present, giving tranexamic acid to trauma patients is by no means
standard - even for the cogaulopathic non-surgical bleeding (which is not
that rare!).  Here is the actual paragraph you're referring to, which I
think is a bit more sensible than the individual sentence.

"The fundamental eligibility criterion is the responsible doctor's
'uncertainty' as to whether or not to use an antifibrinolytic agent in a
particular adult with traumatic haemorrhage. Patients for whom the
responsible doctor considers there is a clear indication for
antifibrinolytic therapy should not be randomised. Likewise, patients for
whom there is considered to be a clear contraindication to antifibrinolytic
therapy (such as, perhaps, those who have clinical evidence of a thrombotic
disseminated intravascular coagulation) should not be randomised. Where the
responsible doctor is substantially uncertain as to whether or not to use an
antifibrinolytic, all these patients are eligible for randomisation and
should be considered for the trial."

The main issue I have with the protocol is that the inclusion criteria could
be interpreted as giving the drug to a patient who has had an episode of
haemorrhage, has now stopped bleeding, but is still within the 8 hour
window.  Ie - you don't have to have on-going haemorrhage to give the drug.
(This may just be my reading of it).  This was one of the main issues with
the Factor VIIa trial

Karim

-----Original Message-----
From: trauma-list-bounces at trauma.org [mailto:trauma-list-bounces at trauma.org]
On Behalf Of Guy Jackson
Sent: 11 October 2004 08:14
To: Trauma & Critical Care mailing list
Subject: Re: CRASH 2

Karim,

Yes, I agree with all that, but it is not the point I was trying to make.
Check out the protocols section of their web site
(http://www.crash2.lshtm.ac.uk/). It clearly says that you should only
randomise if you are uncertain as to weather to give or not, i.e. you are in
a state of equipoise. This may be excellent research ethics (unsurprizing as
it comes from a group associated with the Cochrane Group), but my point is
that I think this situation is a relatively rare occurence. My question
therefore is do people use tranexamic acid routinely in anything other than
extreme situations? There is certainly little enough published evidence. Put
'trauma' and 'tranexamic acid' into Ovid and combine the results and you get
three papers:

Murphy DP. O'Donnell T. McDonnell J. McElwain JP. Treatment of anaemia in
the polytrauma Jehovah's Witness. [Review] [26 refs] [Journal Article.
Review. Review, Tutorial] Irish Medical Journal. 96(1):8-10, 2003 Jan.

. Mattsson J. Peterson HI. Risberg B. Influence of tranexamic acid on lung
tissue fibrinolysis after trauma. [Journal Article] Bibliotheca Anatomica.
(16 Pt 2):416-8, 1977.

Risberg B. Fibrinolysis in the lung. Experimental studies on tissue
localization and on the response to drug induced antifibrinolysis and to
trauma. [Journal Article] Acta Chirurgica Scandinavica - Supplementum.
458:1-36, 1975.

Put it into PubMed (which does not have the indexing to MeSH terms that Ovid
does) and you get 65, but many of them off topic. The best is a recent
review from Kovesi T and Royston D which concludes that there is no
adequately powered study in cardiac, hepatic, or orthopaedic surgery. I
can't get to the Cochraine review at present, but I doubt it comes to a
different conclusion. The problem comes when you decide what question to ask
in order to solve the riddle. This is one of the reasons for a pilot study:
To try out the question in a real world setting. The question they have
asked is 'Does tranexamic acid benefit the patient if I am unsure whether to
give it or not?'. You will get a different result if you ask the
question:'Does tranexamic acid benefit the patient survival rate if I give
it to all patients with a severe injury?' You can argue that the lack of
evidence leads us all to equipoise, but I worry that the question as asked
injects a note of uncontrolled into the population being studied if you
follow this route. Some will think that you have to have severe polytrauma,
and some will give it to every patient with an isolated compound fractured
femur. I would simply like to see some pilot work out there to help resolve
these issues.

This leads me on to your concerns regarding patient numbers in CRASH1. If I
remember correctly the study aimed to recruit more than 22,000 patients so
that it was properly powered (one can only admire the investigators
scientific integrity and determination). These studies have their interim
analysis at fixed points determined in advance from the power studies. I
agree that an analysis might have shown problems earlier, and may even have
been done. Unfortunately the results of these never get published, so we
will never know. At least they did do one before the half way mark and act
on it. I would be worried in deed if they had done one earlier and ignored a
adverse finding.

I also do not understand why they comment on cause of death. They admit that
they did not collect data on this. Why not hypothesise that steroids cause
salt and water retention, the knock on effect is to worsen brain oedema?

Cheers,

Guy

----- Original Message -----
From: Karim Brohi <karim at trauma.org>
To: 'Trauma & Critical Care mailing list' <trauma-list at trauma.org>
Sent: Friday, October 08, 2004 11:40 PM
Subject: CRASH 2

Guy ,

I think the CRASH 2 trial has more merit.

"CRASH 2 is a large efficient placebo controlled trial of the effects of the
early administration of the antifibrinolytic agent tranexamic acid on death,
vascular events and transfusion requirements. Adults with trauma who are
within 8 hours of injury and have either significant haemorrhage, or who are
considered to be at risk of significant haemorrhage, are eligible if the
responsible doctor is for any reason substantially uncertain whether or not
to use an antifibrinolytic agent. Numbered drug or placebo packs will be
available in each participating emergency department. Randomisation will
involve calling a 24-hour freecall randomisation service."

There is renewed interest in the so-called 'anti-fibrinolytics' in trauma.
Aprotinin is the more widely studied - and being a serine protease
inhibitor, has more wide-ranging effects that an anti-fibrinolytic -
including an antiinflammatory action.  With the current trials of Factor
VIIa in haemorrhagic shock and TBI - it is interesting to study a cheaper
alternative with a different mechanism.  (Of course it would be nice if we
knew a bit more about traumatic coagulopathy before we started <wink>).

Most people have forgotten about this German study - which was, I think,
remarkable for it's time (1976).

Chirurg.  1976 Apr;47(4):185-8.
[Field study on the therapeutic value of trasylol in traumatic shock]
[Article in German]

Schneider B, Schnells G, Trentz O, Tscherne H.
A report of the results of a multicenter study including 4686 patients
concerning the therapeutic value of Trasylol (Aprotinin) in traumatic shock.
The group treated additionally with Trasylol showed, beside a reduced
overall mortality, a statistically significant reduction of mortality in
those treated within the first 30 min after the injury. Surgery performed in
the posttraumatic stage showed a lower mortality in the Trasylol group. The
importance of a time factor in shock treatment and the effects of Trasylol
in traumatic shock are emphasized.

I have the article but have not been able to get it translated from the
German yet.  Of course 1976 is a long time ago - and clinical trials were
conducted very differently then.  But it certainly bears further
investigation.

Hopefully we are moving into a new era where we understand traumatic
coagulopathy a bit better, have better markers than PT/PTT, and will have
new agents other than 'lots of FFP' to manage it.  Now whether  one of those
agents is Tranexamic Acid or not is another issue.

Karim

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