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Thu Oct 8 14:53:46 BST 2009

We are all expressing some of the same things, but from different  angles.  
  From the very earliest reports out of Israel over 10  years ago, it 
appeared that rVIIa had some beneficial effect in some selected  patients.  The 
reports at AAST were indeed analysis of our processes in  earlier reports.   
I almost felt that the AAST papers were an attempt  to respond to some of 
the recent criticism in the press.   It is true  that to date, in trauma, no 
survival advantage has been demonstrated from the  use of rVIIa.   It reminds 
me of the studies of xigris in trauma  patients.   We all are desperate to 
find some tools in some of  our most desperately ill and injured patients, 
and we were hopeful that rVIIa  would be such a magic bullet.   When studies 
have been done,  especially those from the Israel and US military 
experience, entry criteria and  of course randomization are not precise.    As a 
result,  statements made by the last presenter at AAST of a rVIIa paper stated 
that  analysis of exactly who might benefit from rVIIa in trauma was virtually 
 impossible to determine.  That same presenter off line told me, what I 
have  heard from many of my colleagues, the TEG or similar tests might help to 
define  just who would and would not benefit from rVIIa.   

Of course there are a number of other variables which contribute to  
coagulopathy and Dr. Brohi has indeed reported on those.     Others have reported 
on the deleterious effect of crystalloid solutions on both  dilution of 
clotting factors and popping the clot to produce further  bleeding.     There 
are indeed factors under our control and  subject to our inputs to decrease 
coagulopathy and to determine the cause of  bleeding in the post injury 
patient.      

Following Dr. Brohi's post last evening, I went back and read some of the  
initial criticisms of the initial Israel studies as well as the Baltimore 
Sun  article criticizing the recent US Military medical approaches in  Iraq.   
 I do wish that we had defined entry criteria for this  potentially 
powerful tool much better than we did.       Of course rVIIa is not the only area 
where industry has influenced our over use  of new tools.   One needs to look 
no further than interventional  radiology and vascular surgery, 
interventional cardiology, and simply use of the  CT scan for everything to realize 
that technology drives the use of a lot of  things.    

k

In a message dated 10/8/2009 1:29:11 A.M. Central Daylight Time,  
Zsolt.Balogh at hnehealth.nsw.gov.au writes:

I agree  with Karim, currently we are losing potentially powerful agents 
for shock  therapy because the way trials are designed. If we can not show 
with our  current methods (how the FDA want to see) that a drug is effective 
that does  not necessarily means that the drug is ineffective. Certainly an 
expensive  drug like 7a will not be able to recover from the damage severed 
from the  CONTROL. Zsolt

>>> Karim Brohi  <karimbrohi at gmail.com> 10/08/09 8:37 AM >>>
Ken
I have to  disagree with you.  The two papers presented were  registry
analyses.  They were well-designed registry analyses but  fundamentally
that's all they were.  The only real conclusions to take  away from them is
that Factor VII has been used in patients and that rF7a  appears safe.  The
rest is open to bias, confounders, missing patients  etc etc etc and no real
information about utility can be made.

The  results of the Phase III CONTROL trial were presented at the
International  Society for Thrombosis & Haemostasis in Boston this year  (
http://bit.ly/5oBdS).  As many on the list will know this trial was  stopped
for futility for the mortality endpoint.  As with the Phase II  2159 study
there was a trend to saving blood products but not outright  mortality.

There was NO data presented at AAST to suggest that TEG/TEM  can guide F7a
therapy (although we presented a poster on using ROTEM to  diagnose Acute
Traumatic Coagulopathy).  Jeff Kashuk from Denver  presented a small case
series of 35 patients describing their experience  with TEG.  Nothing solid
about guiding transfusion therapy nor about  F7a.

I don't think any more nails have been hammered into rF7a's  coffin.  rF7a 
is
in the coffin already because of CONTROL and because  of Novonordisk
withdrawing from the trauma arena.  Unfortunately  CONTROL was poorly
designed because of lack of knowledge of the disease  process and poor entry
criteria, so any signal was lost within the noise of  a study that tried to
give a very high dose of F7a to a very large number  of patients.

It would not surprise me that we're about to lose a useful  drug because of
lack of knowledge of a disease process combined with the  desperation of
trauma surgeons to adopt an unproven therapy and the  regulator's insistence
on a mortality endpoint for trials of patients  without capacity.  Hopefully
when we have more robust observational  trials to characterise traumatic
coagulopathy we'll be able to design  appropriate studies for future
procoagulants and other  therapies.

Karim

2009/10/6  <KMATTOX at aol.com>

>
> In my view, the biggest thing to  come out of the recent Amer Assoc 
Surgery
> of Trauma (AAST) meetings in  Pittsburgh were TWO papers on analysis of
> studies  of rVIIa in  real people and analyzing the past publications.
> Each
> could  have been labeled , "The rise and fall of rVIIa.      The  studies
> stated
> that basically there is no advantage of any  kind that can be  discovered
> from either of these two well  designed studies.  One was  performed by 
one
> of
> the  most respected researchers in blood, blood products,  clotting,  and
> resuscitation in the world.    He stated that the   entry criteria in the
> cases
> from the military were so poorly  controlled, that no  good statement 
could
> be
> made about  just what the entry criteria should be to  design a good study
> at  this point in order to study this  product.      WOW.   No different 
from
> the early  Israeli studies of  13 years ago.       If there  was one
>  observation that I could make is that maybe the TEG could have been a   
good
> instrument to determine which cases just might benefit from rVIIa  to be
>  given.
>
> k
>
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