[HSF] More Bad News About Trasylol

[Ben Bidstrup]

>Hal and Ben
>Hal is that because you think it does not have useful effects if  selectively
>used at a particular dosage or because you fear that the Medical  Politically
>Correct Police have allowed an opening for the Malpractice  Industrial
>Complex to gear up its dirty engine?
>The story is on the front page of the New York Times this  Saturday morning
>quoting aggrieved FDA spokespersons, the usual cast of  selfrighteous pious
>commentators who are everready to pick on doctors or drug  companies 
>or both and
>a Senator (perhaps  running for  reelection?), saying this proves how useless
>the FDA is. Everyone with an axe to  grind, everyone with an agenda and none
>of them with the remotest idea of the  complexity of cardiac 
>surgical cases and
>the many effects of trasylol.
>The Bayer study was a review of  the charts of 67,000 hospital  patients,
>30,000 of whom had received trasylol. (The reporter pointed out the  obvious
>difficulties in coming to conclusions about such a study).    Here 
>is grist for
>your mill Tea.
>
>Ben, the reporter says that aprotinin has been on the market for 13 years.  I
>remember trasylol being used for pancreatitis 35 years ago. Surely  trasylol
>was used in cardiac surgery earlier than 13 years ago? What would you  regard
>as a definitive study that shows benefit for trasylol? I speak  now on te
>level of the reporter in Shaw's hundred year old play "The  Doctor's 
>Dilemma"; it
>has to be kept simple for me.
>
>Bob

I am not familiar with this study. I do not read  the New York Times 
to get information about medical treatments, and surgery etc.
Aprotinin was first released in 1959 by Bayer in Germany to treat 
pancreatitis. It was used in the early 80's in higher doses for 
prevention of DVT in hip replacement and to reduce blood loss in 
trauma patients in Germany.
In 1985 I was a co investigator in a study at the Hammersmith 
Hospital in which we examined the prophylactic use of aprotinin in a 
dose regimen similar but not identical to the currently approved 
regimen. The dosing was designed to reduce kallikrein release and 
thus reduce complement activation, believed to be a source of lung 
injury after cardiopulmonary bypass. One somewhat unexpected finding 
was a remarkable reduction in blood loss and use. (van Oeveren, W., 
et al., Effects of aprotinin on haemostatic mechanisms during 
cardiopulmonary bypass. Ann Thorac Surg, 1987. 44(6): p. 640-5.) 
Several double blind studies followed, funded by Bayer who did not 
interfere in any way with analysis of data or report writing. David 
Royston's letter to the Lancet followed in 1987 (Royston, D., et al., 
The effect of aprotinin on need for blood transfusion after repeat 
open heart surgery. Lancet, 1987. ii: p. 366-367.) This jumped the 
gun a bit as it was a small study (22 patients) but in what then was 
a high risk group, showed major benefits. Once  the primary CABG 
study was  completed, I presented the findings at the AATS in 1988 
and this was subsequently published in 1989. (Bidstrup, B.P., et al., 
Reduction in blood loss and blood use after cardiopulmonary bypass 
with high dose aprotinin (Trasylol). Journal of Thoracic and 
Cardiovascular Surgery, 1989. 97: p. 364-372.) We looked at larger 
numbers of re-operations and also patients who had active 
endocarditis at the time. Many of these were prosthetic valve 
endocarditis. Many further studies followed from Germany and Holland.
The USA then started to examine its use. The first study was from the 
Cleveland Clinic and published in 1992 (Bidstrup, B.P., et al., 
Reduction in blood loss and blood use after cardiopulmonary bypass 
with high dose aprotinin (Trasylol). Journal of Thoracic and 
Cardiovascular Surgery, 1989. 97: p. 364-372.). This certainly caused 
a lot of discussion, partly because there were several post hoc 
analyses included (for MI) and a limited review of mortalities.
One issue was that heparin  monitoring allowed lower dosing of 
heparin to be given in some patients.
Several studies in the USA followed. These were RCTs set up to prove 
the effectiveness and for the purposes of FDA registration. A study 
in valve surgery patients did not show the required efficacy but the 
CABG studies did and approval by the FDA for use in CABG patients was 
given in 1994.
Trasylol is available in many countries nd has been in regular use in 
Europe since the late 1980s. Reporting to drug evaluation agencies 
has been around for many years, and as we can see many physicians 
report in anecdotal fashion  adverse events they see a need to 
publicise.
Numerous studies have been done looking at graft patency and other effects.
Perhaps the most important is that of re-exposure. It si a foreign 
protein, and can engender an immunological response if used 
repeatedly. This was examined by Dietrich and colleagues in several 
reports. The latest of these is a review by Beierlein. (Beierlein, 
W., et al., Forty years of clinical aprotinin use: a review of 124 
hypersensitivity reactions. Ann Thorac Surg, 2005. 79(2): p. 741-8.)
Hence the warnings re test doses.


Any retrospective study has major limitations.  Questions that can be 
asked but not necessarily answered would include basic patient 
parameters, age, weight, sex, indication for surgery, ventricular 
function, no of  diseased vessels,  therapy planned, therapy 
performed, urgency, preoperative drugs including recent exposure to 
antiplatelet or anticoagulants, intra-operative data such as use of 
anticoagulants and other drugs, use of inotropes, blood transfusions 
intra- and post operatively, etc etc.
Selection of patients for use of any therapy is not always easily 
determined. Note our discussions on the HSF of complex cases. Many 
different views are given and that is the beauty of this forum. Any 
analysis of such data needs to take into account all these variables, 
but how do you account for the selective use of various agents.

Use of any of the antifibrinolytic drugs can be subject to many 
influences. As we have seen, one way of trying to even this up is the 
use of the propensity score and its many variations and indeed there 
are lots of them. A look at an overview by Gene Blackstone is useful 
especially to understand the limitations of such analyses. 
(Blackstone, E.H., Comparing apples and oranges. J Thorac Cardiovasc 
Surg, 2002. 123(1): p. 8-15.)

What must be done is an estimate of the risk of each complication 
occurring. Now if appropriate co-variates are collected beforehand, 
then with use of a propensity score it may be possible to determine a 
treatment effect. It also relies on a suitable number of patients 
with similar characteristics (e.g. level of risk of bleeding, renal 
failure and or death ) to be present in each group.  This was the 
deficiency (one of many) in the study by Mangano published earlier 
this year. (Mangano, D.T., I.C. Tudor, and C. Dietzel, The risk 
associated with aprotinin in cardiac surgery. N Engl J Med, 2006. 
354(4): p. 353-65.)

Cardiac Surgeons have several characteristics. One may be not reading 
long posts as they have a short attention span. But we also 
understand risk assessment and risk adjustment. Be certain that we 
are comparing apples with apples and Granny Smith with Granny Smiths 
not Red Delicious or Cooking.

How comparable are these groups ?  What is the 'acceptable rate' of 
each event when compared to a similar group in the literature? We 
will have to wait (again?)

Don't throw the baby out with the bath water!






The text of the FDA statement is included below. It is available from 
http://www.fda.gov/bbs/topics/NEWS/2006/NEW01472.html

FDA Statement Regarding New Trasylol Data
Since January, 2006, the Food and Drug Administration (FDA) has been 
conducting a safety review of Trasylol (aprotinin injection). The 
review was triggered by the results of two published research 
studies: one that reported an increase in the chance of kidney 
failure, heart attack and stroke in patients treated with Trasylol 
compared to those treated with other similar drugs, and the other 
that reported an increase in kidney dysfunction compared to another 
drug.  On September 21, 2006, FDA held a public meeting of the 
Cardiovascular and Renal Drugs Advisory Committee to discuss the 
safety and overall risk-benefit profile for Trasylol.  At that 
meeting, the committee discussed the findings from the two published 
observational studies, the Bayer worldwide safety review, and the FDA 
review of its own post-marketing database. 
On September 27, 2006, Bayer Pharmaceuticals told FDA that it had 
conducted an additional safety study of Trasylol.  The preliminary 
findings from this new observational study of patients from a 
hospital database reported that use of Trasylol may increase the 
chance for death, serious kidney damage, congestive heart failure and 
strokes.  FDA was not aware of these new data when it held the 
September 21, 2006, Advisory Committee meeting on Trasylol safety. 
 FDA is actively evaluating these new data and their implications for 
appropriate use of the drug.
While FDA conducts its evaluation of this new safety study, we 
recommend the following to healthcare providers:
	*	Physicians who use Trasylol should carefully monitor 
patients for the occurrence of toxicity, particularly to the kidneys, 
heart, or brain, and promptly report observed adverse event 
information to Bayer Pharmaceuticals, the drug manufacturer, or to 
the FDA MedWatch program, by phone (1-800-FDA-1088), by fax 
(1-800-FDA-0178), or by the Internet at 
http://www.fda.gov/medwatch/index.html.
	*	Physicians should consider limiting Trasylol use to 
those situations where the clinical benefit of reduced blood loss is 
essential to medical management of the patient and outweighs the 
potential risks.
These recommendations are similar to those provided in a February 8, 
2006, FDA Public Health Advisory and information sheets for health 
care professionals and patients which were based on the published 
studies mentioned above. See 
http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm.  
Trasylol works to slow or prevent bleeding, and is used to reduce 
blood loss and the need for blood transfusion during some types of 
heart surgeries.  Trasylol is made from the lung tissue of cattle. 
In the published studies and the recently supplied Bayer study, 
patients were not assigned at random to receive various treatments, 
but rather had their treatment chosen by their physician as part of 
their standard medical care.  Consequently, in these safety studies, 
patients receiving Trasylol may have had a higher chance for serious 
complications to begin with as compared to patients receiving no 
treatment or treatment with another drug intended to decrease 
bleeding.  This possibility complicates the assessment of whether the 
available studies show that Trasylol treatment, rather than other 
factors, increased the chance for serious kidney or heart 
complications.
The new study was done for Bayer by a contract research organization. 
Existing hospital data from 67,000 records of patients undergoing 
coronary artery bypass graft surgery were examined.  30,000 of the 
patients were treated with Trayslol and 37,000 were treated with 
alternate products.  Using complex epidemiological and statistical 
methods, the report suggested that patients receiving Trasylol were 
at increased risk for death, kidney failure, congestive heart failure 
and stroke. 
Healthcare providers and patients are encouraged to report adverse 
event information to FDA via the MedWatch program by phone 
(1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet at 
http://www.fda.gov/medwatch/index.html.
-- 
Ben Bidstrup FRACS FRCSEd FEBCTS
Consultant Cardiothoracic Surgeon