[HSF] More Bad News About Trasylol
Jacob Lavee, MD
jaylavee at netvision.net.il
Sun Oct 1 16:20:51 EDT 2006
Ben,
I fully concur with your position regarding the continuation of selective
use of aprotinin in patients with high risk of postoperative bleeding.
Having had the honor to follow your seminal aprotinin papers with several of
my own: Lavee J, Raviv Z, Smolinsky A, Savion N, Varon D, Goor DA, Mohr R.
Platelet protection by low-dose aprotinin in cardiopulmonary bypass:
electron microscopic study.
Ann Thorac Surg. 1993 Jan;55(1):114-9.
Mohr R, Goor DA, Lusky A, Lavee J.
Aprotinin prevents cardiopulmonary bypass-induced platelet dysfunction.
A scanning electron microscope study.
Circulation. 1992 Nov;86(5 Suppl):II405-9.
Lavee J, Savion N, Smolinsky A, Goor DA, Mohr R.
Platelet protection by aprotinin in cardiopulmonary bypass: electron
microscopic study.
Ann Thorac Surg. 1992 Mar;53(3):477-81.
I certainly agree that we should not dismiss this powerful drug, with
which so much clinical experience has been gained globalwise, in spite of
its known side effects. For those who are rightfully worried about the side
effects of massive blood products transfusion, may I remind you of another
old-tested method to reduce the number of transfusions, namely transfusing
one unit of fresh whole blood which is equivalent in its haemostatic effect
to 10 platelet units:
Lavee J, Martinowitz U, Mohr R, Goor DA, Golan M, Langsam J,
Malik Z, Savion N.
The effect of transfusion of fresh whole blood versus platelet
concentrates after cardiac operations. A scanning electron microscope study
of platelet aggregation on extracellular matrix.
J Thorac Cardiovasc Surg. 1989 Feb;97(2):204-12.
Jay Lavee
Israel
----- Original Message -----
From: "Ben Bidstrup" <benjamin.bidstrup at bigpond.com>
To: <OpenHeart-L at lists.hsforum.com>
Sent: Sunday, October 01, 2006 1:55 AM
Subject: Re: [HSF] More Bad News About Trasylol
> >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
> _______________________________________________
> OpenHeart-L mailing list
>
> Send postings to:
> OpenHeart-L at lists.hsforum.com
>
> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
> http://mmp.cjp.com/mailman/listinfo/openheart-l
>
> All messages transmitted by the OpenHeart-L are subject to the policies
> and disclaimers posted at:
> http://www.hsforum.com/listdisclaim
> -----------------------------------------
>
> __________ NOD32 1.1784 (20060929) Information __________
>
> This message was checked by NOD32 antivirus system.
> http://www.eset.com
>
>
More information about the OpenHeart-L
mailing list