[HSF] Aprotinin
Ben Bidstrup
benjamin.bidstrup at bigpond.com
Tue Nov 21 07:41:15 EST 2006
If I and others actually knew why they 'withheld'
information then I would let you know. All I know
is what has been said and that is 2 employees
commissioned a group who undertook a study
using administrative databases to which they had
access as their sources. This is a retrospective,
observational study. What were the entry
criteria, what were the end points what were the
results, only they know and apparently what was
said to those wonderful peer reviewed medical
Journals we all read (well Hal does) the NY
Times and WSJ. These 2 employees now on gardening
leave, did NOT inform their superiors. I have
spoken with many of the medical people who like
me have been associated with Trasylol and Bayer
for many years and who were at the FDA meeting
and they all were blindsided by this. Was it a
deliberate act -- maybe by the employees, but not
by Bayer. As soon as they (Bayer people) found
out about it, they were as disturbed as everyone
else (including myself). Do I believe this? Yes.
I know and have worked with these people for over
a decade and I believe them. Would they put their
jobs at risk by concealing stuff. NO.
Will this 'study' add to our body of evidence.
Only time will tell. But as an observational
study with sourcing from administrative
databases, I can say that there are plenty of
potential problems. Look at this paper from
Michael Mack's group looking at comparisons
between administrative and clinical datasets. (It
will only show associations, not cause and
effect. If propensity scoring is used in some
way, it can only rely on collected co-variates.
There is the issue of allocation bias as I have
discussed earlier. We will have to wait and see
what the FDA who have all the data (unlike the
data from Mangano, who might appear top be a good
researcher but has chosen to violate a basic
principle of science of free access to the data
so that each and every reader can confirm
independently the analyses performed.)
Now, using a PC and something like SPSS, you can
get a series a statistically significant figures
on anything. I will quote directly from the FDA
transcript of the Advisory Board. Stan Young is
an independent statistician from the National
Institute of Statistical Science (p 102 of the
afternoon transcript)
"It's error only and not truth that shrinks from
inquiry. So, serious scientists should give up
the dataset. They should give it up to anyone
that wants it and it should be in a form that
people can build on and understand and further
the research that's in the dataset. I'll turn and
make a few comments on the analysis of complex
datasets. This is an area that I have worked on
for maybe 20 years or so. There, in these
particular datasets scientists tests here
responded, commented, there are multiple response
questions. So there's not one question here. The
point of the human mind is we focus on one thing
at a time. But in the sweep through this dataset,
lots of questions are being asked. There are
fairly standard ways to adjust analysis for
asking multiple questions and they should be
done. Responses can be combined in numerous ways.
Sort of the off-the-wall kind of a comment is
attributed to Johnny van Noyman. You give me four
parameters and I can fit an elephant. You give me
five and I can make him wiggle his trunk. Okay?
So with multiple responses and being able to
combine them in multiple ways, it's no trick at
all to get P values of .001, no trick at all. Any
graduate student given random data and a few
hours on the computer can produce results of that
sort. P values can be moved many orders of
magnitude through analysis, manipulations. In
exploratory analysis, P values and risk ratios
essentially have no meaning."
Available from
http://www.fda.gov/ohrms/dockets/ac/cder06.html#CardiovascularRenal
In essence, data dredging in a post hoc manner
(or rather in the absence of an a priori plan for
analysis) can tell you almost anything. At best
it will point you in the direction of a future
study to answer a specific question. To look at
the DES issue, how many times have we seen a
subgroup analysis (post hoc) which then is
extrapolated to a much wider population and the
cardiologists put their hands on their hearts and
state 'Look at the evidence.'
Here endeth the lesson according to the Book of Ben, Ch 4, vs 7.
Disclosure: Associated with Trasylol for 21
years and still supporting my research findings!
I have been the recipient of funds from Bayer to
support my research in the past and have acted
as a speaker and consultant for which I have
been at times remunerated.
I have read that news article. It is the same
issue. Risk vs benefit. HM of those soldiers
survive the initial insult only to die of later
complications. Novo 7 may get them over the first
hurdle whereas a few years ago they would not
have got out of the initial receiving aid
station. These guys are being blasted by stuff
causing such massive trauma that cardiac surgery
on bypass is like a walk in the park. These
soldiers are truly having the 'third degree
burns' to which Prasanna or Hal (correct me if I
am wrong ) referred a few months ago.
>Ben,
>Thanks for the link. FDA panel approved to keep the drug based on the
>information here. What bothers me is why Bayer withheld information
>about another study from FDA panel and announced within days after this.
>I am afraid that this kind of behavior will get this drug off the
>market. I still think Aprotinin is a very useful drug with some risk and
>I continue to use it in select patients until it is taken off the
>market.
>
>While the forum members were discussing the Aprotinin and Novoseven I
>found an article in our Local news paper.
>Here is the link for our local Newspaper article (Last Saturday) about
>NOVOSEVEN(r)
>
>http://www.kentucky.com/mld/kentucky/living/health/16047224.htm
>
>
>Chand
>
>
>-----Original Message-----
>From: openheart-l-bounces at lists.hsforum.com
>[mailto:openheart-l-bounces at lists.hsforum.com] On Behalf Of Ben Bidstrup
>Sent: Sunday, November 19, 2006 9:26 PM
>To: OpenHeart-L at lists.hsforum.com
>Subject: RE: [HSF] Aprotinin
>
>http://www.fda.gov/ohrms/dockets/ac/cder06.html#CardiovascularRenal
>
>> > do you have a link?
>>
>>NFA
>>
>>> -----Original Message-----
>>> From: openheart-l-bounces at lists.hsforum.com [mailto:openheart-l-
>>> bounces at lists.hsforum.com] On Behalf Of Michael Firstenberg
>>> Sent: Sunday, November 19, 2006 7:20 PM
>>> To: OpenHeart-L at lists.hsforum.com
>>> Subject: Re: [HSF] Aprotinin
>>>
>>> do you have a link?
>>>
>>> michael
>>>
>>>
>>> On Nov 19, 2006, at 7:16 PM, Ben Bidstrup wrote:
>>>
>>> > You might find it interesting to read the FDA transcript of the
>>> > Cardiovascular and Renal Advisory Board 21 September.
>>> >
>>> >> Please don't disparage Dennis Mangano too much. He is, or at
>>> >> least was, a
>>> >> very capable clinical cardiac anesthesiologist and is fully
>>> >> cognizant of all
>>> >> of the issues regarding intra-operative bleeding and post-
>>> >> operative care of
>>> >> cardiac surgery patients. That explains Dennis' consistent
>>> >> ability to focus
>>> >> and publish provocatively on real life issues that confronting
>>> >> surgeons and
>>> >> anesthesiologists on a day to day basis. The methodology of his
>>> >> paper in
>>> >> the NEJM is open to question. Dr. Mangano's credentials are not!
>>> >> Fraser Keith
>>> >>
>>> >> -----Original Message-----
>>> >> From: openheart-l-bounces at lists.hsforum.com
>>> >> [mailto:openheart-l-bounces at lists.hsforum.com] On Behalf Of
>Michael
>>> >> Firstenberg
>>> >> Sent: Sunday, November 19, 2006 10:18 AM
>>> >> To: OpenHeart-L at lists.hsforum.com
>>> >> Subject: Re: [HSF] Aprotinin
>>> >>
>>> >> If I recall Mangino is not a surgeon - in fact is he not an
>>> >> anesthesiologist, as are many of the people who recently write
>>> >> these articles about "bad cardiac drugs"? Has he actually had to
>>> >> stand at the foot of a bed or in the OR for countless hours
>>> >> watching patient bleed to death and deal first hand with the
> >> >> consequences of massive transfusions. Yes, renal failure and
>>> >> dialysis is bad bad bad - but compare that with right heart
>>> >> failure/ARDS/massive pressor requirements/etc from excessive
>>> >> bleeding (and the hypotension and associated ATN/renal failure
>>> >> anyhow). My guess is he is home in bed all nice an cozy with his
> >> >> pager off at the end of his shift.
>>> >>
>>> >> -michael
>>> >>
>>> >>
>>> >>
>>> >>
>>> >> On Nov 19, 2006, at 2:24 AM, Ani Anyanwu wrote:
>>> >>
>>> >>> Prasanna
>>> >>>
>>> >>> Well many would I suspect call it unbridled.
>>> >>>
>>> >>> The following would generally receive aprotinin in my
>institution
>>> >>> 1) reoperations
>>> >>> 2) operations on the aortic arch or descending aorta
>>> >>> 3) transplant and VAD procedures
>>> >>> 4) operations on patients on clopidogrel
>>> >>> 5) combined valvular and CABG
>>> >>> 6) Patients with renal impairment
>>> >>> 7) Patients where ability to tolerate transfusion or bleeding
>>> >>> complications is thought to be marginal including - most
>>> >>> patients aged 70 or above, patients with severe lung disease,
>>> >>> poor LV function, severe pulmonary hypertension, multiple
>>> >>> comorbidity etc. Certainly almost all octogenrians would get
>>> >>> aprotinin - even for CABG.
>> > >>> 8) Paradoxically, young patients in their 20s or 30s (where
>>> >>> avoidance of blood transfusion should be the goal in all
>patients)
>>> >>> 9) Multiple valvular procedures (excluding tricuspid valve)
>>> >>> 10) cases with anticipated bypass run more than 3 hours
>>> >>> (including complex mitral repairs)
>>> >>>
>>> >>> As you can see there is not much left - so maybe it is
>>> >>> unbridled! As you implied we obviously would not use it for an
>>> >>> ASD or isolated AVR, but these constitute a small minority of
>>> >>> our procedures. Personally I would use it for practically every
>>> >>> operation - including all CABGs - but that is a personal
>opinion
>>> >>> as I believe there are non-hematological benefits of the drug
>>> >>> and like you
>>> >> > strongly believe in blood conservation. I do not have any
>>> >> interests
>>> >>> or links to industry.
>>> >>>
>>> >>> Actually Ben brought up something that I had never thought of -
>> > >>> correct me if I am wrong but Aprotinin is the only agent
>>> >>> licensed as a blood conservation agent for heart surgery?
>>> >>>
>>> >>> Ani
>>> >>> ----- Original Message -----
>>> >>> From: psimha<mailto:prasannasimha at gmail.com>
>>> >>> To: OpenHeart-L at lists.hsforum.com<mailto:OpenHeart-
>>> >>> L at lists.hsforum.com>
>>> >>> Sent: Sunday, November 19, 2006 12:00 AM
>>> >>> Subject: Re: [HSF] Aprotinin
>>> >>>
>>> >>>
>>> >>> Ani - are you really using it "unbridled" or liberally ? Do
>>> >>> you use it
>>> >>> for an ASD or for a straight forward valve replacement ? or
>>> >>> any other
>>> >>> case with a short bypass run ?
>>> >>> I did not say I will not use it in a redo - in fact if you
>>> >>> note my
>>> >>> original post I said I did use it in redo's ?
>>> >>> And Yes , I believe very strongly in blood conservation and
>>> >>> believe that
>>> >>> Aprotinin is one (and not the only ) cog in the wheel.
>>> >> > Prasanna
>>> >>>
>>> >>> Ani Anyanwu wrote:
>>> >>>> Prasanna
>>> >>>>
>>> >>>> We use aprotinin in an unbridled way and are certainly yet to
>>> >>>> see this price.
>>> >>>> - we have no more an incidence of renal failure than other
>>> >>>> institutions have (this we know because incidence of dialysis
>>> >>>> postop in all New York Hospitals is tracked by the State
>>> >>>> Department of Health)
>>> >>>> - we have no suggestion of an increase in early vein graft
>>> >>>> thrombosis (this should transform into higher periop MI and
>>> >>>> mortality, our CABG mortality rate has remained around 1.5%
>last
>>> >>>> 3 years)
>>> >>>> - we have not experienced any adverse events that caused us to
>>> >>>> be concerned about its use, except fatal thrombosis in 2
>>> >>>> patients with Factor V Lieden deficiency having circulatory
> >> >>>> arrest so we now routinely screen for this defect in all
>>> >>>> circulatory arrest cases.
>>> >>>>
>>> >>>> The price we are paying is a low incidence of transfusion of
>>> >>>> blood products and a low re-exploration rate (<2% last 2 years
>>> >>>> even with 18% being redos and almost 20% aortic cases). Maybe
> >> >>>> there are other unknown adverse effects which will catch up
>>> >>>> with us, but for know they are unknown (and we wont be
>>> >>>> responsible; remember it is the drug companies not doctors
>>> >>>> being sued for COX2 inhibitors).
>>> >>>>
>>> >>>> Maybe when Mangano is bored he might do another study, and
>>> >>>> then what will you do? For those who use Amicar, how do we
>>> >>>> really know it is any safer - the drug is not even licensed
>for
>>> >>>> human use in many European countries. Perhaps even his next
>>> >>>> study will be on morbidity of plasma and platelet
>>> >>>> transfusions....then what will we do?
>>> >>>>
>>> >>>> Ani
>>> >>>> ----- Original Message -----
>>> >>>> From:
>>> >>>>
>prasannasimha<mailto:prasannasimha at gmail.com<mailto:prasannasimha at g
>>> >>>> ma
>>> >>>> il.com>>
>>> >>>> To: OpenHeart-L at lists.hsforum.com<mailto:OpenHeart-
>>> >>>> L at lists.hsforum.com<mailto:OpenHeart-
>>> >>>> L at lists.hsforum.com<mailto:OpenHeart-L at lists.hsforum.com>>
>>> >>>> Sent: Saturday, November 18, 2006 9:37 PM
>>> >>>> Subject: Re: [HSF] Aprotinin
>>> >>>>
>>> >>>>
>>> >>>> The thing I want to say is that be it Vioxx /
>Aprotinin/blood/
>> > >>>> Oxygen -
>>> >>>> they are all drugs and have effects and side effects. The
>>> >>>> present mess
>>> >>>> that the pharmacological companies are in is just because of
>>> >>>> their
>>> >>>> unbridled enthusiasm (or greed) to ,make a quick buck and it
>>> >>>> backfires
>>> >>>> on them. COX2 Inhibitors have a specific role unfortunately
>>> >>>> I even saw
>>> >>>> my dentist prescribing it for tooth pain !! Who marketed it
>>> >>>> to him as a
>>> >>>> good NSAID ? I told him about the literature and my
>>> >>>> concerns (this was
>>> >>>> prior to Vioxx) . They were trying to market Valdecoxib for
>>> >>>> post cardiac
>>> >>>> surgery pain !!_ and I told them you should not be doing
>that
>>> >>>> - but did
>>> >>>> they listen ? and bang in a few months a controversy breaks
>>> >>>> out. The
>>> >>>> wife of colleague of mine was taking valdecoxib sample (she
>> > >>>> is a Doctor
>>> >>>> too) as the sample was around and the premenopausal lady
>>> >>>> ended up with a
>>> >>>> coronary thrombosis !!
>>> >>>> Every drug has a role and an indication based on good
>>> >>>> clinical judgment
>>> >> >> - unfortunately we pay the price when its use is unbridled.
>>> >>>> Prasanna
>>> >>>>
>>> >>>>
>>> hgrmd at aol.com<mailto:hgrmd at aol.com<mailto:hgrmd at aol.com<mailto:hgrm
>>> >>>> d@
>>> >>>> aol.com>> wrote:
>>> >>>>> Prasanna and Ajit,
>>> >>>>> At the risk of great bodily harm from Ben, Ani, and others,
>>> >>>>> I again think the use of aprotinin should be limited as much
>>> >>>>> as possible. I know there are cases where the benefit
>>> >>>>> seemingly outweighs the risk. However, the mounting
>>> >>>>> literature against it is becoming increasingly compelling.
>In
>>> >>>>> addition, my own impression, made years before any of this
>>> >>>>> came out, was that the drug increased the risk of ATN. I'm
>>> >>>>> also convinced that this has the potential to be the Vioxx of
>>> >>>>> cardiac surgery. All I can say is you guys who continue to
>>> >>>>> indiscriminantly use it have got some really big ones.
>>> >>>>> Hal
>>> >>>>>
>>> >>>>>
>>> >>>>> -----Original Message-----
>>> >>>>> From:
>>> >>>>>
>prasannasimha at gmail.com<mailto:prasannasimha at gmail.com<mailto:pras
>>> >>>>> an
>>> >>>>> nasimha at gmail.com<mailto:prasannasimha at gmail.com>>
>>> >>>>> To: OpenHeart-L at lists.hsforum.com<mailto:OpenHeart-
>>> >> >>> L at lists.hsforum.com<mailto:OpenHeart-
>>> >>>>> L at lists.hsforum.com<mailto:OpenHeart-L at lists.hsforum.com>>
>>> >>>>> Sent: Sat, 18 Nov 2006 1:00 PM
> >> >>>>> Subject: Re: [HSF] Aprotinin
>>> >>>>>
>>> >>>>>
>>> >>>>> Very Sorry used Aprotinin on my redo - can't help using it
>>> >>>>> selectively !!
>>> >>>>> Prasanna
>>> >>>>>
>>> >>>>> Ajit Damle wrote:
>>> >>>>>
>>> >>>>>> Journal club critique >
>>> >>>>>> A disheartening story: Aprotinin in cardiac surgery >
> >> >>>>>> Lien M, Milbrandt E
>>> >>>>>>
>>> >>>>>> Critical Care, 2006 10:317 ( 8 November 2006 )
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Journal club critique
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> A disheartening story: Aprotinin in cardiac surgery
>>> >>>>>>
>>> >>>>>> Marcus Lien1 and Eric B Milbrandt2 >
>>> >>>>>> 1Clinical Fellow, Department of Critical Care Medicine,
>>> >>>>>> University of
>>> >>>>>> Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
>>> >>>>>>
>>> >>>>>> 2Assistant Professor, Department of Critical Care Medicine,
>>> >>>>>> University of
>>> >>>>>> Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Critical Care 2006, 10:317 doi:10.1186/cc5072
>>> >>>>>>
>>> >>>>>>
>>> >>>>>>>
>>> >>>>>>>
>>> >>>>>> Evidence based medicine journal club critique edited by E B
>>> >>>>>> Milbrant
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> The electronic version of this article is the complete one
>>> >>>>>> and can be found
>>> >>>>>> online at: http://ccforum.com/content/10/6/317<http://
>>> >>>>>> ccforum.com/content/10/6/317<http://ccforum.com/content/
>>> >>>>>> 10/6/317<http://ccforum.com/content/10/6/317>>
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Published 8 November 2006 >
>>> >>>>>>
>>> >>>>>> C 2006 BioMed Central Ltd
>>> >>>>>>
>>> >>>>>> Citation
>>> >>>>>>
>>> >>>>>> Mangano DT, Tudor IC, Dietzel C: The risk associated with
>> > >>>>>> aprotinin in
>>> >>>>>> cardiac surgery. N Engl J Med 2006, 354:353-365 [1].
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Background
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> The majority of patients undergoing surgical treatment for
>ST-
>>> >>>>>> elevation
>>> >>>>>> myocardial infarction receive antifibrinolytic therapy to
>>> >>>>>> limit blood loss.
>>> >>>>>> This approach appears counterintuitive to the accepted
>>> >>>>>> medical treatment of
>>> >>>>>> the same condition - namely, fibrinolysis to limit
>>> >>>>>> thrombosis. Despite this
>>> >>>>>> concern, no independent, large-scale safety assessment has
>>> >>>>>> been undertaken.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Methods
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Design and setting
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Prospective observational cohort study in 69 institutions in
>>> >>>>>> North and South
>>> >>>>>> America, the Middle East, Europe, and Asia.
>>> >>>>>>
>> > >>>>>>
>>> >>>>>> Subjects
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> 4374 patients undergoing coronary-artery revascularization.
>>> >>>>>> All patients
>>> >>>>>> were >18 years old and completed a pre-surgery interview.
>>> >>>>>> Patients were
>>> >>>>>> classified as undergoing primary surgery (no previous heart
>>> >>>>>> surgery and no
>>> >>>>>> other surgery besides a coronary artery bypass graft), or
>>> >>>>>> complex surgery
>>> >>>>>> (all other surgery).
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Intervention
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> None.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Measurements
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> The authors prospectively assessed three agents (aprotinin
>>> >>>>>> [1295 patients],
>>> >>>>>> aminocaproic acid [883], and tranexamic acid [822]) as
>>> >>>>>> compared with no
>>> >>>>>> agent (1374 patients) with regard to serious cardiovascular,
>>> >> >>>> renal, and
>>> >>>>>> cerebrovascular outcomes by propensity and multivariable
>>> >>>>>> methods.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Results
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> In propensity-adjusted, multivariable logistic regression
>(C-
>>> >>>>>> index, 0.72),
>>> >>>>>> use of aprotinin was associated with a doubling in the risk
>>> >>>>>> of renal failure
>>> >>>>>> requiring dialysis among patients undergoing complex
>coronary-
>>> >>>>>> artery surgery
>>> >>>>>> (odds ratio, 2.59; 95 percent confidence interval, 1.36 to
> >> >>>>>> 4.95) or primary
>>> >>>>>> surgery (odds ratio, 2.34; 95 percent confidence interval,
>>> >>>>>> 1.27 to 4.31).
>>> >>>>>> Similarly, use of aprotinin in the latter group was
>>> >>>>>> associated with a 55
>>> >>>>>> percent increase in the risk of myocardial infarction or
>>> >>>>>> heart failure (P <
> >> >>>>>> 0.001) and a 181 percent increase in the risk of stroke or
>>> >>>>>> encephalopathy (P
>>> >>>>>> = 0.001). Neither aminocaproic acid nor tranexamic acid was
>>> >>>>>> associated with
>>> >>>>>> an increased risk of renal, cardiac, or cerebral events.
>>> >>>>>> Adjustment
>>> >>>>>> according to propensity score for the use of any one of the
>>> >>>>>> three agents as
>>> >>>>>> compared with no agent yielded nearly identical findings.
>All
>>> >> >>>> the agents
>>> >>>>>> reduced blood loss.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Conclusion
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> The association between aprotinin and serious end-organ
>>> >>>>>> damage indicates
>>> >>>>>> that continued use is not prudent. In contrast, the less
>>> >>>>>> expensive generic
>>> >>>>>> medications aminocaproic acid and tranexamic acid are safe
>>> >>>>>> alternatives.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>>>
>>> >>>>>> The medical and surgical approaches to acute ST-elevation
>>> >>>>>> myocardial
>>> >>>>>> infarction present an interesting paradox. The medical
>>> >>>>>> approach focuses on
>>> >>>>>> fibrinolytic therapy. Due to concerns over bleeding, the
>>> >>>>>> surgical approach
>>> >>>>>> avoids fibrinolytic agents and instead uses agents that
>>> >>>>>> mitigate bleeding,
>>> >>>>>> so called antifibrinolytic agents, which include aprotinin,
>>> >>>>>> aminocaproic
>>> >>>>>> acid, and tranexamic acid. These agents were generally
>>> >>>>>> considered safe based
>>> >>>>>> on a number of secondary analyses of studies that were not
>>> >>>>>> primarily
>>> >>>>>> intended to assess safety. These relatively small studies
>> > >>>>>> were underpowered
>>> >>>>>> to detect adverse events and did not involve head-to-head
>>> >>>>>> comparisons of the
>>> >>>>>> commonly used antifibrinolytic agents. Animal studies
>>> >>>>>> suggest that these
>>> >>>>>> agents have the potential to cause ischemic damage to
>>> >>>>>> multiple organ systems
>>> >>>>>> and small, largely single-center studies have suggested
>>> >>>>>> increased graft
>>> >>>>>> thrombosis and renal dysfunction [2-6]. Ideally, the safety
>>> >>>>>> of these agents
>>> >>>>>> would be compared in a large, multi-center, randomized
>>> >>>>>> controlled trial.
>>> >>>>>> However, because their use is embedded in practice and
>>> >>>>>> because regulatory
>>> >>>>>> approval of these agents differs by country, conducting such
>>> >>>>>> a trial will be
>>> >>>>>> difficult if not impossible.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> To address the safety of these agents for cardiopulmonary
>> > >>>>>> bypass surgery,
>>> >>>>>> Mangano and colleagues [1] conducted a large, prospective,
>>> >>>>>> observational
>>> >>>>>> cohort assessing aprotinin, aminocaproic acid, and
>>> >>>>>> tranexamic acid as
>>> >>>>>> compared to no agent in 4374 patients undergoing
>>> >>>>>> revascularization. Because
>>> >>>>>> this was a prospective study, the authors were able to
>>> >>>>>> collect a wealth of
>>> >>>>>> clinical information, including approximately 7500 data
>>> >>>>>> fields per patient.
>>> >>>>>> This permitted consideration of variables that might
>>> >>>>>> influence both choice
>>> >>>>>> of antifibrinolytic agent and clinical outcome. The authors
>>> >>>>>> used a
>>> >>>>>> propensity score based on 45 treatment-selection covariates
>and
>>> >>>>>> multivariable modeling to control for baseline differences
>>> >>>>>> between groups.
>>> >>>>>> In doing so, they found that aprotinin, but not aminocaproic
>>> >>>>>> acid or
>>> >>>>>> tranexamic acid, was associated with serious cardiovascular,
>>> >>>>>> renal, and
>>> >>>>>> cerebrovascular adverse events. Furthermore, a dose-response
>>> >>>>>> relationship
> >> >>>>>> was demonstrated, strengthening the inference of causality.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> The main weakness of this study is that the authors failed
>to
>>> >> >>>> report details
>>> >>>>>> of the surgery itself, such as whether the surgery was on
>>> >>>>>> vs. off-pump, time
>>> >>>>>> on pump, and number of vessels bypassed. These variables are
> >> >>>>>> likely to
>>> >>>>>> influence not only choice of antifibrinolytic agent but also
>>> >>>>>> outcome, and
>>> >>>>>> are, therefore, a source of indication bias that could
>>> >>>>>> reflect unfavorably
>>> >>>>>> on aprotinin.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Based on the results of this study and those of another
>>> >>>>>> observational study
>>> >>>>>> suggesting renal toxicity [7], the United States Food and
>Drug
>>> >>>>>> Administration (FDA) held an advisory committee meeting
>>> >>>>>> September 21, 2006
>>> >>>>>> to consider the cardiovascular safety of aprotinin. Because
>>> >>>>>> of concerns
>>> >>>>>> about the methodology of the study by Mangano and colleagues
>>> >>>>>> and because it
>>> >>>>>> was the only study to suggest cardiovascular adverse events
>>> >>>>>> [8], the
>>> >>>>>> advisory committee concluded that there was insufficient
>>> >>>>>> evidence to support
>>> >>>>>> changing the cardiovascular safety labeling of the drug.
>>> >>>>>> However, just six
>>> >>>>>> days after the committee met, it was revealed that the
>>> >>>>>> drug's manufacturer,
>>> >> >>>> Bayer, had preliminary results from an observational study
>of
>>> >>>>>> 67,000 cardiac
>>> >>>>>> bypass patients that suggested aprotinin was associated with
>>> >>>>>> increased risk
>>> >>>>>> of death, renal dysfunction, congestive heart failure, and
>>> >>>>>> stroke [9]. The
>>> >>>>>> FDA subsequently issued a statement indicating it was
>unaware
>>> >>>>>> of this study
>>> >>>>>> when the advisory committee met and that it is evaluating
>>> >>>>>> the results of
>>> >>>>>> this study and the potential implications for the use of
>>> >>>>>> aprotinin [10]. In
>>> >>>>>> the mean time, the FDA suggests that physicians who use
>>> >>>>>> aprotinin should
>> > >>>>>> carefully monitor patients for the occurrence of toxicity,
>>> >>>>>> particularly to
>>> >>>>>> the kidneys, heart, or brain, and promptly report observed
>>> >>>>>> adverse events.
>>> >>>>>> They go on to recommend that physicians should consider
>>> >>>>>> limiting aprotinin
>>> >>>>>> 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.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Recommendation >
>>> >>>>>>
>>> >>>>>> The weight of evidence suggests that aprotinin increases the
>>> >>>>>> risk for a poor
>>> >>>>>> outcome among patients undergoing cardiac operations. Not
>>> >>>>>> only is this drug
>>> >>>>>> very expensive, it seems to be toxic. Although the risk of
>>> >>>>>> excessive
>>> >>>>>> bleeding is certainly a cause for concern in certain
>>> >>>>>> patients, and treatment
>> > >>>>>> with aprotinin can decrease blood loss in selected
>patients,
>>> >>>>>> data are
>>> >>>>>> lacking to show that administration of this agent actually
>>> >>>>>> improves
>>> >>>>>> survival.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> Competing interests
>>> >>>>>>
>>> >>>>>> The authors declare that they have no competing interests.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>>>
>>> >>>>>> 1. Mangano DT, Tudor IC, Dietzel C: The risk associated with
>>> >>>>>> aprotinin in
>>> >>>>>> cardiac surgery.
>>> >>>>>>
>>> >>>>>> N Engl J Med 2006, 354:353-365. >
>>> >>>>>>
>>> >>>>>> 2. Cosgrove DM III, Heric B, Lytle BW, Taylor PC, Novoa R,
>>> >>>>>> Golding LA,
>>> >>>>>> Stewart RW, McCarthy PM, Loop FD: Aprotinin therapy for
>>> >>>>>> reoperative
>>> >>>>>> myocardial revascularization: a placebo-controlled study.
>>> >>>>>>
>>> >>>>>> Ann Thorac Surg 1992, 54:1031-1036.
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> 3. D'Ambra MN, Akins CW, Blackstone EH, Bonney SL, Cohn LH,
> >> >>>>>> Cosgrove DM,
>>> >>>>>> Levy JH, Lynch KE, Maddi R: Aprotinin in primary valve
>>> >>>>>> replacement and
>>> >>>>>> reconstruction: a multicenter, double-blind, placebo-
>>> >>>>>> controlled trial.
>>> >>>>>>
>>> >>>>>> J Thorac Cardiovasc Surg 1996, 112:1081-1089
>>> >>>>>>
>>> >>>>>>
>>> >>>>>> 4. Feindt PR, Walcher S, Volkmer I, Keller HE, Straub U,
> >> >>>>>> Huwer H, Seyfert
>>> >>>>>> UT, Petzold T, Gams E: Effects of high-dose aprotinin on
>>> >>>>>> renal function in
>>> >>>>>> aortocoronary bypass grafting.
>>> >>>>>>
>>> >>>>>> Ann Thorac Surg 1995, 60:1076-1080 >
>>> >>>>>>
>>> >>>>>> 5. Sundt TM III, Kouchoukos NT, Saffitz JE, Murphy SF,
>>> >>>>>> Wareing TH, Stahl
>>> >>>>>> DJ: Renal dysfunction and intravascular coagulation with
>>> >>>>>> aprotinin and
>>> >>>>>> hypothermic circulatory arrest.
>>> >> >>>>
>>> >>>>>> Ann Thorac Surg 1993, 55:1418-1424 >
>>> >>>>>>
>>> >>>>>> 6. Umbrain V, Christiaens F, Camu F: Intraoperative coronary
>>> >>>>>> thrombosis:
>>> >>>>>> can aprotinin and protamine be incriminated?
>>> >>>>>>
>>> >>>>>> J Cardiothorac Vasc Anesth 1994, 8:198-201 >
>>> >>>>>>
>>> >>>>>> 7. Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam
>>> >>>>>> M, Hamdy A,
>>> >>>>>> Wijeysundera DN, Fedorko L, Yau TM: A propensity score case-
>>> >>>>>> control
>>> >>>>>> comparison of aprotinin and tranexamic acid in
>high-transfusion-
>>> >>>>>> risk cardiac
>>> >>>>>> surgery.
>>> >>>>>>
>>> >>>>>> Transfusion 2006, 46:327-338 >
>>> >>>>>>
>>> >>>>>> 8. Hughes S: Aprotinin safety again in spotlight as new
>>> >>>>>> study suggests
>>> >>>>>> increased cardiac events.
>>> >>>>>>
>>> >>>>>> http://www.medscape.com/viewarticle/545400<http://
>>> >>>>>> www.medscape.com/viewarticle/545400<http://www.medscape.com/
>>> >>>>>> viewarticle/545400<http://www.medscape.com/viewarticle/
>>> >>>>>> 545400>> >
>>> >>>>>> October 2, 2006 >
>>> >>>>>> 9. Harris G: FDA says Bayer failed to reveal drug risk
>study.
>>> >>>>>>
>>> >>>>>> [http://www.nytimes.com/2006/09/30/health/30fda.html] New
>>> >>>>>> York Times >
>>> >>>>>>
>>> >>>>>> 10. US Food and Drug Administration: FDA Public Health
>>> >>>>>> Advisory: Aprotinin
>>> >>>>>> Injection (marketed as Trasylol).
>>> >>>>>>
>>> >>>>>>
>[http://www.fda.gov/cder/drug/advisory/aprotinin20060929.htm] >
>>> >> >>>> September 29, 2006 >
>> > >>>>>>
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>>> > --
>>> > Ben Bidstrup FRACS FRCSEd FEBCTS
>>> > Consultant Cardiothoracic Surgeon
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