[HSF] Aprotinin
psimha
prasannasimha at gmail.com
Tue Nov 21 08:45:44 EST 2006
That was me.
Prasanna
Ben Bidstrup wrote:
>> Are you referring to 200 % burns ?
>
>
> Yup! Sorry I meant 200% burns !!
>
>> Prasanna
>> Ben Bidstrup wrote:
>>> 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 TrasylolÅ 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 TrasylolÅ 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
>>>>>>> _______________________________________________
>>>>>>> OpenHeart-L mailing list
>>>>>>>
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>>>>
>>>> --
>>>> Ben Bidstrup FRACS FRCSEd FEBCTS
>>>> Consultant Cardiothoracic Surgeon
>>>> _______________________________________________
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>>>
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