[HSF] Aprotinin

Tue Nov 21 07:57:51 EST 2006

Are you referring to 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 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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>>>> >>>>> -----------------------------------------
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>> >> __________________________________________________________________
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>>>> >
>>>> >
>>>> > --
>>>> > Ben Bidstrup FRACS FRCSEd FEBCTS
>>>> > Consultant Cardiothoracic Surgeon
>>>> > _______________________________________________
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>>>> >
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>>>> _______________________________________________
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>>
>> -- 
>> Ben Bidstrup FRACS FRCSEd FEBCTS
>> Consultant Cardiothoracic Surgeon
>> _______________________________________________
>> OpenHeart-L mailing list
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>> _______________________________________________
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>> -----------------------------------------
>
>