[HSF] Aprotinin
Ben Bidstrup
benjamin.bidstrup at bigpond.com
Tue Nov 21 14:03:15 EST 2006
>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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>>> >> __________________________________________________________________
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>>>>>>
>>>>>>
>>>>>> --
>>>>>> Ben Bidstrup FRACS FRCSEd FEBCTS
>>>>>> Consultant Cardiothoracic Surgeon
>>>>>> _______________________________________________
>>>>>> OpenHeart-L mailing list
>>>>>>
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>>>>>> -----------------------------------------
>>>>>
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>>>
>>>
>>>--
>>>Ben Bidstrup FRACS FRCSEd FEBCTS
>>>Consultant Cardiothoracic Surgeon
>>>_______________________________________________
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>>
>>
>
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>-----------------------------------------
--
Ben Bidstrup FRACS FRCSEd FEBCTS
Consultant Cardiothoracic Surgeon
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