[HSF] Aprotinin
Ben Bidstrup
benjamin.bidstrup at bigpond.com
Mon Nov 20 13:25:37 EST 2006
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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>> >>>>> 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>>
>> >>>>>
>> >>>>> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> >>>>> http://mmp.cjp.com/mailman/listinfo/openheart-l<http://
>> >>>>> mmp.cjp.com/mailman/listinfo/openheart-l<http://mmp.cjp.com/
>> >>>>> mailman/listinfo/openheart-l<http://mmp.cjp.com/mailman/listinfo/
>> >>>>> openheart-l>>
>> >>>>>
>> >>>>> All messages transmitted by the OpenHeart-L are subject to
>> >>>>> the policies and
>> >>>>> disclaimers posted at:
>> >>>>> http://www.hsforum.com/listdisclaim<http://www.hsforum.com/
>> >>>>> listdisclaim<http://www.hsforum.com/listdisclaim<http://
>> >> >>> www.hsforum.com/listdisclaim>>
>> >>>>> -----------------------------------------
>> >>>>>
>> >>>>>
>> >>>>>
>> >>>>
>> >>>> _______________________________________________
>> >>>> OpenHeart-L mailing list
>> >>>>
>> >>>> Send postings 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>>
>> >>>>
>> >>>> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> >>>> http://mmp.cjp.com/mailman/listinfo/openheart-l<http://
>> >>>> mmp.cjp.com/mailman/listinfo/openheart-l<http://mmp.cjp.com/
>> >>>> mailman/listinfo/openheart-l<http://mmp.cjp.com/mailman/listinfo/
>> >>>> openheart-l>>
>> >>>>
>> >>>> All messages transmitted by the OpenHeart-L are subject to
>> >>>> the policies and
>> >>>> disclaimers posted at:
>> >>>> http://www.hsforum.com/listdisclaim<http://www.hsforum.com/
> > >>>> listdisclaim<http://www.hsforum.com/listdisclaim<http://
>> >>>> www.hsforum.com/listdisclaim>>
>> >>>> -----------------------------------------
>> >>>> _______________________________________________
>> >>>> OpenHeart-L mailing list
>> >>>>
>> >>>> Send postings to:
>> >>>> OpenHeart-L at lists.hsforum.com<mailto:OpenHeart-
>> >>>> L at lists.hsforum.com>
>> >>>>
>> >>>> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> >>>> http://mmp.cjp.com/mailman/listinfo/openheart-l<http://
>> >>>> mmp.cjp.com/
>> >> >> mailman/listinfo/openheart-l>
>> >>>>
>> >>>> All messages transmitted by the OpenHeart-L are subject to the
>> >>>> policies and
>> >>>> disclaimers posted at:
>> >>>> http://www.hsforum.com/listdisclaim<http://www.hsforum.com/
>> >>>> listdisclaim>
>> >>>> -----------------------------------------
>> >>>>
>> >>>>
>> >>>>
>> >>>
>> >>> _______________________________________________
>> >>> OpenHeart-L mailing list
> > >>>
>> >>> Send postings to:
>> >>> OpenHeart-L at lists.hsforum.com<mailto:OpenHeart-
>> >>> L at lists.hsforum.com>
>> >>>
>> >>> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> >>> http://mmp.cjp.com/mailman/listinfo/openheart-l<http://
>> >>> mmp.cjp.com/mailman/listinfo/openheart-l>
>> >>>
>> >>> All messages transmitted by the OpenHeart-L are subject to
>> >>> the policies and
>> >>> disclaimers posted at:
>> >>> http://www.hsforum.com/listdisclaim<http://www.hsforum.com/
>> >>> listdisclaim>
>> >>> -----------------------------------------
>> >>> _______________________________________________
>> >>> OpenHeart-L mailing list
>> >>>
>> >>> Send postings to:
>> >>> OpenHeart-L at lists.hsforum.com
>> >>>
>> >>> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> >>> http://mmp.cjp.com/mailman/listinfo/openheart-l
>> >>>
>> >>> All messages transmitted by the OpenHeart-L are subject to the
>> >>> policies and
>> >>> disclaimers posted at:
>> >>> http://www.hsforum.com/listdisclaim
>> >>> -----------------------------------------
>> >>
>> >> _______________________________________________
>> >> OpenHeart-L mailing list
>> >>
>> >> Send postings to:
>> >> OpenHeart-L at lists.hsforum.com
>> >>
>> >> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> >> http://mmp.cjp.com/mailman/listinfo/openheart-l
>> >>
>> >> All messages transmitted by the OpenHeart-L are subject to the
>> >> policies and
>> >> disclaimers posted at:
>> >> http://www.hsforum.com/listdisclaim
>> >> -----------------------------------------
>> >>
>> >> _______________________________________________
>> >> OpenHeart-L mailing list
>> >>
>> >> Send postings to:
>> >> OpenHeart-L at lists.hsforum.com
>> >>
>> >> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> >> http://mmp.cjp.com/mailman/listinfo/openheart-l
>> >>
>> >> All messages transmitted by the OpenHeart-L are subject to the
>> >> policies and
>> >> disclaimers posted at:
>> >> http://www.hsforum.com/listdisclaim
>> >> -----------------------------------------
>> >
>> >
>> > --
>> > Ben Bidstrup FRACS FRCSEd FEBCTS
>> > Consultant Cardiothoracic Surgeon
>> > _______________________________________________
>> > OpenHeart-L mailing list
>> >
>> > Send postings to:
>> > OpenHeart-L at lists.hsforum.com
>> >
>> > To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> > http://mmp.cjp.com/mailman/listinfo/openheart-l
>> >
>> > All messages transmitted by the OpenHeart-L are subject to the
>> > policies and disclaimers posted at:
>> > http://www.hsforum.com/listdisclaim
>> > -----------------------------------------
>>
>> _______________________________________________
>> OpenHeart-L mailing list
>>
>> Send postings to:
>> OpenHeart-L at lists.hsforum.com
>>
>> To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>> http://mmp.cjp.com/mailman/listinfo/openheart-l
>>
>> All messages transmitted by the OpenHeart-L are subject to the policies
>and
>> disclaimers posted at:
>> http://www.hsforum.com/listdisclaim
>> -----------------------------------------
>
>_______________________________________________
>OpenHeart-L mailing list
>
>Send postings to:
> OpenHeart-L at lists.hsforum.com
>
>To UNSUBSCRIBE, to CHANGE email address, or to view archives:
>http://mmp.cjp.com/mailman/listinfo/openheart-l
>
>All messages transmitted by the OpenHeart-L are subject to the policies and
>disclaimers posted at:
>http://www.hsforum.com/listdisclaim
>-----------------------------------------
--
Ben Bidstrup FRACS FRCSEd FEBCTS
Consultant Cardiothoracic Surgeon
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