[HSF] Aprotinin
Nasser F. Abou'Seada
nfaabouseada at gmail.com
Sun Nov 19 19:35:26 EST 2006
> 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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> >>>>> 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
> -----------------------------------------
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