[HSF] Aprotinin
Nasser F. Abou'Seada
nfaabouseada at gmail.com
Sun Nov 19 19:23:45 EST 2006
Dear Claudia ....
I "concur with" you ..... what more can I say ....
NFA
> -----Original Message-----
> From: openheart-l-bounces at lists.hsforum.com [mailto:openheart-l-
> bounces at lists.hsforum.com] On Behalf Of claudia miranda
> Sent: Sunday, November 19, 2006 11:59 AM
> To: OpenHeart-L at lists.hsforum.com
> Subject: Re: [HSF] Aprotinin
>
> Dear all,
>
> I disclose no conflict of interest. Some observations, derived mostly from
> personal experience at a cardiovascular surgical ICU:
> Aprotinin is an useful drug, however, it is not for all patients, and I
> believe that it should be used only in patients classified as 'high risk
of
> bleeding" with normal renal function. In several studies and in my own
> experience it reduced post surgical bleeding, transfusions and rushing
back
> to the OR because of high drainage. This cannot be ignored, and that´s why
> aprotinin became so popular: it works for what it was designed. Can you do
a
> difficult bleeding risk case without it? yes, but it´s harder to do it,
and
> the patient will be at a higher risk of hypertransfusion and post surgical
> bleeding, depending on the surgeon´s expertise. This is my view. And I
share
> it with many, many cardiac surgeons, who are silently watching this
debâcle
> between EBM and what you see in the real theatre.
> We cannot accept irresponsible marketing from the pharm industry, but we
> also should not listen to the "cheaper is better" motto of those who want
to
> reduce costs of medical technology at the price of patient´s safety and
> quality of care. Every study comprises a BIAS, and the limitations of this
> specific study are visible, and well described in the body of the text. I
> interpret it as it is: some more data regarding on how to use aprotinin in
a
> responsible way. But never, never a good reason to banish the drug. I also
> observe that the paper present the data, but not necessarily I have to
agree
> with the authors´conclusions taken at the end of it. We must learn to
> criticize what we read in a healthier way - and read the whole paper, in
> between the lines, not conclusion and abstract only.
> If clinical complications and iatrogeny were reasons to abandon the use of
> any substance, thalidomide and warfarin would have already been banished
> from the face of earth.
> Re do´s, patients on heavy anticoagulation or recent antiplatelet therapy
> with pre-operative tests showing significant derangement of platelet
> function - like first aggregation wave suppression to epi or ADP triggered
> aggregometry, and with good kidneys, are a nice indication for aprotinin.
> The use outside of this cohort IMHO, could be aceptable in order to
control
> a clinically important status of fibrinolysis, which can make the
surgeon´s
> job much more difficult, but this maneuver should be monitored by some
> reliable method in order to achieve a favourable cost-benefit situation.
> Therefore, an accurate fibrinolysis diagnosis recquires
> thromboelastography, or the quick realization of tests such as euglobulin
> lysis time, plasmin-antiplasmin (PAP) complexes, D dimers, and others,
> which can be altered in the cardiac surgery scenario to some extent even
in
> the absence of clinically important fibrinolysis and must be interpreted
> according to the situation that the surgeon is actually facing on the
field.
>
> Fibrinolysis is usually underrated as a cause of bleeding, mostly because
> people do not have the proper diagnostic tools available and cannot make
> something about it in time.
>
> These are my two unimportant brazilian cents, sorry if I said something
that
> might hurt anybody
>
>
> Claudia Teles, MD
> Lamina Laboratories, Pro Cardiaco Hospital, Rio de Janeiro, Brazil
>
> 2006/11/19, Michael Firstenberg <msfirst at gmail.com>:
> >
> > 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 gma
> > >> 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:hgrmd@
> > >> 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:prasan
> > >>> 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 >
> > >>>>
> > >>>> _______________________________________________
> > >>>> 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<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>>
> > >>> -----------------------------------------
> > >>>
> ____________________________________________________________________
> > >>> ____
> > >>> Check out the new AOL. Most comprehensive set of free safety and
> > >>> security tools, free access to millions of high-quality videos
> > >>> from across the web, free AOL Mail and more.
> > >>> _______________________________________________
> > >>> 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<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
> -----------------------------------------
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