[HSF] Aprotinin
prasannasimha
prasannasimha at gmail.com
Sun Nov 19 22:34:55 EST 2006
I was waiting for you Claudia !! Clap Clap. (Can't get a smiley for that)
"Selective rational use" seems to be the need of the hour.
Prasanna
claudia miranda wrote:
> 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 >
>> >>>>
>> >>>> _______________________________________________
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>> >>> -----------------------------------------
>> >>> ____________________________________________________________________
>> >>> ____
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>> >>>
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>> >>> http://mmp.cjp.com/mailman/listinfo/openheart-l<http://
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>> >>> 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>>
>> >>> -----------------------------------------
>> >>>
>> >>>
>> >>>
>> >>
>> >> _______________________________________________
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>> >>
>> >> 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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