[HSF] Aprotinin
Ben Bidstrup
benjamin.bidstrup at bigpond.com
Mon Nov 20 11:16:58 EST 2006
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 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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--
Ben Bidstrup FRACS FRCSEd FEBCTS
Consultant Cardiothoracic Surgeon
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