[HSF] Aprotinin
Michael Firstenberg
msfirst at gmail.com
Sun Nov 19 17:41:17 EST 2006
Recently we have been using thromboelastrograms for managing
anticoagulation in complex patients - and as I/we work with them more
and more one thing that have become is how little we (not to mention
hematologist) know about the clotting/bleeding - let alone how to
control it. How many times have you been told "the ACT is below
baseline" only to see blood welling up without a clot in sight. How
often do you take people back for bleeding to find nothing?
-michael
On Nov 19, 2006, at 4:55 PM, Ben Bidstrup wrote:
> Claudia,
> What a refreshing view. You mention EBM. This is the crux. An
> observational study provides only an association, not cause and
> effect. Do some Googling on Bias in Statistics (Put Austin in as an
> author.) It provides, as you suggest that possible need for further
> evaluation. However, one must also look for example at the Concord
> statement. If the findings of a study are at variance with those of
> the general body of evidence, then an explanation is warranted. Is
> this truly a new finding that has been overlooked in the past, or
> is it an anomaly that the study methods have permitted.
> Let us look at renal dysfunction.
> How do we define it?
> Is it:
> A rise on serum creatinine above a certain level ? Many would say a
> doubling of se creatinine or a rise of >38 umol/l (0.5 mg/dl)
> indicates renal dysfunction. Many renal physicians tell me that se
> creatinine alone is not sufficient.
> Is it a new incidence of renal dialysis - little argument about
> this but some use a form of dialysis ie CVVHD for volume control.
> Is it other biochemical evidence of ATN - oliguria, changes in
> urinary electrolytes and microscopy etc. etc over time consistent
> with renal shutdown then recovery.
> Is it a fall in GFR. eGFR in many labs is now calculated for you.
> Although as Prasanna has pointed out, it is not properly validated
> in various races other than Caucasian.
> When was the renal function measure done? Was it a single isolated
> reading that returned to normal at some time point before or even
> after discharge from hospital? Was it persistently elevated after
> having been not so?
> Autopsy data - what findings does one need to see. Many kidneys are
> pale and have evidence of perimortem thrombosis and changes in the
> renal tubules etc when the death was due to low cardiac output.
>
> So let us go forward an and analyse the available evidence on
> 'changes in renal function ' or should it just be 'changes in serum
> creatinine ' after cardiac surgery and the influence of adjunctive
> therapies.
> That has been done, but only within the limitations of author
> designated definitions of renal dysfunction. This may or may not
> include some or all of the above. I mean the meta-analyses that
> have been done by Sedrakyan (aprotinin use in CABG), Henry
> (Cochrane Review all antifibrinolytics in cardiac surgery) and Levi
> (Antifibrinolytics). Using author definitions, there is no
> difference in the reported incidence of whatever we have chosen. In
> most cases it is changes in serum creatinine.
> So how do we find the answer? Well we need to define the question
> first. What do we want to know? Renal dialysis is a potentially
> lethal complication of cardiac surgery. Is this increased by
> aprotinin? The STS reports the incidence of new dialysis at 0.5%.
> In a review of the Bayer data, both placebo and treated patients
> have an incidence of 0.3%. (NS)
> There is a statistically significant difference in the number of
> patients having a rise in Se Creatinine of > 0.5 mg/dl (38µmol/l)
> (OR 1.41). How long did it take to resolve. The median time for se
> creatinine to return to within 20% of baseline was 6 days for
> placebo and 9 days for aprotinin. There was no difference in those
> having a rise of > 2.0 mg/dl.
>
> If you look at Mangano's paper, you will note an interesting
> anomaly that does not come up in the discussion. The rate of
> 'reported renal dysfunction' in the so called placebo group, a
> misnomer of there ever was one - no treatment group is more correct
> - was about 3.5%. In several large studies using similar
> definitions from around the world, Duke, Finland and Italy as well
> as an earlier study by Mangano reported rates of 7.7 - 11 %. (Not
> with aprotinin just the rate of creatinine rise). So how does one
> explain the fall in the rate ? Different patients or does the
> exclusion of a large cohort of patients have something to do with
> it? Now in the 2006 Mangano paper, the rate is 8%. How does one
> explain the similarity between the rest of the world data and NEJM
> data?
>
> As Claudia suggests, read the papers, do not take at face value all
> that is said. And like some have done, examine your own data.
>
> Disclosure: A long term worker with Aprotinin, who has been
> supported by Bayer and who supports them. Maybe I will go down with
> the ship, but it ain't sinking yet!
>
>
>> 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@
>>>>> 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:hgr
>>>>> md@
>>>>> 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:pra
>>>>>> san
>>>>>> 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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