[HSF] Aprotinin
Ben Bidstrup
benjamin.bidstrup at bigpond.com
Mon Nov 20 13:23:43 EST 2006
Where do you get the evidence for 15% ATN ?
>Terrible side effects .... horrible precautions ....
>bottom line
>> Every drug has a role and an indication based on good clinical judgment >
>can't but agree to that
>even venoms do have their guarded indications , based on scrupulous clinical
>judgment ... ..... "drugs are venoms in small doses .... venoms are drugs
>in large doses"
>
>Certainly its use has got a place in our armamentarium ...... all what we
>use have got side effects ....... suffice enough with anaesthetic drugs
>.....
>
>.. too hard to jeopardize safety of a re-replacement for a 10-15% chance of
>ATN .... to let in complications of multiple donors blood transfusion with
>a > 60-70% complications of MOF ... among other things ....
>
>Still .... agree with Hal's opinion for guarded indiscriminate use ...
>
>NFA
>
>> -----Original Message-----
>> From: openheart-l-bounces at lists.hsforum.com [mailto:openheart-l-
>> bounces at lists.hsforum.com] On Behalf Of prasannasimha
>> Sent: Saturday, November 18, 2006 9:37 PM
>> To: OpenHeart-L at lists.hsforum.com
>> 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 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
>> > To: 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
>> >>
>> >>
>> >> 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 >
>> >> 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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