[HSF] Aprotinin
Ben Bidstrup
benjamin.bidstrup at bigpond.com
Sun Nov 19 15:22:14 EST 2006
Ani,
It is not even licensed for use in cardiac surgery in the USA!
>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>
> To: 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> 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>
> > To: 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>
> >>
> >>
> >> 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> >
> >> 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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