[HSF] Aprotinin
Nasser F. Abou'Seada
nfaabouseada at gmail.com
Sun Nov 19 19:06:54 EST 2006
totally concur with your opinion Prasanna
NFA
> From: psimha
> 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>
> > 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/viewartic
l
> e/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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