[HSF] Aprotinin
Nasser F. Abou'Seada
nfaabouseada at gmail.com
Mon Nov 20 03:17:31 EST 2006
NO .....
just an imaginary virtual example of a supposed side effect ..... the number
is irrelevant .... just an imaginary example to stress that non use of the
drug is also bound to be associated with grave consequences of higher
probabilities .... in high risk cases ....
what I tried to say is that having a side effect of a certain useful tool
certainly calls for "rational selection" in Prasanna's and Claudia's words
....
the use of numbers is totally irrelevant ...... just as an "what if" example
.....
IMHO ..... we all are just expressing different facets of the same truth
..... that we all admit and agree about .. "Hal, Tomas, Prasanna, Ben,
Claudia "... albeit ... everyone is expressing his worrisome about a certain
point .....
NFA
> -----Original Message-----
> From: openheart-l-bounces at lists.hsforum.com [mailto:openheart-l-
> bounces at lists.hsforum.com] On Behalf Of Ben Bidstrup
> Sent: Sunday, November 19, 2006 9:24 PM
> To: OpenHeart-L at lists.hsforum.com
> Subject: RE: [HSF] Aprotinin
>
> 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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