[HSF] Aprotinin
Ben Bidstrup
benjamin.bidstrup at bigpond.com
Sun Nov 19 15:20:16 EST 2006
I agree. Many drugs are on the market very shortly after approval
which is early in their 'career.' This is naturally to recoup the
huge development costs. Look at VIIa, and some of the Monoclonal
anti-cancer drugs. In Australia the federal government is complaining
about the cost of the cervical cancer vaccine and will only subsidize
it if the cost is reduced.
Now aprotinin was released in Germany by Bayer in 1959 (that is 47
years ago!!!!!) It has been used admittedly for many things. The list
is too long to mention, but things like improving the performance of
soccer teams and more latterly peri-articular injections for sports
trauma come to mind. It has been used in cardiac surgery since 1965.
David Tice had publications in 1965 and 1966 using it. It was widely
available in Europe, Canada Australia, but until we described the
high dose regime in 1987 was not popular. Its use took off in Europe
as it paralleled a world wide concern about blood use with Hep B, and
then HIV/AIDS being transmitted via transfusion. Arthur Ashe died
because of this after CABG. It was licensed in the USA in 1994, but
had been available there prior to that for compassionate use.
We should note that blood use in CABG in those days was significant
and by today's standard they would be considered lower risk. Fewer
poor LVs, but lots of patients taking ASA and younger. As the years
have progressed as well know, the age and co-morbidities have risen
and despite this mortalities have fallen. (STS Data, UK national Data
and I am sure there is similar information for many other countries.)
The use of aprotinin has likewise risen. Initially used in lower risk
cases it now is used in higher risk cases. These tend to have higher
mortality, incidence of renal failure, CVA etc etc. Maybe if we just
used vecuronium in high risk cases, then it would have an
unfavourable risk benefit profile.
So if we use aprotinin only in these cases, guess what we will have a
higher incidence of these poor outcomes. (In statistics parlance this
is known as inextricable confounding. Collinearity is also another
expression that has been used)
As aprotinin use has increased in the USA since 1994 (12 years now,
if I can subtract OK), we have seen also a change in the patient
profile, older more comorbidities and as we look at the risk scores
still higher risk for mortality in the high risk cases.
So it is not so much a case of a drug company trying to get its money
back, but keeping a drug with a known risk benefit profile (see the
FDA submissions and transcripts) available to those who need it.
Every country including the FDA has a voluntary adverse drug reaction
reporting system. This tends to under report events. However, if
there was what appeared to be a problem, and surgeons are very quick
to blame the most recent change as the cause for a problem, then even
with under reporting we would have heard something over 20 years.
As Prasanna says, every thing we do has a benefit and a risk. We must
balance all of them, unfortunately in some places and some surgeons
are more sensitive, one of the perceived risks comes from the scum
suckers.
Disclosure. I have been involved with Bayer since 1985 with Trasylol.
Many of the studies were funded by them. I have acted as a consultant
to them and have received funding for this and as a speaker. All
papers were written without editorial control by Bayer. I have most
of the raw data if anyone wants to see early studies' results!
Bear in mind, observational studies do not prove cause and effect,
but provide associations. These tend to be the basis for further
specific studies. (For example the BART study)
>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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