[HSF] Aprotinin

Salerno, Tomas TSalerno at med.miami.edu
Sun Nov 19 11:56:23 EST 2006 

Seems like the FDA did not take into consideration the facts reported by Michael and went ahead and sent out a warning to all surgeons.  It seems to me that for now, Aprotinin is history in the USA, due to liability issues.
 
Tomas

________________________________

From: openheart-l-bounces at lists.hsforum.com on behalf of Michael Firstenberg
Sent: Sun 11/19/2006 10:17 AM
To: OpenHeart-L at lists.hsforum.com
Subject: Re: [HSF] Aprotinin



If I recall Mangino is not a surgeon - in fact is he not an 
anesthesiologist, as are many of the people who recently write these 
articles about "bad cardiac drugs"?  Has he actually had to stand at 
the foot of a bed or in the OR for countless hours watching patient 
bleed to death and deal first hand with the consequences of massive 
transfusions.  Yes, renal failure and dialysis is bad bad bad - but 
compare that with right heart failure/ARDS/massive pressor 
requirements/etc from excessive bleeding (and the hypotension and 
associated ATN/renal failure anyhow).  My guess is he is home in bed 
all nice an cozy with his pager off at the end of his shift.

-michael




On Nov 19, 2006, at 2:24 AM, Ani Anyanwu wrote:

> Prasanna
>
> Well many would I suspect call it unbridled.
>
> The following would generally receive aprotinin in my institution
> 1) reoperations
> 2) operations on the aortic arch or descending aorta
> 3) transplant and VAD procedures
> 4) operations on patients on clopidogrel
> 5) combined valvular and CABG
> 6) Patients with renal impairment
> 7) Patients where ability to tolerate transfusion or bleeding 
> complications is thought to be marginal including - most patients 
> aged 70 or above, patients with severe lung disease, poor LV 
> function, severe pulmonary hypertension, multiple comorbidity etc. 
> Certainly almost all octogenrians would get aprotinin - even for CABG.
> 8) Paradoxically, young patients in their 20s or 30s (where 
> avoidance of blood transfusion should be the goal in all patients)
> 9) Multiple valvular procedures (excluding tricuspid valve)
> 10) cases with anticipated bypass run more than 3 hours (including 
> complex mitral repairs)
>
> As you can see there is not much left - so maybe it is unbridled! 
> As you implied we obviously would not use it for an ASD or isolated 
> AVR, but these constitute a small minority of our procedures. 
> Personally I would use it for practically every operation - 
> including all CABGs - but that is a personal opinion as I believe 
> there are non-hematological benefits of the drug and like you 
> strongly believe in blood conservation. I do not have any interests 
> or links to industry.
>
> Actually Ben brought up something that I had never thought of - 
> correct me if I am wrong but Aprotinin is the only agent licensed 
> as a blood conservation agent for heart surgery?
>
> Ani
>   ----- Original Message -----
>   From: psimha<mailto:prasannasimha at gmail.com>
>   To: OpenHeart-L at lists.hsforum.com<mailto:OpenHeart- 
> L at lists.hsforum.com>
>   Sent: Sunday, November 19, 2006 12:00 AM
>   Subject: Re: [HSF] Aprotinin
>
>
>   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<mailto:prasannasimha at gma 
>> il.com>>
>>   To: OpenHeart-L at lists.hsforum.com<mailto:OpenHeart- 
>> L at lists.hsforum.com<mailto: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<mailto:hgrmd at aol.com<mailto:hgrmd@ 
>> 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<mailto:prasan 
>>> nasimha at gmail.com<mailto:prasannasimha at gmail.com>>
>>> To: OpenHeart-L at lists.hsforum.com<mailto:OpenHeart- 
>>> L at lists.hsforum.com<mailto: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<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<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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