[HSF] Aprotinin

Sat Nov 18 23:30:46 EST 2006

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 )
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>  
>
> 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
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>  
>
>  
>
>  
>
> Evidence based medicine journal club critique edited by E B Milbrant
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>  
>
> 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 
>
>  
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> C 2006 BioMed Central Ltd
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> 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.
>
>  
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> Methods
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> Design and setting
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> Prospective observational cohort study in 69 institutions in North and South
> America, the Middle East, Europe, and Asia.
>
>  
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> Subjects
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>  
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> 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).
>
>  
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> Intervention
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>  
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> None.
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> Measurements
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>  
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> 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
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>  
>
> 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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