[HSF] Aprotinin

Sun Nov 19 08:08:42 EST 2006

Hal remember you used

I again think the use of aprotinin should be limited as much as possible.
And I used
"Selectively"
Actually aren't we speaking the same ??
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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