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Table of Contents
EDITORIAL  
Year : 2012  |  Volume : 15  |  Issue : 1  |  Page : 4-5
Are tranexamic acid and ε-aminocaproic acid adequate substitutes for aprotinin?


Department of Anaestheisology and Intensive Care, G.B. Pant Hospital, New Delhi, India

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Date of Web Publication5-Jan-2012
 

How to cite this article:
Tempe DK, Hasija S. Are tranexamic acid and ε-aminocaproic acid adequate substitutes for aprotinin?. Ann Card Anaesth 2012;15:4-5

How to cite this URL:
Tempe DK, Hasija S. Are tranexamic acid and ε-aminocaproic acid adequate substitutes for aprotinin?. Ann Card Anaesth [serial online] 2012 [cited 2019 Nov 13];15:4-5. Available from: http://www.annals.in/text.asp?2012/15/1/4/91465


Blood transfusion during cardiac surgery can negatively impact the short- and long-term outcomes. The Society of Thoracic Surgeons Workforce strongly recommends interventions aimed at reducing bleeding and blood transfusion during cardiac surgery, including hemostatic agents. [1] Until recently, aprotinin was the most effective and widely used antifibrinolytic agent in cardiac surgery requiring cardiopulmonary bypass (CPB). [2] The major well-known concerns with its use were graft thrombosis, renal failure and anaphylactic reaction. However, due to variability in the results and lack of concrete evidence against its use, the use of aprotinin continued. The multicenter study of the Perioperative Research Group, Ischemia Research Education Foundation (McSPI), published a report in 2006 that discouraged the use of aprotinin due to concerns of serious end-organ damage, including renal failure and death, in favor of tranexamic acid (TA) and e-aminocaproic acid (EACA). However, it was the Blood Conservation Using Antifibrinolytics in a Randomized Controlled Trial (BART) that led to withdrawal of aprotinin from the worldwide market in November 2007 by its manufacturer (Bayer Healthcare Pharmaceuticals, Leverkusen, Germany). The results of the BART trial showed a higher mortality in patients receiving aprotinin in a comparison of antifibrinolytics in cardiac surgery. [3]

The predicament was overcome to some degree due to the availability of two alternative drugs - TA and EACA. However, the question is, are these effective and safe alternatives? In this issue of the Annals of Cardiac Anesthesia, Montes and colleagues have reported that seizures occurred in 28 of 903 (3.5%) patients undergoing cardiac surgery on CPB in whom TA was administered. [4] They found that seizures were more likely to occur in patients having a serum creatinine level higher than 1.29 mg/dL and that the mortality was higher (14.3% vs. 3.6%) in them. Similar reports describing association of seizures with TA are available in the literature. [5] A recent paper has reported that the seizure rate is doubled after intraoperative treatment with TA (7.6%) compared with EACA (3.3%) in adult patients undergoing open heart surgery, and renal dysfunction occurred more frequently with EACA (30.1% vs. 20.0%). [6] TA and EACA cause seizures by a dose-dependant antagonistic effect on gamma-aminobutyric acid (A) receptors. [7]

If one examines the incidence of bleeding and blood transfusion requirements in the post-aprotinin era, it is seen that there is a significant increase in the requirement of blood and blood products. In one study conducted for 6 months before (n = 1699) and 6 months after (n = 2225) the withdrawal of aprotinin, it was shown that the magnitude of blood loss, reoperation for bleeding and transfusion of blood products increased significantly in the group that did not receive any antifibrinolytic versus the group that received aprotinin. [8] The non-use of aprotinin did not lead to any decrease in the rate of renal failure. Moreover, the time on mechanical ventilation increased, attributable to the use of more blood products. Another study comparing aprotinin with TA revealed that the requirement of blood products and recombinant factor VIIa and reexploration rate were higher with TA. [9] In neonates, switching over from aprotinin to EACA led to an increase in the blood loss (36 mL/kg/24 h vs. 46 mL/kg/24 h), although no difference in transfusion requirement was demonstrated. [10] The relative risk of early postoperative outcomes, such as mortality and renal dysfunction, have not improved, but the risk for the intraoperative use of blood products has increased. [11]

The question remains whether the withdrawal of aprotinin has led to decreased mortality and lowered cost without causing an undue increase in bleeding and transfusion requirement? Bleeding and transfusion usage have increased since the withdrawal of aprotinin, and there is no evidence for improved mortality. On the contrary, seizures and renal failure have been shown to be the major problems with TA and EACA. The reported seizure rate with aprotinin is 1.2% compared with 4.6% with TA. [12] In addition, in experiments on piglets, Ishibashi and colleagues have demonstrated that aprotinin protects the cerebral microcirculation and accelerates neurological recovery after circulatory arrest. [13] They concluded that current lack of aprotinin is a serious disadvantage. Further, the cost-effectiveness of TA and EACA may be nullified by the increased requirement of blood products, especially recombinant factor VIIa. A survey performed in Great Britain has revealed that 33% doctors felt that their patients have suffered due to lack of aprotinin, and no physicians informed that their patients were doing better due to non-use of aprotinin. [14] In the absence of definite evidence, opinions matter; however, even the opinions are conflicting. The Food and Drug Administration does not explicitly approve the use of either TA or EACA. Spiess has vehemently argued in favor of aprotinin, stating "the entire series of events have been most unfortunate in that they were not driven by science, level I evidence and cool heads." [15] An independent analysis of the BART trial has shown that aprotinin is not associated with increased mortality, especially in patients who are at high risk of massive blood loss (emergency surgery, prolonged CPB). [16]

It is a bit worrying to think that we have been using a harmful medicine for almost 20 years. All medicines have side-effects, and aprotinin is no exception. What is important is to evaluate the risk-benefit ratio and restrict the use in a group of patients in whom this ratio is better and obviously beneficial. This seems to be the case with aprotinin, especially as the current evidence does not suggest that TA and EACA are effective and safe alternatives to it. Therefore, is it time to revisit the judicious use of aprotinin on an individualized basis? The authors believe so, but time will tell what the eventual fate of aprotinin is.

 
   References Top

1.Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, et al: 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists. Blood conservation clinical practice guidelines. Ann Thorac Surg 91:944-82, 2011.  Back to cited text no. 1
    
2.Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:2801-13.  Back to cited text no. 2
    
3.Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319-31.  Back to cited text no. 3
    
4.Montes FR, Pardo DF, Carreño M, Arciniegas C, Dennis RJ, Umaña JP. Risk factors associated with postoperative seizures in patients undergoing cardiac surgery who received tranexamic acid: A case-control study. Ann Card Anaesth 2012;15:6-12.   Back to cited text no. 4
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5. Murkin JM, Falter F, Grantan J, Young B, Burt C, Chu M. High-dose tranexamic acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg 2010;110:350-3.  Back to cited text no. 5
    
6.Martin K, Knorr J, Breuer T, Gertler R, Macguill M, Lange R, et al. Seizures after open heart surgery: comparison of e-aminocaproic acid and tranexamic acid. J Cardiothorac Vasc Anesth 2011;25:20-5.  Back to cited text no. 6
    
7.Furtmüller R, Schlag MG, Berger M, Hopf R, Huck S, Sieghart W, et al. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid (A) receptor antagonistic effect. J Pharmacol Exp Ther 2002;301:168-73.  Back to cited text no. 7
    
8.Wang X, Zheng Z, Ao H, Zhang S, Wang Y, Zhang H, et al. A comparison before and after aprotinin was supended in cardiac surgery: Different results in the real world from a single cardiac center in China. J Thorac Cardiovasc Surg 2009;138:897-903.  Back to cited text no. 8
    
9.Sniecinski RM, Chen EP, Makadia SS, Kikura M, Bolliger D, Tanaka KA. Changing from aprotinin to tranexamic acid results in increased use of blood products and recombinant factor VIIa for aortic surgery requiring hypothermic arrest. J Cardiothorac Vasc Anesth 2010;24:959-63.  Back to cited text no. 9
    
10.Martin K, Gertler R, Liermann H, Mayr NP, Macguill M, Schreiber C, et al. Switch from aprotinin to {varepsilon}-aminocaproic acid: impact on blood loss, transfusion, and clinical outcome in neonates undergoing cardiac surgery. Br J Anaesth 2011;107:934-9.  Back to cited text no. 10
    
11.DeSantis SM, Toole JM, Kratz JM, Uber WE, Wheat MJ, Stroud MR, et al. Early postoperative outcomes and blood product utilization in adult cardiac surgery: the post-aprotinin era. Circulation 2011;124:S62-9.  Back to cited text no. 11
    
12.Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg 2008;107:1783-90.  Back to cited text no. 12
    
13.Ishibashi N, Iwata Y, Zurakowski D, Lidov HG, Jonas RA. Aprotinin protects the cerebral microcirculation during cardiopulmonary bypass. Perfusion 2009;24:99-105.  Back to cited text no. 13
    
14.McMullan V, Alston RP. The effect of the suspension of the license for aprotinin on the care of patients undergoing cardiac surgery: a survey of cardiac anesthesiologists' and surgeons' opinions in the United Kingdom. J Cardiothorac Vasc Anesth 2010;24:418-21.  Back to cited text no. 14
    
15.Spiess BD. Pro: The practice of cardiac anesthesia has changed after the withdrawal of aprotinin. J Cardiothorac Vasc Anesth 2010;24:875-8.  Back to cited text no. 15
    
16.Beattie WS, Karkouti K. The post-BART anti-fibrinolytic dilemma? J Cardiothorac Vasc Anesth 2011;25:3-5.  Back to cited text no. 16
    

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Correspondence Address:
Deepak K Tempe
Department of Anaesthesiology and Intensive Care, G.B. Pant Hospital, New Delhi - 110 002
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.91465

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