Eur J Anaesthesiol 2015; 32:591–595
EDITORIAL
Aprotinin: is it time to reconsider? The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesiaM
European Journal of Anaesthesiology 2015, 32:591–595
Background Aprotinin, a nonspecific serine protease inhibitor, was originally introduced into clinical practice for the treatment of hyperfibrinolytic conditions such as acute pancreatitis. In 1987 after the publication of a small study of 22 recipients of repeat cardiac surgery, the medical indications of the drug were expanded.1 The authors observed a dramatic reduction in blood loss and the need for transfusion in the aprotinin-treated patients. The findings prompted the widespread use of aprotinin to reduce perioperative blood loss and requirement for transfusion not only in cardiac surgery2,3 but also in hepatic4 and major orthopaedic surgery.5 In addition, the potential antiinflammatory effect of aprotinin triggered a more systematic use in infants having cardiac surgery.6,7 The publication of the study by Mangano et al.8 in 2006 constituted the first major challenge for the perioperative use of aprotinin. In this study, which included 4374 adult coronary surgery patients, aprotinin use – in contrast to epsilon-aminocaproic acid and tranexamic acid administration – was associated with an increased risk of renal failure, myocardial infarction, heart failure, stroke, encephalopathy and mortality. A second study in the same year by Karkouti et al.9 reported an increased incidence of renal dysfunction in aprotinin-treated patients. In 2006, following these reports, the U.S. Food and Drug Administration added renal dysfunction to the drug’s other safety concerns, anaphylaxis, graft occlusion and stroke. However, the association between aprotinin and perioperative renal dysfunction has been challenged because the existing direct relationship between packed red cell transfusion and renal failure prohibits identification of the exact role of aprotinin in the development of perioperative renal dysfunction.10 Nevertheless, subsequent
studies have provided additional arguments about the potential adverse effects of the perioperative use of aprotinin. In 2007, Mangano et al. published the results of a new analysis of their 2006 data, wherein they identified aprotinin as an independent predictor of 5-year mortality.11 At the same time, in-house research commissioned by Bayer from the i3 Drug Safety research organisation’s database on coronary artery bypass graft patients showed a higher risk of death and acute renal failure in aprotinin-treated patients than patients treated with other antifibrinolytics. This increased risk, however, was not indicative of a causal association.12 The death blow for aprotinin was given by the publication of the results from Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART).13 In this multicentre, randomised controlled trial that included2331 high-risk cardiac surgicalpatients, theeffects of aprotinin, tranexamic acid andepsilon-aminocaproic acid on massive postoperative bleeding and death from any cause at 30 days were compared. The study was terminated early by the safety committee because of a (nonsignificant) higher mortality in the aprotinin-treated patients compared with the patients treated with the other two drugs [aprotinin 6%; tranexamic acid 3.9% and aminocaproic acid 4%; relative risk (RR) aprotinin vs. tranexamic acid: 1.55, 95% confidence interval (95% CI) 0.99 to 2.42, P ¼ 0.05); RR aprotinin vs. aminocaproic acid: 1.52 (95% CI 0.98 to 2.36, P ¼ 0.06)]. Following these publications, the manufacturer temporarily suspended marketing in November 2007. In December 2007, the UK license of aprotinin was suspended on advice from the Commission on Human Medicines. In February 2008, the license was also suspended by the European Commission and finally aprotinin was permanently withdrawn from the market in May 2008. Of note, in some countries, aprotinin remains available on the market through a limited access plan.
From the University of Ghent, Ghent, Belgium Correspondence to Stefan G. De Hert, MD, PhD, Department of Anaesthesiology, Ghent University Hospital, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium Tel: +32 0 9 332 32 81; fax: +32 0 9 332 49 87; e-mail: [email protected] The members of the task force are listed at the end of the article. 0265-0215 Copyright ß 2015 European Society of Anaesthesiology. All rights reserved.
DOI:10.1097/EJA.0000000000000284
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
592 The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesia
The decision for suspension seemed to be further supported by the findings of a recent Cochrane review. This publication concluded that – although aprotinin appeared to be more effective in reducing blood loss and the need for blood transfusion than tranexamic acid and aminocaproic acid – it was associated with a higher risk of death.14 However, the different studies on which the evidence is based have now been challenged, raising a number of potential methodological issues.15–19 Several debatable methodological concerns over the BART trial prompted the regulatory authority in Canada (Health Canada) to convene an expert advisory panel to examine the issues. They indeed identified a number of serious methodological problems with the study and concluded that the benefit of using aprotinin in noncomplex cardiac surgery might outweigh the risk.20 As a result, aprotinin was made available again in Canada but restricted to use in isolated coronary artery bypass surgery.21 In February 2012, the European Medicines Agency also recommended the lifting of the suspension of aprotinin after a review of the risks and benefits of antifibrinolytic drugs.22 Of note, the authors of the BART study have recently refuted these conclusions.23 The nature of the debate on aprotinin has led to confusion among clinicians regarding its role, particularly since the release of the license by the European Medicines Agency. To clarify the situation, the European Society of Anaesthesiology set up a task force to assess the current evidence and provide a brief overview on the current indications of the drug. Members of the task force consisted of the chair of the European Society of Anaesthesiology Scientific Committee and members of the scientific subcommittees on Transfusion, Haemostasis and Thrombosis and Paediatrics. In addition, key European opinion leaders on the use and place of aprotinin in adult and paediatric anaesthesia were asked to join the task force. The present consensus statement is the result of an intensive debate based on the available literature and the expert opinion of the task force members.
Which indications for which risk? Risk stratification of cardiac surgical procedures is classically divided into low-risk surgery, which refers to isolated coronary artery bypass graft or single valve surgery; intermediate-risk surgery, which refers to combined cardiac surgery; and high-risk surgery, which refers to complex surgery, such as re-sternotomy, multiple valve surgery, surgery of the ascending aorta or aortic arch, or emergency surgery.24 Currently, the regulatory agencies have licensed the prophylactic use of aprotinin to reduce blood loss and blood transfusion only in adult patients undergoing isolated cardiopulmonary bypass graft surgery (i.e. coronary artery bypass graft surgery that is not combined with other cardiovascular surgery), who are
at a high risk of major blood loss. However, the risk of bleeding with isolated coronary artery surgery is relatively low, and theoretically, the benefit of aprotinin might be higher in more complex procedures. Indeed, before its withdrawal from the market, most cardiac centres would use aprotinin specifically in complex and high-risk surgery such as re-operation, surgery for endocarditis and multiple and complex cardiac and aortic procedures, and not in isolated coronary surgery. Interestingly, several studies suggest that in these more complex procedures, aprotinin might have advantages over the other available antifibrinolytic drugs. In a retrospective analysis, Karkouti et al.25 observed a lower incidence of massive bleeding associated with a significant reduced mortality in high-risk cardiac surgery. In another retrospective study, Sander et al.26 observed that the use of tranexamic acid was associated with higher cumulative drainage losses and a higher rate of repeat thoracotomy for bleeding than in the group of patients treated with aprotinin. In the subgroup of patients with open-chamber procedures, mortality was lower in the aprotinin group than in the tranexamic acid group (7.5 vs. 16.2%; P ¼ 0.02).26 Similarly, Walkden et al.27 reported a 2.5-fold increase in mortality in the high-risk surgical population, after the withdrawal of aprotinin. It should be noted that techniques in cardiac surgery have made an important evolution during the last decade with the introduction of less invasive techniques. Parallel to this evolution, an increasing interest in the implementation of patient blood management strategies has helped to substantially reduce perioperative blood loss.28 The consequence is that the impact of major blood loss in cardiac and major noncardiac surgery now is not as it was before aprotinin withdrawal.29,30 With the passage of time, the health profile of patients presenting for cardiac surgery has also changed. Coexisting diseases are more numerous and more complex, and the same is true for the drug therapy attached to them, among which are agents that profoundly affect the coagulation system. The result is an increased risk for major perioperative bleeding.31,32 Accordingly, the definition of ‘high risk’ should better describe patient characteristics than the complexity of surgery. Patient characteristics considered to increase the risk for perioperative bleeding
(1) (2) (3) (4) (5) (6)
underlying comorbidities inherited/acquired coagulation abnormalities low platelet count platelet dysfunction dual antiplatelet therapy new oral anticoagulants (dabigatran, rivorixaban, apixaban) (7) Jehovah’s witness/refusal of blood transfusion
Eur J Anaesthesiol 2015; 32:591–595 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Aprotinin: is it time to reconsider? 593
Contraindications Contraindications to aprotinin include hypersensitivity to the active substance. Patients with a positive aprotininspecific IgG antibody test are at an increased risk of anaphylactic reaction when treated with aprotinin, providing an absolute contraindication. If no aprotininspecific IgG antibody test is available prior to treatment, administration of aprotinin to patients with a suspected previous exposure, including fibrin sealant products, during the last 12 months is contraindicated.
Precautions Aprotinin should only be used after careful consideration of the risk-to-benefit ratio, and after alternative treatments have been considered. Its safety and efficacy in the paediatric population have not yet been unequivocally established. Some studies report a beneficial action on perioperative bleeding without adverse effects,33–35 whereas other authors observe side effects such as a higher incidence of acute renal failure.36 According to the health regulatory organisations, aprotinin should not be used in adults when coronary surgery is combined with another cardiovascular surgical procedure because the benefit–risk balance in this situation has not yet been established. Before administration of aprotinin, an appropriate aprotinin-specific IgG antibody test should be considered. Because of the risk of allergic or anaphylactic reactions, a 1 ml (10 000 KIU) test dose could be given at least 10 min before being followed by the remainder of the dose. In adults, the Marketing Authorisation Holder recommends a loading dose of 1 to 2 million KIU, which should be administered as a slow intravenous injection or infusion over 20 to 30 min after induction of anaesthesia and prior to sternotomy. A further 1 to 2 million KIU should be added to the pump prime of the heart-lung machine. To avoid physical incompatibility of aprotinin with heparin when added to the pump prime solution, each agent must be added during recirculation of the pump prime to ensure adequate dilution prior to admixture with the other component. The initial bolus infusion is followed by the administration of a continuous infusion of 250 000 to 500 000 KIU per hour until the end of the operation. In general, the total amount of aprotinin administered per treatment course should not exceed 7 million KIU. As mentioned above, a number of studies have associated aprotinin use with the occurrence of renal dysfunction. Therefore, particularly in patients with preexisting renal dysfunction, careful consideration of the balance of risk to benefit is advised before administration of aprotinin. This is also the case for those patients with known risk factors for development of renal dysfunction, such as concomitant treatment with aminoglycosides. Available clinical experience suggests that patients with decreased renal
function do not require special dose adjustment. No data are available on dosage recommendations for patients with hepatic dysfunction. Finally, reported clinical experience has not identified differences in responses with elderly patients. It is important to note that aprotinin results in elevated partial thromboplastin time (PTT) and celite activated clotting time (ACT). Therefore, these indices should not be used to monitor adequacy of heparin anticoagulation in aprotinin-treated patients during surgery and in the hours that follow. If ACT is used to maintain adequate anticoagulation, a minimal celite-ACT of 750 s or kaolin-ACT of 480 s is recommended, and this should be independent of the effects of haemodilution and hypothermia. Administration of aprotinin, especially to patients who have received aprotinin (including aprotinin-containing fibrin sealants) in the past, requires careful risk–benefit assessment because an allergic reaction may occur. Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also single case reports of anaphylaxis following re-exposure after a longer interval. Standard emergency treatment for allergic and anaphylactic reactions should be readily available during treatment with aprotinin.
Monitoring aprotinin in clinical practice The re-introduction of aprotinin has been authorised subject to adherence to very strict requirements. Apart from the limited indication of use solely in adult patients who are at a high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery, the CHMP (Committee for Medicinal Products for Human Use) has obliged all Marketing Authorisation Holders for aprotinin-containing medicinal products to submit an updated risk management plan before re-launch of the product to the European Union market. In addition, a patient registry needs to be established to include a statistical analysis plan and data collection form. A restricted distribution is proposed with aprotinin available only to centres that perform cardiac surgery on cardiopulmonary bypass and commit to participate in the registry. This registry should enhance information on the benefit–risk balance and collect information that is sufficiently robust to address the current uncertainties, given that the organisation of a large randomised control trial is currently considered to be unfeasible. In 2012, the Nordic Pharma Group acquired the worldwide rights (except U.S.) to Trasylol from Bayer. It is expected that the product will be re-launched in the European Union in 2015. However, given the restricted indications and the potential adverse effects, it is as yet unclear whether anaesthetists who are now used to performing cardiac surgery without aprotinin will re-invest their confidence in this agent. Improvement in patient
Eur J Anaesthesiol 2015; 32:591–595 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
594 The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesia
blood management strategies, the wide availability and efficacy (and low cost) of tranexamic acid, combined with a better knowledge of aprotinin-induced potential complications, could limit the enthusiasm for this agent. Obviously, no further development is scheduled in noncardiac surgery and, pending the continuously decreasing risk of blood transfusion, it is going to be difficult to demonstrate a positive benefit–risk ratio for aprotinin based on well designed randomised controlled trials. Introduction of a mandatory international registry is highly supported by the European Society of Anaesthesiology and might help clinicians and scientists to respond to these concerns.
Members of the ESA task force (in alphabetical order) Stefan De Hert, Department of Anaesthesiology, Ghent University Hospital, Ghent, Belgium. Ravi Gill, Department of Anaesthesiology, University Hospital Southampton, Southampton, United Kingdom. Walid Habre, Paediatric Anaesthesia Unit, Geneva Children’s Hospital, Geneva University Hospitals, Geneva, Switzerland. Marcus Lance´, Department of Anaesthesia and Pain Treatment, Department of Intensive Care, Maastricht University Medical Centre MUMC, Maastricht, The Netherlands. Juan Llau, Department of Anaesthesiology and Critical Care, University Hospital of Valencia, Spain. Jens Meier, Department of Anaesthesiology and Intensive Care Medicine, Kepler University Hospital, Linz, Austria. Philippe Pouard, Paediatric Cardiac Intensive Care, Anaesthesia and Perfusion Unit, University Hospital Necker Enfants Malades, Paris, France. Charles-Marc Samama, Department of Anaesthesia and Intensive Care Medicine, Cochin University Hospital, Paris, France. Jan van der Linden, Department of Cardiothoracic Surgery and Anaesthesiology, Karolinska University Hospital, Stockholm, Sweden. Philippe van der Linden, Department of Anaesthesiology, Centre Hospitalier Universitaire BrugmannHUDERF, Brussels, Belgium.
Financial support and sponsorship: European Society of Anaesthesiology has received an educational grant from Nordic Pharma to convene the task force. There was no interference by industry in the choice of the experts and the content of the consensus statement. Conflicts of interest: CvH has received honoraria for consultancy work for Nordic Pharma; JvdL was an invited speaker on aprotinin at the 15th NATA meeting in Porto, Portugal, April 2013 with support from Nordic Pharma. Comment from the editor: this editorial was checked by the editors but was not sent for external peer review. WH is a deputy editor-inchief, and SDH and CMS are associate editors of the European Journal of Anaesthesiology.
References 1
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Christian von Heyman, Department of Anaesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Therapy, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
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Acknowledgements relating to this article Assistance with the editorial: none.
19
Royston D, Taylor KM, Bidstrup BP, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987; 330:1289–1291. Sedrakayan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thor Cardiovasc Surg 2004; 128:442–448. Van der Linden PJ, Hardy JF, Daper A, et al. Cardiac surgery with cardiopulmonary bypass: does aprotinin affect outcome? Br J Anaesth 2007; 99:646–652. Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomized double-blind study. EMSALT study group. Lancet 2000; 355:1303– 1309. Samama CM. A direct antifibrinolytic agent in major orthopedic surgery. Orthopedics 2004; 27 (Suppl 6):s675–s680. Murugesan C, Banakal SK, Garg R, et al. The efficacy of aprotinin in arterial switch operations in infants. Anest Analg 2008; 107:783– 787. Hsia TY, McQuinn TC, Mukherjee R, et al. Effects of aprotinin or tranexamic acid on proteolytic/cytokine profiles in infants after cardiac surgery. Ann Thorac Surg 2010; 89:1843–1852. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354:353–365. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high- transfusion-risk cardiac surgery. Transfusion 2006; 46:327– 338. Furnary AP, Wu YX, Hiratzka LF, et al. Aprotinin does not increase the risk of renal failure in cardiac surgery patients. Circulation 2007; 116:I127–I133. Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass surgery. J Am Med Assoc 2007; 297:471–479. Trasylol (aprotinin injection) briefing document 2007. http://www.fda.gov/ ohrms/dockets/ac/07/briefing/2007–4316b1–03-Bayer.pdf [Accessed 20 December 2014]. Fergusson DA, He´bert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358:2319–2331. Henry DA, Carless PA, Moxey AJ, et al. Antifibrinolytic use for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011; CD001886. FDA Cardiology and Renal Drugs Advisory Committee. Trasylol (aprotinin injection) risk benefit review 2006. http://www.fda.gov/ohrms/dockets/ac/ 06/slides/2006–4234S3–01-Bayer.pdf [Accessed 20 December 2014]. The Committee of the Association of Cardiothoracic Anaesthetists. Statement on the use of aprotinin in cardiac surgery 2011. http:// www.acta.org.uk/store/docs/publications/ ACTA_aprotinin_response_160306–762321–31–08–2011.pdf [Accessed 20 December 2014]. McMullan V, Alston RP. Aprotinin and cardiac surgery: a sorry tale of evidence misused. Br J Anaesth 2013; 110:675–678. Ortmann E, Besser MW, Klein AA. Antifibrinolytic agents in current anaesthetic practice. Br J Anaesth 2013; 111:549–563. Royston D. The current place of aprotinin in the management of bleeding. Anaesthesia 2015; 70 (Suppl 1):46–49.
Eur J Anaesthesiol 2015; 32:591–595 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Aprotinin: is it time to reconsider? 595
20
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Health Canada. Final report – expert advisory panel on Trasylol (aprotinin) 2011. http://hc-sc.gc.ca/dhp-mps/medeff/advise-consult/eapgce_trasylol/final_rep-rap-eng.php [Accessed 20 December 2014]. Notice to Hospitals: Health Canada endorsed important safety information on trasylol (aprotinin) 2011. http://www.healthycanadians.gc.ca/recall-alertrappel-avis/hc-sc/2011/14666a-eng.php2011 [Accessed 20 December 2014]. European Medicines Agency. European Medicines Agency recommends lifting suspension of aprotinin: review finds that benefits of all antifibrinolytic medicines outweigh risks in restricted range of indications. http:// www.ema.europa.eu/ema/pages/news_and_events/news/2012/02/ news_detail_001447.jsp. [Accessed 20 December 2014]. Hebert PC, Fergusson DA, Hutton B, et al. Regulatory decisions pertaining to aprotinin may be putting patients at risk. Can Med Ass J 2014; 186:1379–1386. Meybohm P, Herrmann E, Nierhoff J, Zacharowski K. Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and e-aminocaproic acid: a metaanalysis of randomised and observational trials of over 30.000 patients. PLoS One 2013; 8:e58009. Karkouti K, Wijeysundera DN, Yau TM, et al. The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery. Anesth Analg 2010; 110:21–29. Sander M, Spies CD, Martiny V, et al. Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis. Crit Care 2010; 14:R148. Walkden GJ, Verheyden V, Goudie R, Murphy GJ. Increased perioperative mortality following aprotinin withdrawal: a real-world analysis of blood management strategies in adult cardiac surgery. Int Care Med 2013; 39:1808–1817.
28
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Van der Linden P, De Hert S, Daper A, et al. A standardized multidisciplinary approach reduces the use of allogeneic blood products in patients undergoing cardiac surgery. Can J Anaesth 2001; 48:894–901. Razavi SA, Carter AB, Puskas JD, et al. Reduced red blood cell transfusion in cardiothoracic surgery after implementation of a novel clinical decision support tool. J Am Coll Surg 2014; 219:1028–1036. Vonk ABA, Meesters MI, van Dijk WB, et al. Ten-year patterns in blood product utilization during cardiothoracic surgery with cardiopulmonary bypass in a tertiary hospital. Transfusion 2014; 54:2608–2616. ElBardissi AW, Aranki SF, Sheng S, et al. Trends in isolated coronary artery bypass grafting: an analysis of the Society of Thoracic Surgeons adult cardiac surgery database. J Thorac Cardiovasc Surg 2012; 143:273–281. Ferraris VA, Brown JR, Despotis GJ, et al., Society of Thoracic Surgeons Blood Conservation Guideline Task Force. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011; 91:944–982. Pasquali SK, Hall M, Li JS, et al. Safety of aprotinin in congenital heart operations: results from a large multicenter database. Ann Thorac Surg 2011; 90:14–21. Pasquali SK, Li JS, He X, et al. Comparative analysis of antifibrinolytic medications in pediatric heart surgery. J Thorac Cardiovasc Surg 2012; 143:550–557. Scott JP, Costigan DJ, Hoffman GM, et al. Increased recombinant activated factor VII use and need for surgical reexploration following a switch from aprotinin to epsilon-aminocaproic acid in infant cardiac surgery. J Clin Anesth 2014; 26:204–211. Leyvi G, Nelson O, Yedlin A, et al. A comparison of the effect of aprotinin and e-aminocaproic acid on renal function in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 2011; 25:402–406.
Eur J Anaesthesiol 2015; 32:591–595 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
EDITORIAL
Aprotinin: is it time to reconsider? The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesiaM
European Journal of Anaesthesiology 2015, 32:591–595
Background Aprotinin, a nonspecific serine protease inhibitor, was originally introduced into clinical practice for the treatment of hyperfibrinolytic conditions such as acute pancreatitis. In 1987 after the publication of a small study of 22 recipients of repeat cardiac surgery, the medical indications of the drug were expanded.1 The authors observed a dramatic reduction in blood loss and the need for transfusion in the aprotinin-treated patients. The findings prompted the widespread use of aprotinin to reduce perioperative blood loss and requirement for transfusion not only in cardiac surgery2,3 but also in hepatic4 and major orthopaedic surgery.5 In addition, the potential antiinflammatory effect of aprotinin triggered a more systematic use in infants having cardiac surgery.6,7 The publication of the study by Mangano et al.8 in 2006 constituted the first major challenge for the perioperative use of aprotinin. In this study, which included 4374 adult coronary surgery patients, aprotinin use – in contrast to epsilon-aminocaproic acid and tranexamic acid administration – was associated with an increased risk of renal failure, myocardial infarction, heart failure, stroke, encephalopathy and mortality. A second study in the same year by Karkouti et al.9 reported an increased incidence of renal dysfunction in aprotinin-treated patients. In 2006, following these reports, the U.S. Food and Drug Administration added renal dysfunction to the drug’s other safety concerns, anaphylaxis, graft occlusion and stroke. However, the association between aprotinin and perioperative renal dysfunction has been challenged because the existing direct relationship between packed red cell transfusion and renal failure prohibits identification of the exact role of aprotinin in the development of perioperative renal dysfunction.10 Nevertheless, subsequent
studies have provided additional arguments about the potential adverse effects of the perioperative use of aprotinin. In 2007, Mangano et al. published the results of a new analysis of their 2006 data, wherein they identified aprotinin as an independent predictor of 5-year mortality.11 At the same time, in-house research commissioned by Bayer from the i3 Drug Safety research organisation’s database on coronary artery bypass graft patients showed a higher risk of death and acute renal failure in aprotinin-treated patients than patients treated with other antifibrinolytics. This increased risk, however, was not indicative of a causal association.12 The death blow for aprotinin was given by the publication of the results from Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART).13 In this multicentre, randomised controlled trial that included2331 high-risk cardiac surgicalpatients, theeffects of aprotinin, tranexamic acid andepsilon-aminocaproic acid on massive postoperative bleeding and death from any cause at 30 days were compared. The study was terminated early by the safety committee because of a (nonsignificant) higher mortality in the aprotinin-treated patients compared with the patients treated with the other two drugs [aprotinin 6%; tranexamic acid 3.9% and aminocaproic acid 4%; relative risk (RR) aprotinin vs. tranexamic acid: 1.55, 95% confidence interval (95% CI) 0.99 to 2.42, P ¼ 0.05); RR aprotinin vs. aminocaproic acid: 1.52 (95% CI 0.98 to 2.36, P ¼ 0.06)]. Following these publications, the manufacturer temporarily suspended marketing in November 2007. In December 2007, the UK license of aprotinin was suspended on advice from the Commission on Human Medicines. In February 2008, the license was also suspended by the European Commission and finally aprotinin was permanently withdrawn from the market in May 2008. Of note, in some countries, aprotinin remains available on the market through a limited access plan.
From the University of Ghent, Ghent, Belgium Correspondence to Stefan G. De Hert, MD, PhD, Department of Anaesthesiology, Ghent University Hospital, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium Tel: +32 0 9 332 32 81; fax: +32 0 9 332 49 87; e-mail: [email protected] The members of the task force are listed at the end of the article. 0265-0215 Copyright ß 2015 European Society of Anaesthesiology. All rights reserved.
DOI:10.1097/EJA.0000000000000284
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
592 The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesia
The decision for suspension seemed to be further supported by the findings of a recent Cochrane review. This publication concluded that – although aprotinin appeared to be more effective in reducing blood loss and the need for blood transfusion than tranexamic acid and aminocaproic acid – it was associated with a higher risk of death.14 However, the different studies on which the evidence is based have now been challenged, raising a number of potential methodological issues.15–19 Several debatable methodological concerns over the BART trial prompted the regulatory authority in Canada (Health Canada) to convene an expert advisory panel to examine the issues. They indeed identified a number of serious methodological problems with the study and concluded that the benefit of using aprotinin in noncomplex cardiac surgery might outweigh the risk.20 As a result, aprotinin was made available again in Canada but restricted to use in isolated coronary artery bypass surgery.21 In February 2012, the European Medicines Agency also recommended the lifting of the suspension of aprotinin after a review of the risks and benefits of antifibrinolytic drugs.22 Of note, the authors of the BART study have recently refuted these conclusions.23 The nature of the debate on aprotinin has led to confusion among clinicians regarding its role, particularly since the release of the license by the European Medicines Agency. To clarify the situation, the European Society of Anaesthesiology set up a task force to assess the current evidence and provide a brief overview on the current indications of the drug. Members of the task force consisted of the chair of the European Society of Anaesthesiology Scientific Committee and members of the scientific subcommittees on Transfusion, Haemostasis and Thrombosis and Paediatrics. In addition, key European opinion leaders on the use and place of aprotinin in adult and paediatric anaesthesia were asked to join the task force. The present consensus statement is the result of an intensive debate based on the available literature and the expert opinion of the task force members.
Which indications for which risk? Risk stratification of cardiac surgical procedures is classically divided into low-risk surgery, which refers to isolated coronary artery bypass graft or single valve surgery; intermediate-risk surgery, which refers to combined cardiac surgery; and high-risk surgery, which refers to complex surgery, such as re-sternotomy, multiple valve surgery, surgery of the ascending aorta or aortic arch, or emergency surgery.24 Currently, the regulatory agencies have licensed the prophylactic use of aprotinin to reduce blood loss and blood transfusion only in adult patients undergoing isolated cardiopulmonary bypass graft surgery (i.e. coronary artery bypass graft surgery that is not combined with other cardiovascular surgery), who are
at a high risk of major blood loss. However, the risk of bleeding with isolated coronary artery surgery is relatively low, and theoretically, the benefit of aprotinin might be higher in more complex procedures. Indeed, before its withdrawal from the market, most cardiac centres would use aprotinin specifically in complex and high-risk surgery such as re-operation, surgery for endocarditis and multiple and complex cardiac and aortic procedures, and not in isolated coronary surgery. Interestingly, several studies suggest that in these more complex procedures, aprotinin might have advantages over the other available antifibrinolytic drugs. In a retrospective analysis, Karkouti et al.25 observed a lower incidence of massive bleeding associated with a significant reduced mortality in high-risk cardiac surgery. In another retrospective study, Sander et al.26 observed that the use of tranexamic acid was associated with higher cumulative drainage losses and a higher rate of repeat thoracotomy for bleeding than in the group of patients treated with aprotinin. In the subgroup of patients with open-chamber procedures, mortality was lower in the aprotinin group than in the tranexamic acid group (7.5 vs. 16.2%; P ¼ 0.02).26 Similarly, Walkden et al.27 reported a 2.5-fold increase in mortality in the high-risk surgical population, after the withdrawal of aprotinin. It should be noted that techniques in cardiac surgery have made an important evolution during the last decade with the introduction of less invasive techniques. Parallel to this evolution, an increasing interest in the implementation of patient blood management strategies has helped to substantially reduce perioperative blood loss.28 The consequence is that the impact of major blood loss in cardiac and major noncardiac surgery now is not as it was before aprotinin withdrawal.29,30 With the passage of time, the health profile of patients presenting for cardiac surgery has also changed. Coexisting diseases are more numerous and more complex, and the same is true for the drug therapy attached to them, among which are agents that profoundly affect the coagulation system. The result is an increased risk for major perioperative bleeding.31,32 Accordingly, the definition of ‘high risk’ should better describe patient characteristics than the complexity of surgery. Patient characteristics considered to increase the risk for perioperative bleeding
(1) (2) (3) (4) (5) (6)
underlying comorbidities inherited/acquired coagulation abnormalities low platelet count platelet dysfunction dual antiplatelet therapy new oral anticoagulants (dabigatran, rivorixaban, apixaban) (7) Jehovah’s witness/refusal of blood transfusion
Eur J Anaesthesiol 2015; 32:591–595 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Aprotinin: is it time to reconsider? 593
Contraindications Contraindications to aprotinin include hypersensitivity to the active substance. Patients with a positive aprotininspecific IgG antibody test are at an increased risk of anaphylactic reaction when treated with aprotinin, providing an absolute contraindication. If no aprotininspecific IgG antibody test is available prior to treatment, administration of aprotinin to patients with a suspected previous exposure, including fibrin sealant products, during the last 12 months is contraindicated.
Precautions Aprotinin should only be used after careful consideration of the risk-to-benefit ratio, and after alternative treatments have been considered. Its safety and efficacy in the paediatric population have not yet been unequivocally established. Some studies report a beneficial action on perioperative bleeding without adverse effects,33–35 whereas other authors observe side effects such as a higher incidence of acute renal failure.36 According to the health regulatory organisations, aprotinin should not be used in adults when coronary surgery is combined with another cardiovascular surgical procedure because the benefit–risk balance in this situation has not yet been established. Before administration of aprotinin, an appropriate aprotinin-specific IgG antibody test should be considered. Because of the risk of allergic or anaphylactic reactions, a 1 ml (10 000 KIU) test dose could be given at least 10 min before being followed by the remainder of the dose. In adults, the Marketing Authorisation Holder recommends a loading dose of 1 to 2 million KIU, which should be administered as a slow intravenous injection or infusion over 20 to 30 min after induction of anaesthesia and prior to sternotomy. A further 1 to 2 million KIU should be added to the pump prime of the heart-lung machine. To avoid physical incompatibility of aprotinin with heparin when added to the pump prime solution, each agent must be added during recirculation of the pump prime to ensure adequate dilution prior to admixture with the other component. The initial bolus infusion is followed by the administration of a continuous infusion of 250 000 to 500 000 KIU per hour until the end of the operation. In general, the total amount of aprotinin administered per treatment course should not exceed 7 million KIU. As mentioned above, a number of studies have associated aprotinin use with the occurrence of renal dysfunction. Therefore, particularly in patients with preexisting renal dysfunction, careful consideration of the balance of risk to benefit is advised before administration of aprotinin. This is also the case for those patients with known risk factors for development of renal dysfunction, such as concomitant treatment with aminoglycosides. Available clinical experience suggests that patients with decreased renal
function do not require special dose adjustment. No data are available on dosage recommendations for patients with hepatic dysfunction. Finally, reported clinical experience has not identified differences in responses with elderly patients. It is important to note that aprotinin results in elevated partial thromboplastin time (PTT) and celite activated clotting time (ACT). Therefore, these indices should not be used to monitor adequacy of heparin anticoagulation in aprotinin-treated patients during surgery and in the hours that follow. If ACT is used to maintain adequate anticoagulation, a minimal celite-ACT of 750 s or kaolin-ACT of 480 s is recommended, and this should be independent of the effects of haemodilution and hypothermia. Administration of aprotinin, especially to patients who have received aprotinin (including aprotinin-containing fibrin sealants) in the past, requires careful risk–benefit assessment because an allergic reaction may occur. Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also single case reports of anaphylaxis following re-exposure after a longer interval. Standard emergency treatment for allergic and anaphylactic reactions should be readily available during treatment with aprotinin.
Monitoring aprotinin in clinical practice The re-introduction of aprotinin has been authorised subject to adherence to very strict requirements. Apart from the limited indication of use solely in adult patients who are at a high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery, the CHMP (Committee for Medicinal Products for Human Use) has obliged all Marketing Authorisation Holders for aprotinin-containing medicinal products to submit an updated risk management plan before re-launch of the product to the European Union market. In addition, a patient registry needs to be established to include a statistical analysis plan and data collection form. A restricted distribution is proposed with aprotinin available only to centres that perform cardiac surgery on cardiopulmonary bypass and commit to participate in the registry. This registry should enhance information on the benefit–risk balance and collect information that is sufficiently robust to address the current uncertainties, given that the organisation of a large randomised control trial is currently considered to be unfeasible. In 2012, the Nordic Pharma Group acquired the worldwide rights (except U.S.) to Trasylol from Bayer. It is expected that the product will be re-launched in the European Union in 2015. However, given the restricted indications and the potential adverse effects, it is as yet unclear whether anaesthetists who are now used to performing cardiac surgery without aprotinin will re-invest their confidence in this agent. Improvement in patient
Eur J Anaesthesiol 2015; 32:591–595 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
594 The European Society of Anaesthesiology task force reports on the place of aprotinin in clinical anaesthesia
blood management strategies, the wide availability and efficacy (and low cost) of tranexamic acid, combined with a better knowledge of aprotinin-induced potential complications, could limit the enthusiasm for this agent. Obviously, no further development is scheduled in noncardiac surgery and, pending the continuously decreasing risk of blood transfusion, it is going to be difficult to demonstrate a positive benefit–risk ratio for aprotinin based on well designed randomised controlled trials. Introduction of a mandatory international registry is highly supported by the European Society of Anaesthesiology and might help clinicians and scientists to respond to these concerns.
Members of the ESA task force (in alphabetical order) Stefan De Hert, Department of Anaesthesiology, Ghent University Hospital, Ghent, Belgium. Ravi Gill, Department of Anaesthesiology, University Hospital Southampton, Southampton, United Kingdom. Walid Habre, Paediatric Anaesthesia Unit, Geneva Children’s Hospital, Geneva University Hospitals, Geneva, Switzerland. Marcus Lance´, Department of Anaesthesia and Pain Treatment, Department of Intensive Care, Maastricht University Medical Centre MUMC, Maastricht, The Netherlands. Juan Llau, Department of Anaesthesiology and Critical Care, University Hospital of Valencia, Spain. Jens Meier, Department of Anaesthesiology and Intensive Care Medicine, Kepler University Hospital, Linz, Austria. Philippe Pouard, Paediatric Cardiac Intensive Care, Anaesthesia and Perfusion Unit, University Hospital Necker Enfants Malades, Paris, France. Charles-Marc Samama, Department of Anaesthesia and Intensive Care Medicine, Cochin University Hospital, Paris, France. Jan van der Linden, Department of Cardiothoracic Surgery and Anaesthesiology, Karolinska University Hospital, Stockholm, Sweden. Philippe van der Linden, Department of Anaesthesiology, Centre Hospitalier Universitaire BrugmannHUDERF, Brussels, Belgium.
Financial support and sponsorship: European Society of Anaesthesiology has received an educational grant from Nordic Pharma to convene the task force. There was no interference by industry in the choice of the experts and the content of the consensus statement. Conflicts of interest: CvH has received honoraria for consultancy work for Nordic Pharma; JvdL was an invited speaker on aprotinin at the 15th NATA meeting in Porto, Portugal, April 2013 with support from Nordic Pharma. Comment from the editor: this editorial was checked by the editors but was not sent for external peer review. WH is a deputy editor-inchief, and SDH and CMS are associate editors of the European Journal of Anaesthesiology.
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