Carrel, Thierry

Englberger, Lars

RERO DOC Digital Library

S.C. Stamou et al. / European Journal of Cardio-thoracic Surgery 36 (2009) 869—876 875Research and Education Foundation. Mortality associated with aprotininduring 5 years following coronary artery bypass graft surgery. J Am MedAssoc 2007;297:471—9.[6] Mangano DT, Tudor IC, Dietzel C, Multicenter Study of PerioperativeIschemia Research Group; Ischemia Research and Education Foundation.The risk associated with aprotinin in cardiac surgery. N Engl J Med2006;354:353—65.[7] Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, WolmanR, Aggarwal A, Marschall K, Graham SH, Ley C. Adverse cerebral outcomesafter coronary bypass surgery. N Engl J Med 1996;335:1857—63.[8] D’Agostino Jr RB. Propensity scores in cardiovascular research. Circula-tion 2007;115:2340—3.[9] Rosenbaum PR, Rubin DB. Reducing bias in observational studies usingsubclassification on the propensity score. J Am Stat Assoc 1984;79:516—24.[10] Fergusson DA, He´bert PC, Mazer CD, Fremes S, Macadams C, Murkin JM,Teoh K, Duke PC, Arellano R, Blajchman MA, Bussie`res JS, Coˆte´ D, Karski J,Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R, theBART Investigators. A Comparison of Aprotinin and Lysine Analogues inHigh-Risk Cardiac Surgery. N Engl J Med 2008;358:2319—31.[11] RayWA, Stein CM. The Aprotinin Story—is BART the Final Chapter? N Engl JMed 2008;358:2398—400.[12] Walker AM. Confounding by indication. Epidemiology 1996;7:335—6.[13] Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A,Wijeysundera DN, Fedorko L, Yau TM. A propensity score case-controlcomparison of aprotinin and tranexamic acid in high-transfusion-riskcardiac surgery. Transfusion 2006;46:327—38.[14] Beattie WS, Karkouti K. Con: aprotinin has a good efficacy and safetyprofile relative to other alternatives for prevention of bleeding in cardiacsurgery. Anesth Analg 2006;103:1360—4.[15] Furnary AP, Wu Y, Hiratzka LF, Grunkemeier GL, Page 3rd US. Aprotinindoes not increase the risk of renal failure in cardiac surgery patients.Circulation 2007;116(11, Suppl.):I127—33.Editorial commentKeywords: Aprotinin; Cardiac surgery; Mortality; Late survivalltammfawsuaiwdw[pIrsudba[amtophtlStamou and colleagues present another critical articleabout adverse outcome following administration of aprotininin adult cardiac surgery [1]. In this retrospective study,haemostatic effects of aprotinin were confirmed but theauthors found an increased risk for in-hospital cardiac arrest.Another intriguing finding was found, namely that the risk oflate cardiac death was higher in patients who receivedaprotinin than after aminocaproic acid (EACA). Unfortu-nately, neither the cause of early mortality nor the problemof cardiac-related attrition (graft occlusion, perioperativemyocardial infarction, malignant arrhythmias or others) wereanalysed or specified.Because of the retrospective character of the study,several limitations and bias have to be considered: the use ofaprotinin or EACA was left at the discretion of the surgeons.The patients who received aprotinin were older, had moreprior surgery, suffered more frequently from congestiveheart failure (NYHA class IV) and underwent more oftencomplex and emergency surgery than those who receivedEACA. It is questionable if propensity score matching may besufficient to eliminate ‘confounding by treatment’ differ-ences of the two study groups. The authors conclude that therisk of aprotinin may not be worth the benefit of reducedtransfusion requirements.There are a tremendous number of publications dealingwith aprotinin, but a single finding seems to be consistent:aprotinin is associated with decreased transfusion require-ment and re-exploration rate because of bleeding. This wasalready the main finding of the initial report of Royston andcolleagues [2]. Inmore recent years, the question appeared ifaprotinin increases the risk of renal dysfunction and is anindependent predictor of increased mortality. Concerningthe last two end-points, conflicting results are present inliterature.The two most important ‘negative’ trials for aprotinin(Mangano et al. [3] as well as the Bart trial [4]) have beenargely discussed in literature. Not only the power but alsohe limitations of these trials are very well pointed out. Someuthors believe that the recent ‘attacks’ against aprotininay have been statistically unsound [5]. Even extensiveeta-analysis of the Cochrane collaboration in 2007 have notound an increased risk of death caused by the use ofprotinin compared to lysine analogues. The use of aprotininas recommended especially in high-risk patients in whom aubstantial blood loss has to be expected [6]. In amore recentpdate, this option has been contradicted by the sameuthors [7].What are the remaining questions? There has been anncreasing concern that questions the safety of aprotinin. Ife accept this, we are forced to ask why this was notetected during the two decades of extensive use of the drugith published good results. As a result of the aprotinin story8], studies should — if ever possible — focus on clinical end-oints that are not confounded with surrogate markers.ndependent clinical safety studies are mandatory even afteregulatory approval.Unfortunately, the large majority of studies that demon-trated adverse outcome following aprotinin were performedsing the original Hammersmith protocol, whichmeans a highosage. More than 15 years ago, we published similareneficial haemostatic results with low-dose aprotinin and nodverse cardiac outcomewas observed, neither early nor late9]. We do not understand why the low-dose regime was notdopted by more institutions.Finally, it is today still not clear which patient subgroupsay benefit from aprotinin. However, this is more ofheoretical interest since the drug is no longer availablen a regular basis. Considering that low-risk cardiac surgicalatients are at increased risk for bleeding events (e.g.,aving operation under ongoing combined anti-plateletherapy), other potent measures in addition to the availableysine analogues in order to reduce postoperative bleeding,S.C. Stamou et al. / European Journal of Cardio-thoracic Surgery 36 (2009) 869—876876the need for transfusion and the incidence of haemorrhagicre-exploration are welcome.References[1] Stamou SC, Reames MK, Skipper E, Stiegel RM, Nussbaum M, Geller R,Robicsek F, Lobdell KW. Aprotinin in cardiac surgery patients: is the riskworth the benefit? Eur J Cardio-thorac Surg 2009;36:869—75.[2] Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on needfor blood transfusion after repeat open-heart surgery. Lancet1987;2:1289—91.[3] Mangano DT, Tudor IC, Dietzel C, Multicenter Study of PerioperativeIschemia Research Group, Ischemia Research, Education Foundation.The risk associated with aprotinin in cardiac surgery. N Engl J Med2006;354:353—65.[4] Fergusson DA, He´bert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM,Teoh K, Duke PC, Arellano R, Blajchman MA, Bussie`res JS, Coˆte´ D, Karski J,Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R, BARTInvestigators. A comparison of aprotinin and lysine analogues in high-riskcardiac surgery. N Engl J Med 2008;358:2319—31.[5] Grunkemeier GL, Wu Y, Furnary AP. What is the value of a p value? AnnThorac Surg 2009;87:1337—43.[6] Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, McClelland B,Laupacis A, Fergusson D. Anti-fibrinolytic use for minimising perioperativeallogeneic blood transfusion. Cochrane Database Syst Rev 2007. CD001886.[7] Henry DA, Carless PA, Fergusson D, Laupacis A. The safety of aprotinin andlysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis.CMAJ 2009;180:183—93.[8] Ray WA, Stein CM. The aprotinin story—is BART the final chapter? N Engl JMed 2008;358:2398—400.[9] Carrel T, Bauer E, Laske A, von Segesser LK, Turina M. Low-dose aprotininalso allows reduction of blood loss and blood transfusion after cardiopul-monary bypass. J Thorac Cardiovasc Surg 1991;102:801—2.Thierry Carrel*, Lars EnglbergerClinic for Cardiovascular Surgery,University Hospital of Berne, Berne, Switzerland*Corresponding author. Tel.: +41 31 632 23 75;fax: +41 31 632 44 43E-mail address: thierry.carrel@insel.ch (T. Carrel)doi:10.1016/j.ejcts.2009.05.015

Editorial comment

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library