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• W2071781908 abstract "That aprotinin is a highly effective hemostatic agent in cardiopulmonary surgery is not debatable – its efficacy has been proven definitively by placebo‐controlled randomized‐clinical trials (RCTs) to the point of redundancy [1Fergusson D. Glass K.C. Hutton B. Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding.Clin Trials. 2005; 2: 218-29Crossref PubMed Scopus (0) Google Scholar]. Our position that aprotinin is not a useful first choice hemostatic agent in cardiopulmonary surgery is based on the availability of a class of drugs – the lysine analogs tranexamic acid and epsilon‐aminocaproic acid – that are as efficacious as aprotinin and are about 4‐fold less expensive. What is more, they may also have a better safety profile, as suggested by two recent publications that seem to be responsible for re‐igniting this debate [2Mangano D.T. Tudor I.C. Dietzel C. The risk associated with aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 353-65Crossref PubMed Scopus (959) Google Scholar, 3Karkouti K. Beattie W.S. Dattilo K.M. McCluskey S.A. Ghannam M. Hamdy A. Wijeysundera D.N. Fedorko L. Yau T.M. A propensity score case–control comparison of aprotinin and tranexamic acid in high‐transfusion‐risk cardiac surgery.Transfusion. 2006; 46: 327-38Crossref PubMed Scopus (0) Google Scholar]. The primary issue here, in our opinion, is efficacy, not safety. After all, we often use drugs that have important side‐effects, but only if they offer a clinically important benefit compared with available alternatives. Aprotinin does not seem to meet this criterion. There is a plethora of evidence that blood loss that leads to transfusion of blood products is harmful, and that the degree of harm is directly related to the amount of blood loss [4Spiess B.D. Transfusion of blood products affects outcome in cardiac surgery.Semin Cardiothorac Vasc Anesth. 2004; 8: 267-81Crossref PubMed Scopus (119) Google Scholar]. Although it is not known whether it is the blood loss or the resultant blood transfusion that is harmful, this distinction has little practical relevance. In one recent study, transfusion of five or more units of blood was independently associated with an 8‐fold increase in the risk of death, and this risk was exceeded only by postoperative renal failure and stroke [5Karkouti K. Wijeysundera D.N. Yau T.M. Beattie W.S. Abdelnaem E. McCluskey S.A. Ghannam M. Yeo E. Djaiani G. Karski J. The independent association of massive blood loss with mortality in cardiac surgery.Transfusion. 2004; 44: 1453-62Crossref PubMed Scopus (322) Google Scholar]. It has also been clearly shown (by numerous randomized, placebo‐controlled trials) that both classes of antifibrinolytic drugs reduce perioperative blood loss and red blood cell (RBC) transfusions by about 30% [6Levi M. Cromheecke M.E. De Jonge E. Prins M.H. De Mol B.J. Briet E. Buller H.R. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta‐analysis of clinically relevant endpoints.Lancet. 1999; 354: 1940-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 7Henry D.A. Moxey A.J. Carless P.A. O'Connell D. McClelland B. Henderson K.M. Sly K. Laupacis A. Fergusson D. Anti‐fibrinolytic use for minimising perioperative allogeneic blood transfusion.Cochrane Database Syst Rev. 2001; Crossref Scopus (4) Google Scholar]. Thus, the evidence is compelling that an antifibrinolytic drug should be used in all patients undergoing cardiopulmonary surgery to decrease blood loss, and there seems to be a general consensus on this point. What is controversial is whether aprotinin has a better balance of benefit and harms than the cheaper lysine analogs. The optimal trial design for comparing the relative efficacy of different therapies is the head‐to‐head RCT, but the validity of such trials is influenced by numerous factors including the degree of blinding and the size of the trial [8Ioannidis J.P. Haidich A.B. Pappa M. Pantazis N. Kokori S.I. Tektonidou M.G. Contopoulos‐Ioannidis D.G. Lau J. Comparison of evidence of treatment effects in randomized and nonrandomized studies.JAMA. 2001; 286: 821-30Crossref PubMed Google Scholar]. Although several RCTs have directly compared the relative efficacy of aprotinin and lysine analogs, many of them are admittedly not of the highest quality; their primary limitations being incomplete blinding, exclusion of high‐risk patients, and small sample sizes. Nevertheless, these studies provide valuable information when their results are pooled together by meta‐analytic techniques to overcome their small sample sizes. In one recent meta‐analysis, head‐to‐head studies comparing aprotinin with tranexamic acid were identified and their results were pooled [9Carless P.A. Moxey A.J. Stokes B.J. Henry D.A. Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta‐analysis of randomized head‐to‐head trials.BMC Cardiovasc Disord. 2005; 5: 19Crossref PubMed Scopus (0) Google Scholar]. This meta‐analysis found aprotinin to be associated with a modest (and clinically unimportant) reduction in perioperative blood loss [weighted mean difference, without accounting for significant heterogeneity between study results, was 106 mL (95% confidence interval; CI = 37, 176 mL)]. There were, however, no statistical or clinical differences in the relative risk of requiring an RBC transfusion (RR = 1.08, 95% CI = 0.88, 1.32) or re‐exploration (RR = 0.98, 95% CI = 0.51, 1.88). Thus, head‐to‐head studies of aprotinin and tranexamic acid provide a powerful, and logical, rejection of the hypothesis that aprotinin is a superior blood sparing agent. To obtain the best estimate of the relative safety profile of antifibrinolytic drugs, one must consider both the results of systematic reviews of placebo‐controlled RCTs and the results of large observational studies. Available head‐to‐head RCTs are of little additional value for they provide scant information on adverse events. When considering the placebo‐controlled RCTs, it is important to remember that many adverse events – such as stroke, renal failure, myocardial infarction (MI), and death – are directly related to excessive bleeding. As antifibrinolytic drugs decrease excessive bleeding, they should be associated with reduced adverse event rates in placebo‐controlled studies. Reassuringly, systematic reviews of these studies found that, compared with placebo, the point estimates for adverse event rates were, for the most part, lower in those who received either aprotinin or tranexamic acid [6Levi M. Cromheecke M.E. De Jonge E. Prins M.H. De Mol B.J. Briet E. Buller H.R. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta‐analysis of clinically relevant endpoints.Lancet. 1999; 354: 1940-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 7Henry D.A. Moxey A.J. Carless P.A. O'Connell D. McClelland B. Henderson K.M. Sly K. Laupacis A. Fergusson D. Anti‐fibrinolytic use for minimising perioperative allogeneic blood transfusion.Cochrane Database Syst Rev. 2001; Crossref Scopus (4) Google Scholar]. Notable exceptions were an increased risk of MI and renal dysfunction associated with aprotinin use [6Levi M. Cromheecke M.E. De Jonge E. Prins M.H. De Mol B.J. Briet E. Buller H.R. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta‐analysis of clinically relevant endpoints.Lancet. 1999; 354: 1940-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 10Brown J.R. Birkmeyer N.J. O'Connor G.T. Aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 1953-7Crossref PubMed Google Scholar]. These results are consistent with those of recently published observational studies [2Mangano D.T. Tudor I.C. Dietzel C. The risk associated with aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 353-65Crossref PubMed Scopus (959) Google Scholar, 3Karkouti K. Beattie W.S. Dattilo K.M. McCluskey S.A. Ghannam M. Hamdy A. Wijeysundera D.N. Fedorko L. Yau T.M. A propensity score case–control comparison of aprotinin and tranexamic acid in high‐transfusion‐risk cardiac surgery.Transfusion. 2006; 46: 327-38Crossref PubMed Scopus (0) Google Scholar]. Before discussing these studies, it is important to note that although systematic reviews of randomized trials occupy the highest echelon in the hierarchy of medical evidence for measuring the efficacy of a drug, they are not necessarily the best means for identifying the harm that can be caused by a drug. This is particularly true if the associated harmful effects are rare, delayed, or unrelated to the therapeutic indication of the drug. Large observational studies, with appropriate multivariable risk‐adjusted analysis to control for confounding by indication, may be better suited for detecting such harmful effects [11Papanikolaou P.N. Christidi G.D. Ioannidis J.P. Comparison of evidence on harms of medical interventions in randomized and nonrandomized studies.CMAJ. 2006; 174: 635-41Crossref PubMed Scopus (181) Google Scholar]. In both of the recently published observational studies [2Mangano D.T. Tudor I.C. Dietzel C. The risk associated with aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 353-65Crossref PubMed Scopus (959) Google Scholar, 3Karkouti K. Beattie W.S. Dattilo K.M. McCluskey S.A. Ghannam M. Hamdy A. Wijeysundera D.N. Fedorko L. Yau T.M. A propensity score case–control comparison of aprotinin and tranexamic acid in high‐transfusion‐risk cardiac surgery.Transfusion. 2006; 46: 327-38Crossref PubMed Scopus (0) Google Scholar], data from large, comprehensive clinical databases were used to assess the relative benefits and harmful effects of antifibrinolytic drugs by comparing the outcomes of patients who received aprotinin with those who received lysine analogs, using propensity score methods to adjust for baseline differences between the treatment groups. The studies had similar results in that neither found aprotinin to have superior blood‐sparing effects, which is consistent with the findings of the systematic review of head‐to‐head RCTs [9Carless P.A. Moxey A.J. Stokes B.J. Henry D.A. Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta‐analysis of randomized head‐to‐head trials.BMC Cardiovasc Disord. 2005; 5: 19Crossref PubMed Scopus (0) Google Scholar]. Moreover, both studies found aprotinin to be associated with worsening renal function (i.e. increased serum creatinine concentration), which is consistent with the findings of some of the systematic reviews of placebo‐controlled RCTs [10Brown J.R. Birkmeyer N.J. O'Connor G.T. Aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 1953-7Crossref PubMed Google Scholar]. While these studies have important limitations – the limitations of the study by Mangano et al. [2Mangano D.T. Tudor I.C. Dietzel C. The risk associated with aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 353-65Crossref PubMed Scopus (959) Google Scholar] have been clearly highlighted in a recently published letter to the editor [12Ferraris V.A. Bridges C.R. Anderson R.P. Aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 1953-7Crossref PubMed Scopus (0) Google Scholar], and those of the study by Karkouti et al. [3Karkouti K. Beattie W.S. Dattilo K.M. McCluskey S.A. Ghannam M. Hamdy A. Wijeysundera D.N. Fedorko L. Yau T.M. A propensity score case–control comparison of aprotinin and tranexamic acid in high‐transfusion‐risk cardiac surgery.Transfusion. 2006; 46: 327-38Crossref PubMed Scopus (0) Google Scholar] have been discussed in the original paper [13Wijeysundera D.N. Rao V. Beattie W.S. Ivanov J. Karkouti K. Evaluating surrogate measures of renal dysfunction after cardiac surgery.Anesth Analg. 2003; 96: 1265-73Crossref PubMed Google Scholar] – they serve to further strengthen the argument against the first‐line use of aprotinin in cardiac surgery. It has been argued that increased postoperative serum creatinine concentration has little clinical relevance; however, this is a validated surrogate outcome, with one study finding that mortality doubles with every 10% increase in postoperative serum concentration [13Wijeysundera D.N. Rao V. Beattie W.S. Ivanov J. Karkouti K. Evaluating surrogate measures of renal dysfunction after cardiac surgery.Anesth Analg. 2003; 96: 1265-73Crossref PubMed Google Scholar]. Any discussion of aprotinin would be incomplete without noting its proclivity for causing severe allergic reactions, particularly upon re‐exposure. It is telling that the FDA, in approving aprotinin, recommended against its routine use owing to its risk of severe allergic reactions and kidney toxicity [14http://www.fda.gov/bbs/topics/NEWS/NEW00453.html. (accessed on June 5, 2006).Google Scholar]. It has been argued that aprotinin has benefits beyond blood conservation, such as offering neurological protection owing to its action on protease‐activated receptors [12Ferraris V.A. Bridges C.R. Anderson R.P. Aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 1953-7Crossref PubMed Scopus (0) Google Scholar]. There is, however, no clinical evidence that aprotinin reduces the risk of stroke and other adverse events beyond those that can be explained by reduction of blood loss. Thus, until the organ‐protective effects of aprotinin are demonstrated in studies that compare aprotinin with other antifibrinolytic drugs, this argument has no merit. Thus, although important questions remain about the use of antifibrinolytic drugs – such as which of the drugs is more effective in preventing massive blood loss, in very high‐risk patients (such as those with active endocarditis or on clopidogrel), or in preserving organ function – there is sufficient evidence to conclude that, owing to its lack of superiority in reducing blood loss, greater cost, and possibly inferior safety profile compared with available alternatives, aprotinin is not currently an appropriate first‐choice antifibrinolytic drug in cardiopulmonary surgery. Owing to the importance of the questions listed above, however, its investigational use in head‐to‐head clinical trials should be encouraged." @default.
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• W2071781908 title "Aprotinin is useful as a hemostatic agent in cardiopulmonary surgery: no" @default.
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