Correspondence
Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery
N Engl J Med 2008; 359:1181-1182September 11, 2008
- Article
To the Editor:
Fergusson et al. (May 29 issue)1 report the findings of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study. They found a negative mortality trend associated with aprotinin as compared with lysine analogues among patients undergoing high-risk cardiac surgery. This trend could be explained by an increased risk of death from a cardiac cause. In contrast to the study by Mangano et al.,2 the BART study revealed no increase in the risk of stroke or renal failure among patients receiving aprotinin.
In an editorial accompanying the article by Fergusson et al., Ray and Stein3 raise the question of whether there are surgical patients for whom aprotinin might continue to be indicated. In Europe, aprotinin is widely used in patients who are undergoing liver transplantation.4,5 Randomized, controlled trials and a large observational study in liver transplantation have not shown an increase in the risk of renal failure or mortality among patients receiving aprotinin.4,5 Therefore, it is unclear whether the safety concerns in cardiac surgery apply to other types of surgery. Although the recent literature leans toward the cessation of aprotinin use, this could be detrimental for patients undergoing liver transplantation in whom the benefits have been shown and the risks have not been proved.
Robert J. Porte, M.D., Ph.D.
University Medical Center Groningen, 9700 RB Groningen, the Netherlands
r.j. porte@chir. umcg. nl Susan V. Mallette, M.B., B.S.
Andrew K. Burroughs, M.B., Ch.B.
Royal Free Hospital, London NW3 2QG, United KingdomDr. Porte reports receiving an unrestricted educational grant from Bayer. No other potential conflict of interest relevant to this letter was reported.
5 References1
Fergusson DA ,Hebert 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
Full Text | Web of Science | Medline2
Mangano DT ,Tudor IC ,Dietzel C . The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-365
Full Text | Web of Science | Medline3
Ray WA ,Stein CM . The aprotinin story -- is BART the final chapter? N Engl J Med 2008;358:2398-2400
Full Text | Web of Science | Medline4
Molenaar IQ ,Warnaar N ,Groen H ,Tenvergert EM ,Slooff MJ ,Porte RJ . Efficacy and safety of antifibrinolytic drugs in liver transplantation; a systematic review and meta-analysis. Am J Transplant 2007;7:185-194
CrossRef | Web of Science | Medline5
Warnaar N ,Mallett SV ,de Boer MT , et al. The impact of aprotinin on renal function after liver transplantation: an analysis of 1,043 patients. Am J Transplant 2007;7:2378-2387
CrossRef | Web of Science | Medline
To the Editor:
In the editorial accompanying the article about the BART study, Ray and Stein state that “there must be less emphasis on comparisons of new agents with placebo and more emphasis on adequately powered, head-to-head comparisons with other available drugs.” I disagree. Given that earlier in their editorial Ray and Stein raise the possibility of the procoagulatory effects of antifibrinolytic drugs, as suggested by previous studies of the lysine analogues (tranexamic acid and aminocaproic acid),1 then surely the safety of all the antifibrinolytic drugs, not just aprotinin, should be questioned. These agents clearly reduce bleeding,2 but could the lysine analogues also lead to excess mortality? We simply do not know the answer to this question. Large, adequately powered, placebo-controlled trials such as the Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) trial1 are urgently needed to investigate the effectiveness and safety of the lysine analogues in coronary-artery bypass graft surgery.
2 ReferencesPaul S. Myles, M.D., M.P.H.
Alfred Hospital, Melbourne, VIC 3004, Australia
p.myles@alfred. org. au 1
Myles PS ,Smith J ,Knight J , et al. Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) Trial: rationale and design. Am Heart J 2008;155:224-230
CrossRef | Web of Science | Medline2
Henry DA ,Carless PA ,Moxey AJ , et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007;4:CD001886-CD001886
Medline
Author/Editor Response
These letters underscore one of the important lessons of the BART study: blood loss in surgical procedures has many of the characteristics of a surrogate end point. This somewhat surprising conclusion might not have been reached if BART — the type of trial that our editorial advocated should be routinely performed as part of the drug-approval process — had not been conducted. We previously have argued that drugs approved on the basis of a surrogate end point should be studied to determine their effect on clinical end points. Thus, we agree with Myles that it is important to investigate the effects of tranexamic acid on serious complications of coronary-artery surgery.
Porte and colleagues are concerned that the cessation of aprotinin use in patients undergoing liver transplantation could be detrimental. Our opinion, particularly in view of the findings of BART, is that we should not assume a net benefit of aprotinin without rigorous supporting evidence, which is best provided by a large clinical trial that is adequately powered for clinical end points.
Wayne A. Ray, Ph.D.
C. Michael Stein, M.B., Ch.B.
Vanderbilt University School of Medicine, Nashville, TN 37232- Citing Articles (2)
Citing Articles
1
Jan Frädorf, Ragnar Huhn, Nina C. Weber, Dirk Ebel, Nadja Wingert, Benedikt Preckel, Octavian Toma, Wolfgang Schlack, Markus W. Hollmann. (2010) Sevoflurane-induced Preconditioning. Anesthesiology 113:6, 1289-1298
CrossRef2
John G.T. Augoustides. (2009) The Year in Cardiothoracic and Vascular Anesthesia: Selected Highlights From 2008. Journal of Cardiothoracic and Vascular Anesthesia 23:1, 1-7
CrossRef
