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Letters to the Editor

Mortality manifesto: a meta-analysis of aprotinin and tranexamic acid mortality

The Dartmouth Institute for Health Policy and Clinical Practice, Dartmouth College and Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA

Received 16 April 2009; accepted 10 June 2009.

^_* Corresponding author. Tel.: +1 603 6533576; fax: +1 603 653 3554. (Email: jbrown{at}dartmouth.edu).

Key Words: Aprotinin • Tranexamic acid • Mortality • Meta-analysis

Later and colleagues presented the results from a non-sponsored, double-blind, randomised trial comparing the clinical outcomes for tranexamic acid and aprotinin [1]. They report that aprotinin significantly reduced bleeding in comparison with tranexamic acid, but there was no difference in the number of packed red blood cells. With regard to outcomes, they report no significant differences, but negate the twofold difference in mortality. This issue of comparative mortality with anti-fibrinolytic agents has been unresolved as yet. For this reason, we updated our head-to-head meta-analysis to determine the safety of aprotinin over tranexamic acid with regard to mortality.

We conducted a review of the published randomised control trial since our last meta-analysis comparing mortality rates in head-to-head trials between aprotinin and tranexamic acid [2]. We found three additional adult cardiac surgery trials: Fergusson (BART), Dietrich and Later (2008–2009). BART was the first large-scale head-to-head trial comparing aprotinin with lysine analogues, tranexamic acid and epsilon–aminocaproic acid (N = 2331), reporting a significant increased risk of 30-day mortality among patients randomised to aprotinin compared with either lysine analogue (RR: 1.53; 95% confidence interval (CI): 1.06–2.22) [3]. Dietrich reported on a smaller trial (N = 220) of patients randomised to aprotinin (two deaths) or tranexamic acid (one death) with no significant difference [4]. Later reported no significant difference in mortality, but observed a twofold difference. We calculated a pooled estimate on mortality for aprotinin compared with tranexamic acid (Fig. 1 ). Aprotinin had a significant 50% increased risk of death compared with tranexamic acid (RR: 1.50; 95% CI: 1.04–2.17). Recently, the Cochran collaborative reported aprotinin use in all types of surgery, where aprotinin had a non-significant higher rate of death compared with tranexamic acid (RR: 1.43; 95% CI: 0.98–2.08) and epsilon–aminocaproic acid (RR: 1.49; 95% CI: 0.98–2.28) [5].

View larger version (13K): [in this window] [in a new window]   Fig. 1. Meta-analysis comparing mortality between aprotinin and tranexamic acid. The relative risks (RR) of mortality by anti-fibrinolytic agent compared head-to-head are plotted. The RR for each study is plotted (blue box) with 95% confidence interval (horizontal bar). A pooled estimate RR (diamond) and 95% confidence intervals (width of diamonds) summarize the effect using a fixed effects model. Effects left of the 1.0 favors aprotinin over tranexamic acid; effects to the right favors tranexamic acid over aprotinin. When the horizontal bars cross 1.0, the effect is not significantly different from the comparison group. The I2 test for heterogeneity was not significant demonstrating homogeneity in mortality effects across the independent randomized trials (a trend towards increased death risk with aprotinin treatment).

Footnotes

The authors of the original paper [1] were invited to comment on this Letter to the Editor but declined the offer.

References

1. Later AF, Maas JJ, Engbers FH, Versteegh MI, Bruggemans EF, Dion RA, Klautz RJ. Tranexamic acid and aprotinin in low- and intermediate-risk cardiac surgery: a non-sponsored, double-blind, randomised, placebo-controlled trial. Eur J Cardiothorac Surg 2009;36:322-329.[Abstract/Free Full Text]
2. Brown JR, Birkmeyer NJ, O’Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:2801-2813.[Abstract/Free Full Text]
3. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319-2331.[Abstract/Free Full Text]
4. Dietrich W, Spannagl M, Boehm J, Hauner K, Braun S, Schuster T, Busley R. Tranexamic acid and aprotinin in primary cardiac operations: an analysis of 220 cardiac surgical patients treated with tranexamic acid or aprotinin. Anesth Analg 2008;107:1469-1478.[Abstract/Free Full Text]
5. Henry D, Carless P, Fergusson D, Laupacis A. The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis. CMAJ 2009;180:183-193.[Abstract/Free Full Text]

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