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Interact CardioVasc Thorac Surg 2009;9:98-101. doi:10.1510/icvts.2008.198325
© 2009 European Association of Cardio-Thoracic Surgery
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Institutional report - Cardiac general

Aprotinin increases mortality as compared with tranexamic acid in cardiac surgery: a meta-analysis of randomized head-to-head trials

Hisato Takagi*, Hideaki Manabe, Norikazu Kawai, Shin-nosuke Goto and Takuya Umemoto

Department of Cardiovascular Surgery, Shizuoka Medical Center, 762-1 Nagasawa, Shimizu-cho, Sunto-gun, Shizuoka 411-8611, Japan

Received 10 November 2008; received in revised form 29 March 2009; accepted 31 March 2009

*Corresponding author. Tel.: +81-55-975-2000; fax: +81-55-975-2725.

E-mail address: kfgth973{at}ybb.ne.jp (H. Takagi).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
To determine whether aprotinin increases mortality as compared with tranexamic acid in cardiac surgery, we performed a meta-analysis of randomized head-to-head trials. All prospective randomized head-to-head trials of aprotinin vs. tranexamic acid enrolling patients undergoing cardiac surgery were identified using a web-based search engine (PubMed). For each study, data regarding mortality in both the aprotinin and tranexamic acid groups were used to generate risk ratios (RRs) and 95% confidence intervals (CIs). Study-specific estimates were combined using inverse variance-weighted averages of logarithmic RRs in random-effects models. Our search identified nine trials (eight trials included in the previous meta-analysis and the blood conservation using antifibrinolytics in a randomized trial [BART] study). Seven trials were composed of low-risk patients (n=1291) and two trials consisted of low-risk patients (n=1628). Pooled analysis of the nine trials demonstrated a statistically significant 45% increase in mortality with aprotinin relative to tranexamic acid therapy (RR, 1.45; 95% CI, 1.00 [1.0002]–2.11; P=0.05 [0.0499]). The present meta-analysis of updated all randomized head-to-head trials, the best evidence, demonstrated a statistically significant increase in mortality with aprotinin relative to tranexamic acid therapy in cardiac surgery.

Key Words: Aprotinin; Tranexamic acid; Cardiac surgery; Meta-analysis; Randomized head-to-head trial


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
A previous meta-analysis in 2007 [1] of eight randomized head-to-head trials (representing 1689 patients) [2–9] demonstrated that aprotinin compared with tranexamic acid was not significantly different with regard to mortality (relative risk (RR), 1.29; 95% confidence interval (CI), 0.63–2.65; P=0.49) in cardiac surgery. Most recently, however, Fergusson and associates [10] demonstrated in the blood conservation using antifibrinolytics in a randomized trial (BART) study in 2008 that the 30-day rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (RR, 1.55; 95% CI, 0.99–2.42). The trial was terminated early because of a strong trend toward higher mortality in the aprotinin group than in the tranexamic acid group on the basis of interim data. Although the BART study [10] and a trial by Wong et al. [5] were conducted in high-risk patients, low-risk patients were exclusively included in the other trials [2–4, 6–9]. To determine whether aprotinin increases mortality as compared with tranexamic acid in cardiac surgery, we performed a meta-analysis of updated all randomized head-to-head trials including the BART [10] study and the eight trials [2–9] included in the previous meta-analysis [1].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Search strategy

All prospective randomized head-to-head trials of aprotinin vs. tranexamic acid enrolling patients undergoing cardiac surgery were identified using a 2-level search strategy: first, a public domain database (MEDLINE) was searched using a web-based search engine (PubMed); second, relevant studies were identified through a manual search of secondary sources including references of initially identified articles and a search of reviews and commentaries. The MEDLINE database was searched from January 1966 to May 2008, and MeSH keywords included aprotinin, tranexamic acid, cardiac surgical procedures, and randomized controlled trial.

2.2. Study selection

Studies considered for inclusion met the following criteria: the design was a prospective randomized controlled clinical trial; the study population was adult patients undergoing cardiac surgery; patients were randomly assigned to aprotinin vs. tranexamic acid therapy; and main outcomes included mortality. We included data published as full-text journal publications.

2.3. Data abstraction

Data regarding detailed inclusion criteria and mortality were abstracted (as available) from each individual study.

2.4. Statistical analysis

For each study, data regarding mortality in both the aprotinin and tranexamic acid groups were used to generate RRs and 95% CIs. For trials in which either or both of the groups had no event of death, the estimate of treatment effect and its standard error were calculated after adding 0.5 to each cell of the 2x2 table for the trial. Study-specific estimates were combined using inverse variance-weighted averages of logarithmic RRs in both fixed- and random-effects models. Between-study heterogeneity was analyzed by means of standard {chi}2-tests. Where no significant statistical heterogeneity was identified, the fixed-effect estimate was used preferentially as the summary measure. Publication bias was assessed graphically using a funnel plot and mathematically using an adjusted rank-correlation test, according to the method of Begg and Mazumdar [11]. All analyses were conducted using review manager (RevMan) (Computer program) (Version 5.0) (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008) and Microsoft Excel (Version 11.5.0).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Our search identified nine prospective randomized head-to-head clinical trials [2–10] of aprotinin vs. tranexamic acid therapy enrolling patients undergoing cardiac surgery. Eight [2–9] of the nine trials (except for the BART [10] study) had been included in the previous meta-analysis [1].

In the BART study [10], patients underwent one of the following high-risk cardiac surgical procedures for which cardiopulmonary bypass (CPB) was required: repeat cardiac surgery, isolated mitral valve replacement, combined valve and coronary artery bypass grafting (CABG), multiple valve replacement or repair, and surgery of the ascending aorta or aortic arch. Patients who required either urgent or elective procedures were considered eligible. The study excluded patients who were undergoing lower risk operations, such as isolated primary CABG with or without CPB, isolated mitral valve repair or aortic valve replacement (AVR). Kuitunen and associates [2] included patients scheduled for elective primary CABG. In the trial by Diprose and colleagues [3], patients were scheduled to receive either CABG or single valve repair or replacement. Patients undergoing emergency surgery and combined or redo surgery were excluded. Casati and co-workers [4] included patients scheduled for primary elective cardiac surgery necessitating CPB. In the trial by Wong et al. [5], patients undergoing elective, high transfusion risk cardiac procedures were studied. The procedures included repeat cardiac operations (CABG or valvular operations), combined procedures (valvular operation plus CABG), and other complex procedures (multiple valve replacement, ascending aortic graft). Nuttall and associates [6] enrolled patients scheduled for elective revision sternotomy for CABG, or cardiac valve surgery, or a combination of the two. In the study by Casati and colleagues [7], patients scheduled for first-time elective cardiac surgery requiring CPB were included. Mongan and co-workers [8] enrolled patients scheduled for elective primary CABG. In the trial by Blauhut et al. [9], a condition requiring emergency surgery or re-operation was excluded.

Pooled analysis of the nine trials (representing 3229 patients) demonstrated a statistically significant 45% increase in mortality with aprotinin relative to tranexamic acid therapy in fixed-effect models (RR, 1.45; 95% CI, 1.00 [1.0002]–2.11; P=0.05 [0.0499]) (Fig. 1). When the four trials [2, 3, 6, 8] reporting no events of death in both the groups were excluded and data from the remaining five trials [4, 5, 7, 9, 10] were pooled using a fixed-effects model (representing 2834 patients), aprotinin therapy was associated with a 47% increase in mortality relative to tranexamic acid therapy that remained statistically significant (RR, 1.47; 95% CI, 1.01–2.15; P=0.05 [0.0464]) (Fig. 2). There was minimal trial heterogeneity and accordingly no difference in the pooled result from random-effects modeling. To assess publication bias we generated a funnel plot of the logarithm of effect size vs. the standard error for each study (Fig. 3). There was no evidence of significant publication bias (P=1.00 by Begg adjusted rank-correlation test).


Figure 1
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  		Fig. 1. Pooled analysis of all the nine trials. SE, standard error; CI, confidence interval; TA, tranexamic acid.

 

Figure 2
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  		Fig. 2. Pooled analysis of the five trials, excluding the four trials reporting no events of death in both the groups. SE, standard error; CI, confidence interval; TA, tranexamic acid.

 

Figure 3
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  		Fig. 3. A funnel plot of the logarithm of effect size (risk ratio RR) vs. the standard error (SE) for each study.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The safety of aprotinin was called into question in 2006 and 2007 when the results of an international cohort study, by Mangano and associates [12, 13], of patients undergoing CABG were published. The authors demonstrated increased risks of renal failure, myocardial infarction, and stroke and increased 5-year mortality with aprotinin but not with the lysine analogues. Two additional cohort studies showed in 2008 that patients undergoing CABG who received aprotinin had greater mortality than did those who received aminocaproic acid in the short-term as reported by Schneeweiss and colleagues [14] and in the long-term as reported by Shaw and co-workers [15]. The present meta-analysis of updated all randomized head-to-head trials, the best evidence, demonstrated a statistically significant increase in mortality with aprotinin relative to tranexamic acid therapy in cardiac surgery. The previous meta-analysis [1] included seven trials [2–4, 6–9] composed of low-risk patients (representing 1612 patients) and merely one trial [5] consisting of high-risk patients (representing 77 patients). Our updated analysis, which added the BART study [10], included seven trials [2–4, 6–9] composed of low-risk patients (representing 1601 patients) and two trials [5, 10] consisting of high-risk patients (representing 1628 patients). The weight of high-risk trials increased from 4.6% in the previous analysis to 50.4% in the present analysis. Although the BART study itself demonstrated a statistically non-significant increase in mortality with aprotinin relative to tranexamic acid therapy (RR, 1.54; 95% CI, 0.99–2.42) probably due to early termination, adding the trial to a meta-analysis (i.e. increasing the weight of high-risk trials) led the pooled RR for mortality to be statistically significant (RR, 1.45; 95% CI, 1.00 [1.0002]–2.11; P=0.05 [0.0499]). In the present study we focused on the outcome of death. Although the previous meta-analysis [1] demonstrated that aprotinin reduced total blood loss over tranexamic acid (weighted mean difference, –195 ml; 95% CI, –286 to –105 ml; P<0.001), a significant increase in the risk of death associated with aprotinin as compared with tranexamic acid, demonstrated by the present meta-analysis, precludes its use in cardiac surgery.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. 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]
  2. Kuitunen A, Hiippala S, Vahtera E, Rasi V, Salmenperä M. The effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic response after cardiac surgery. Acta Anaesthesiol Scand 2005;49:1272–1279.[CrossRef][Medline]
  3. Diprose P, Herbertson MJ, O'Shaughnessy D, Deakin CD, Gill RS. Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 2005;94:271–278.[Abstract/Free Full Text]
  4. Casati V, Guzzon D, Oppizzi M, Bellotti F, Franco A, Gerli C, Cossolini M, Torri G, Calori G, Benussi S, Alfieri O. Tranexamic acid compared with high-dose aprotinin in primary elective heart operations: effects on perioperative bleeding and allogeneic transfusions. J Thorac Cardiovasc Surg 2000;120:520–527.[Abstract/Free Full Text]
  5. Wong BI, McLean RF, Fremes SE, Deemar KA, Harrington EM, Christakis GT, Goldman BS. Aprotinin and tranexamic acid for high transfusion risk cardiac surgery. Ann Thorac Surg 2000;69:808–816.[Abstract/Free Full Text]
  6. Nuttall GA, Oliver WC, Ereth MH, Santrach PJ, Bryant SC, Orszulak TA, Schaff HV. Comparison of blood-conservation strategies in cardiac surgery patients at high-risk for bleeding. Anesthesiology 2000;92:674–682.[CrossRef][Medline]
  7. Casati V, Guzzon D, Oppizzi M, Cossolini M, Torri G, Calori G, Alfieri O. Hemostatic effects of aprotinin, tranexamic acid and epsilon-aminocaproic acid in primary cardiac surgery. Ann Thorac Surg 1999;68:2252–2257.[Abstract/Free Full Text]
  8. Mongan PD, Brown RS, Thwaites BK. Tranexamic acid and aprotinin reduce postoperative bleeding and transfusions during primary coronary revascularization. Anesth Analg 1998;87:258–265.[Abstract/Free Full Text]
  9. Blauhut B, Harringer W, Bettelheim P, Doran JE, Späth P, Lundsgaard-Hansen P. Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994;108:1083–1091.[Abstract/Free Full Text]
  10. Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, Côté D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R, BART investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319–2331.[Abstract/Free Full Text]
  11. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–1101.[CrossRef][Medline]
  12. Mangano DT, Tudor IC, Dietzel C, Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353–365.[Abstract/Free Full Text]
  13. Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J, Investigators of the Multicenter Study of Perioperative Ischemia Research Group, Ischemia Research and Education Foundation. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. J Am Med Assoc 2007;297:471–479.[Abstract/Free Full Text]
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I. Koniari, E. Apostolakis, and M. Martha
eComment: A comparison of the safety of aprotinin and tranexamic acid in cardiac surgery
Interactive CardioVascular and Thoracic Surgery, July 1, 2009; 9(1): 101 - 101.
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