BACKGROUND: Concerns regarding the safety of transfused blood have led to the 
development of a range of interventions to minimise blood loss during major 
surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac 
surgery, and previous reviews have found them to be effective in reducing blood 
loss, the need for transfusion, and the need for re-operation due to continued 
or recurrent bleeding. In the last few years questions have been raised 
regarding the comparative performance of the drugs. The safety of the most 
popular agent, aprotinin, has been challenged, and it was withdrawn from world 
markets in May 2008 because of concerns that it increased the risk of 
cardiovascular complications and death.
OBJECTIVES: To assess the comparative effects of the anti-fibrinolytic drugs 
aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood 
loss during surgery, the need for red blood cell (RBC) transfusion, and adverse 
events, particularly vascular occlusion, renal dysfunction, and death.
SEARCH STRATEGY: We searched: the Cochrane Injuries Group's Specialised Register 
(July 2010), Cochrane Central Register of Controlled Trials (The Cochrane 
Library 2010, Issue 3), MEDLINE (Ovid SP) 1950 to July 2010, EMBASE (Ovid SP) 
1980 to July 2010. References in identified trials and review articles were 
checked and trial authors were contacted to identify any additional studies. The 
searches were last updated in July 2010.
SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-fibrinolytic 
drugs in adults scheduled for non-urgent surgery. Eligible trials compared 
anti-fibrinolytic drugs with placebo (or no treatment), or with each other.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality 
and extracted data. This version of the review includes a sensitivity analysis 
excluding trials authored by Prof. Joachim Boldt.
MAIN RESULTS: This review summarises data from 252 RCTs that recruited over 
25,000 participants. Data from the head-to-head trials suggest an advantage of 
aprotinin over the lysine analogues TXA and EACA in terms of reducing 
perioperative blood loss, but the differences were small. Compared to control, 
aprotinin reduced the probability of requiring RBC transfusion by a relative 34% 
(relative risk [RR] 0.66, 95% confidence interval [CI] 0.60 to 0.72). The RR for 
RBC transfusion with TXA was 0.61 (95% CI 0.53 to 0.70) and was 0.81 (95% CI 
0.67 to 0.99) with EACA. When the pooled estimates from the head-to-head trials 
of the two lysine analogues were combined and compared to aprotinin alone, 
aprotinin appeared more effective in reducing the need for RBC transfusion (RR 
0.90; 95% CI 0.81 to 0.99).Aprotinin reduced the need for re-operation due to 
bleeding by a relative 54% (RR 0.46, 95% CI 0.34 to 0.62). This translates into 
an absolute risk reduction of 2% and a number needed-to-treat (NNT) of 50 (95% 
CI 33 to 100). A similar trend was seen with EACA (RR 0.32, 95% CI 0.11 to 0.99) 
but not TXA (RR 0.80, 95% CI 0.55 to 1.17). The blood transfusion data were 
heterogeneous and funnel plots indicate that trials of aprotinin and the lysine 
analogues may be subject to publication bias.When compared with no treatment 
aprotinin did not increase the risk of myocardial infarction (RR 0.87, 95% CI 
0.69 to 1.11), stroke (RR 0.82, 95% CI 0.44 to 1.52), renal dysfunction (RR 
1.10, 95% CI 0.79 to 1.54) or overall mortality (RR 0.81, 95% CI 0.63 to 1.06). 
Similar trends were seen with the lysine analogues, but data were sparse. These 
data conflict with the results of recently published non-randomised studies, 
which found increased risk of cardiovascular complications and death with 
aprotinin. There are concerns about the adequacy of reporting of uncommon events 
in the small clinical trials included in this review.When aprotinin was compared 
directly with either, or both, of the two lysine analogues it resulted in a 
significant increase in the risk of death (RR 1.39, 95% CI 1.02, 1.89), and a 
non-significant increase in the risk of myocardial infarction (RR 1.11 95% CI 
0.82, 1.50). Most of the data contributing to this added risk came from a single 
study - the BART trial (2008).
AUTHORS' CONCLUSIONS: Anti-fibrinolytic drugs provide worthwhile reductions in 
blood loss and the receipt of allogeneic red cell transfusion. Aprotinin appears 
to be slightly more effective than the lysine analogues in reducing blood loss 
and the receipt of blood transfusion. However, head to head comparisons show a 
lower risk of death with lysine analogues when compared with aprotinin. The 
lysine analogues are effective in reducing blood loss during and after surgery, 
and appear to be free of serious adverse effects.