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 and the need for transfusion. Recently, questions have been raised regarding the comparative performance of the drugs and the safety of the most popular agent, aprotinin. 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 ( RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death. Search strategy We searched CENTRAL, MEDLINE, EMBASE, and the internet. 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 2006. 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. Main results This review summarises data from 211 RCTs that recruited 20,781 participants. Data from placebo/inactive controlled trials, and from head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of operative blood loss, but the differences were small. Aprotinin reduced the probability of requiring RBC transfusion by a relative 34% ( relative risk [RR] 0.66, 95% confidence interval [CI] 0.61 to 0.71). The RR for RBC transfusion with TXA was 0.61 ( 95% CI 0.54 to 0.69) and it was 0.75 ( 95% CI 0.58 to 0.96) 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 superior in reducing the need for RBC transfusion: RR 0.83 ( 95% CI 0.69 to 0.99). Aprotinin reduced the need for re-operation due to bleeding: RR 0.48 ( 95% CI 0.35 to 0.68). This translates into an absolute risk reduction of just under 3% and a number needed-to-treat (NNT) of 37 ( 95% CI 27 to 56). Similar trends were seen with TXA and EACA, but the data were sparse and the differences failed to reach statistical significance. The blood transfusion data were heterogeneous and funnel plots indicate that trials of aprotinin and the lysine analogues may be subject to publication bias. Evidence of publication bias was not observed in trials reporting re-operation rates. Adjustment for these effects reduced the magnitude of estimated benefits but did not negate treatment effects. However, the apparent advantage of aprotinin over the lysine analogues was small and may be explained by publication bias and non-equivalent drug doses. Aprotinin did not increase the risk of myocardial infarction (RR 0.92, 95% CI 0.72 to 1.18), stroke ( RR 0.76, 95% CI 0.35 to 1.64) renal dysfunction ( RR 1.16, 95% CI 0.79 to 1.70) or overall mortality ( RR 0.90, 95% CI 0.67 to 1.20). The analyses of myocardial infarction and death included data from the majority of subjects recruited into the clinical trials of aprotinin. However, under-reporting of renal events could explain the lack of effect seen with aprotinin. Similar trends were seen with the lysine analogues but data were sparse. These results conflict with the results of recently published non-randomised studies. Authors' conclusions Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the need for allogeneic red cell transfusion. Based on the results of randomised trials their efficacy does not appear to be offset by serious adverse effects. In most circumstances the lysine analogues are probably as effective as aprotinin and are cheaper; the evidence is stronger for tranexamic acid than for aminocaproic acid. In high risk cardiac surgery, where there is a substantial probability of serious blood loss, aprotinin may be preferred over tranexamic acid. Aprotinin does not appear to be associated with an increased risk of vascular occlusion and death, but the data do not exclude an increased risk of renal failure. There is no need for further placebo-controlled trials of aprotinin or lysine analogues in cardiac surgery. The principal need is for large comparative trials to assess the relative efficacy, safety and cost-effectiveness of anti-fibrinolytic drugs in different surgical procedures.
