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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and epsilon-aminocaproic acid – a meta-analysis of randomised and observational trials of over 30,000 patients

P Meybohm, E Herrmann, J Nierhoff, and K Zacharowski.

Review published: 2013.

Link to full article: [PMC free article: PMC3590293]

CRD summary

This review concluded that aprotinin could increase mortality, compared with lysine analogues, for low- and intermediate-risk patients undergoing cardiac surgery, but could be beneficial for high-risk patients. Aprotinin may increase mortality, but the conclusion that it could be beneficial for high-risk patients is contradicted by the randomised trial evidence and cannot be considered to be reliable.

Authors' objectives

To compare aprotinin versus lysine analogues (tranexamic acid and epsilon-aminocaproic acid), for early death in low-, medium- and high-risk patients, undergoing cardiac surgery.


MEDLINE and The Cochrane Library were searched, for studies published in English, from January 1990 to April 2012. Search terms were reported. Reference lists of identified studies were checked.

Study selection

Randomised controlled trials (RCTs) and controlled observational studies that compared aprotinin with tranexamic acid, epsilon-aminocaproic acid, or both, for adult patients, undergoing cardiac surgery, were eligible for inclusion. Studies had to report short-term mortality, which was defined as the rate of deaths within 30 days, or in-hospital mortality. Secondary outcomes were transfusion within 24 hours of surgery, reoperation for bleeding or massive bleeding, and acute renal dysfunction or failure.

Most of the included studies reported in-hospital mortality. All three categories of operation were studied, but most studies were of mainly low-risk procedures. The exclusion criteria varied between studies, and there was no information on patient characteristics beyond the intervention type.

The authors did not state how many reviewers assessed the studies for inclusion in the review.

Assessment of study quality

Study quality was assessed, using the Downs and Black checklist, for reporting, external validity and bias, confounding and power, as aspects of internal validity. The maximum possible score was 29 points.

The authors did not state how many reviewers performed the assessment.

Data extraction

The data were extracted to calculate relative risks, with 95% confidence intervals, for primary and secondary outcomes. Study authors were contacted for any mortality data that were not reported. The interventions were grouped into those with a low risk (isolated coronary artery bypass or single valve replacement), an intermediate risk (combined artery bypass and valve replacement), or a high risk (complex operations such as multiple valve replacement or emergency surgery). They were classified based on the type of surgery most commonly performed, except where subgroup data were available.

One reviewer extracted the data.

Methods of synthesis

The pooled relative risks, with 95% confidence intervals, were calculated, using a DerSimonian and Laird random-effects model. Separate analyses were conducted for low-, intermediate-, and high-risk surgery. Subgroups of RCTs, and adjusted and unadjusted observational studies, were presented. Heterogeneity was assessed using Χ² and Ι².

Funnel plots were used to investigate publication bias.

Results of the review

Thirty-one studies were included (33,501 patients); 16 of them were RCTs. Quality scores ranged from 12 to 27, with a median of 18.5.

Low-risk patients, treated with aprotinin, had an increased risk of dying in the period following surgery, compared with those treated with lysine analogues (RR 1.58, 95% CI 1.13 to 2.21; 19 studies – 12 RCTs, but only six contributing to the estimate; 14,297 patients; Ι²=33.4%). This increased risk was also seen in intermediate-risk patients (RR 1.42, 95% CI 1.09 to 1.84; seven studies – one RCT; 14,427 patients; Ι²=18.3%). High-risk patients did not show an increased risk with aprotinin (RR 1.03, 95% CI 0.67 to 1.58; eight studies – three RCTs, two contributing to estimate; 4,777 patients; Ι²=67.1%). The relative risks for the three groups were not statistically significantly different from each other.

When analysing the RCTs alone, a non-significant increased harm was found in low-risk patients (RR 1.30, 95% CI 0.65 to 2.60; 12 trials – six contributing to the estimate; Ι²=0). One small RCT, with three events in 195 patients, studied intermediate-risk patients; the overall estimate was driven largely by unadjusted observational studies. For high-risk patients, there was statistically significant increased risk of dying with aprotinin (RR 1.50, 95% CI 1.05 to 2.16; three trials – two contributing to the estimate; 2,498 patients; Ι²=0). This was driven by the largest trial (2,331 patients), which had an relative risk of 1.53 (95% CI 1.06 to 2.22); this was a high-quality trial, scoring 27 out of a possible 29 for quality.

The results for secondary outcomes were reported. There were benefits in reduced transfusion, in low- and high-risk groups. There were no significant differences for reoperation or massive bleeding, or for renal dysfunction or failure.

Authors' conclusions

Aprotinin could be associated with increased mortality, compared with lysine analogues, in patients undergoing cardiac surgery at a low or intermediate risk. It could be beneficial for patients at a high risk, as it reduced transfusion and bleeding risks, without affecting mortality.

CRD commentary

The review addressed a clear question, supported by relevant inclusion criteria. The search was reasonable. The authors did not report any methods designed to reduce reviewer bias and error. The quality of the studies was assessed, using an appropriate tool, but the results were not used to inform the synthesis. The studies were considered to assess low-, intermediate- or high-risk patients based on the type of surgery for most patients. There was no information on other risk factors that could moderate that risk.

The methods used for the synthesis were reasonable. The review included both RCTs and observational studies and it was appropriate to provide separate results for these different types of study. The results made it clear that there were differences between the estimates of effect, from the randomised and non-randomised studies. In some cases, these differences were large and changed the conclusions of the review. In particular, the authors' conclusion that aprotinin did not increase the death rate for high-risk patients was based on the overall estimate, but the RCT analysis showed a significantly increased risk. This estimate was driven by a large high-quality trial, which showed a statistically significant higher risk of death with aprotinin.

There was some evidence that aprotinin increased early mortality in cardiac surgery, compared with lysine analogues, but the authors' conclusion that this was not the case for high-risk patients, cannot be considered to be reliable.

Implications of the review for practice and research

Practice: The authors stated that the recent recommendation of the European Medicines Agency, lifting the suspension of aprotinin for lower risk patients, should be critically debated. They suggested that aprotinin could be used for high-risk patients, as determined by their comorbidity, surgical acuity and complexity – this recommendation was not supported by the RCT evidence.

Research: The authors stated that a very large RCT was required to compare aprotinin versus lysine analogues and assess early mortality.


No funding received.

Bibliographic details

Meybohm P, Herrmann E, Nierhoff J, Zacharowski K. Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and epsilon-aminocaproic acid – a meta-analysis of randomised and observational trials of over 30,000 patients. PLOS ONE 2013; 8(3): e58009. [PMC free article: PMC3590293] [PubMed: 23483965]

Indexing Status

Subject indexing assigned by NLM


Aminocaproic Acid /adverse effects; Aprotinin /adverse effects; Cardiac Surgical Procedures /mortality; Humans; Randomized Controlled Trials as Topic; Risk Factors; Tranexamic Acid /adverse effects



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 23483965


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