We appreciate the chance to respond to recent letters regarding our review[1,2]. Dr. Freemantle and colleagues[1] raise two issues: qualitative differences between our review and theirs, and concerns with our inclusion of observational studies using propensity scoring. We have difficulties with their commentary. As for qualitative differences, careful inspection shows the authors appear to have inappropriately compared our mortality estimate[3] for aprotinin versus tranexamic acid with their estimate for re-operation[1], an outcome we did not review. This is uninformative and inappropriate. The authors also question the narrower credible interval of our mortality estimate comparing aprotinin with tranexamic acid and suggest qualitative differences in findings.

We disagree there is a qualitative difference between estimates; the direction of increased mortality risk with aprotinin compared to tranexamic acid is consistent, while our point estimate has narrower credible intervals. More importantly, we explored reasons for the difference in this estimate and were disappointed to find that, despite explicitly stating that their review was for cardiac surgery patients, one can see from their Table 1 that Freemantle et al appear to have inappropriately included trials in liver transplantation[5-7], hip replacement[8], cancer[9], and infrarenal abdominal aneurysm[10] in their analysis. They also included studies of off-pump cardiac procedures, which we excluded a priori[11-14]. As an exercise, we repeated our mortality analysis after incorporating these unrelated RCTs and achieved estimates similar to theirs, however these studies do not belong in a meta-analysis of cardiac surgery. We agree propensity score matching techniques cannot guarantee complete removal of selection bias from observational studies. We noted this previously, and it was the rationale for sequentially pooling our data. It has long been suggested to consider observational data for analyses of harms due to limitations encountered by studying RCTs only[15-22], and our paper used one possible approach for doing so. We stand by findings from our work. Regarding the BART study, the erroneous and misleading criticisms made by the European Medicines Agency and the Expert Advisory Panel on Trasylol are being addressed in a manuscript currently in peer review. Finally, it is disappointing to see researchers in a scientific discussion resort to ad hominems such as ‘scaremongering’ to dismiss conflicting evidence.

The comments from Dr. Weng relate to diversity of patients and treatments and are relevant for meta-analysis. Regarding the testing of homogeneity/similarity, we believe these assumptions are best considered by careful review of study characteristics by methodologists and clinical experts. Our team judged the studies appropriate for meta-analysis based on their clinical and methodologic features, and this is most important as statistical heterogeneity may be present even in the presence of homogeneous studies. Regarding our inclusion criteria, it is fair to describe the patient populations as broad. Our approach is however in line with past reviews of antifibrinolytic agents, and the debate of ‘lumping’ versus ‘splitting’ populations may be argued reasonably both ways. We believe these patients to be appropriate for meta-analyses. Although the desire to look separately at low risk and high risk groups is understandable, doing so in this field is difficult as there are multiple factors to determine risk (surgical history, procedure type, procedure urgency), and many studies include multiple types. The observational studies in this area include many types of patients, making their inclusion in pure subgroup analyses infeasible, and one is then left with small trials for such explorations.

The author’s final suggestion related to splitting nodes in our treatment network to reflect dose. We agree this may be interesting, however we did not do this given our interest in studying associations with any exposure, given the multiple and disparate dosing regimens for these agents, and also given the rarity of the outcomes. The notion is further complicated by the limitation that adequate dosing information is not available for some observational research. Despite this, given the limitations of safety meta-analyses which are restricted to RCTs, we believe efforts to include observational data remains important.

In conclusion, we are not aiming to raise misplaced fears about aprotinin, but rather we hope to highlight evidence clinicians and patients must consider regarding its potential risks.

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Competing interests: None declared