Pasquali and colleagues assessed the effectiveness and safety of aprotinin compared to no drug, tranexamic acid, and aminocaproic acid, in over 22,000 pediatric patients undergoing heart surgery across 25 centers. Data from both the Pediatric Health Information Systems and the Society of Thoracic Surgeons Congenital Heart Surgery databases were used. The primary effectiveness outcome was a composite of in-hospital mortality and reoperation for bleeding while the primary safety outcome was need for temporary or permanent dialysis. Unadjusted and adjusted analyses using multivariable regression were presented for patients overall and two important subgroups (redo sternotomy and neonates).

Their analysis demonstrated that aprotinin appeared to be effective in reducing mortality and reoperation for bleeding although the results did not reach statistical significance except in the redo sternotomy subgroup. This observation is in keeping with the adult cardiac surgery literature. In comparative analysis, tranexamic acid was more effective than aprotinin in reducing the composite endpoint mortality and reoperation for bleeding (53% reduction) after adjusting for important prognostic risk factors. In contrast with the tranexamic acid results, aminocaproic acid was not superior compared to aprotinin. In a secondary instrumental variable analysis of centers that primarily switched to aminocaproic acid from aprotinin during 2007 and 2008, there was no difference in mortality or reoperation for bleeding between the two groups.

In terms of safety (need for dialysis), aprotinin was not associated with increased risk when compared to patients receiving no antifibrinolytic. Tranexamic acid was associated with a much lower risk of dialysis (77% reduction) when compared to aprotinin while there was no demonstrated difference between aminocaproic acid and aprotinin.

The authors present a well-conducted and presented cohort analysis of two valuable databases. The strengths of their data sources comes in numbers (>22,000 patients) and data quality while the weaknesses come in the lack of detail (e.g. hemoglobin and creatinine values, details of procedures) and assessment of benefit (e.g. type and quantity of blood products administered). As with all observational cohort studies, one must be mindful of any unmeasured variables that may confound the relationship between treatment and outcome. Over half the patients analyzed did not receive an antifibrinolytic and despite similar clinical and demographic characteristic, there could have been important unmeasured patient, center, or country differences between those children receiving antifibrinolytics or not. Nonetheless, I support the author’s conclusion that an adequately powered clinical trial is necessary. The question is whether that comparative trial needs to include a placebo arm.

– Dean A. Fergusson