This multi-center contemporary analysis of antifibrinolytic medications in children undergoing heart surgery suggests aprotinin is associated with reduced bleeding requiring surgical intervention and mortality with no increase in dialysis. Comparative analyses suggest similar efficacy of ACA and improved outcomes associated with TXA.
Several previous studies of aprotinin in the pediatric population have suggested aprotinin is effective in reducing bleeding following heart surgery, and a meta-analysis of 12 randomized controlled trials (n=626) found that aprotinin reduced the proportion of children who received transfusions during cardiac surgery by 33% (14
). Our analysis of a contemporary cohort of >20,000 children suggests that aprotinin is associated with reduced bleeding requiring re-operation and mortality. These effects were most prominent in the subgroup of patients undergoing redo sternotomy. Previous analyses have suggested differential efficacy of aprotinin, particularly in those at highest risk for bleeding (7
). Costello and colleagues found that only those undergoing re-operation had a significant decrease in transfusions associated with aprotinin in an observational study of 112 children undergoing heart surgery (7
). Previous studies have also reported a reduction in inflammatory markers in patients who receive aprotinin, as well as a reduction in post-operative myocardial dysfunction and inotropic support (15
). These properties, along with the impact of aprotinin on bleeding, may have contributed to the decreased length of stay and duration of mechanical ventilation we observed in the redo sternotomy subgroup.
However, many of the previous investigations have been limited by important methodologic concerns including small sample size, heterogeneous patient population, lack of standardized transfusion protocols, and varying doses of aprotinin used, and not all studies have demonstrated a beneficial effect of aprotinin (14
). In addition, in a previous analysis of safety outcomes conducted by our group using an administrative datasource, we did not find a significant impact of aprotinin on mortality overall or in those undergoing re-operation (4
). Analyses involving administrative data must rely upon ICD-9 codes from the hospital bill to identify children undergoing heart surgery. In contrast, in the present study we were able to utilize data from a clinical registry to identify the study population. Using our linked dataset, which contains both the clinical registry data in the STS-CHS Database and the ICD-9 codes from the administrative database (PHIS) for each patient, we found that 10% of our overall study cohort would not have been identified if relying upon ICD-9 codes alone, including 18% of patients in the redo sternotomy cohort and 13% of patients in higher STS-EACTS risk categories (categories 3–5) vs. 6% of patients in lower STS-EACTS risk categories (categories 1–2). It is possible that these differences may in part explain differences in study results.
Regarding the safety of aprotinin, we did not find any difference in renal failure requiring dialysis in comparison with no drug. Our data support results of previous single-center observational analyses. Guzzetta et al. evaluated 200 neonates undergoing congenital heart surgery and found that aprotinin was not significantly associated with post-operative creatinine levels or dialysis (18
). Backer et al. evaluated 1251 children and adolescents undergoing congenital heart surgery, and found that aprotinin was not associated with post-operative renal failure or dialysis compared with historical controls (19
). Evaluation of safety was limited in the small randomized trials of aprotinin in children, and in the recent meta-analysis combining results from 12 trials, mortality and renal failure could not be assessed (14
In comparative analyses, our observational data suggested that in general ACA was associated with similar or worse outcome compared with aprotinin. There are few previous studies comparing outcomes in patients receiving different antifibrinolytic medications and it is difficult to draw conclusions due to differences in study design, dosing, and outcomes, and small sample sizes. Chauhan and colleagues compared aprotinin to ACA in 300 children undergoing heart surgery and found no difference in blood loss, transfusion, and need for re-exploration (5
In contrast, we found that TXA appeared to be associated with improved outcomes compared with aprotinin. These results differ from a previous analysis of 100 children undergoing heart surgery which found no difference in blood loss or transfusion in those randomized to aprotinin vs. TXA (6
). This study included fewer patients compared with our analysis and evaluated different outcomes. The reasons for potential greater efficacy of TXA are unclear. There are limited pediatric pharmacokinetic data available and in our study we were unable to evaluate medication doses. It has been previously reported that TXA may be a more potent inhibitor of fibrinolysis than ACA (20
). In addition, TXA may have anti-inflammatory properties (22
). In regard to safety, we did not detect any difference comparing ACA to aprotinin. TXA appeared to be associated with a lower rate of dialysis compared with aprotinin. However the overall number of events was small and it may be premature to draw any conclusions from these data. There were also few neurologic events in our study. Nonetheless, we did not find any difference comparing ACA, TXA, and aprotinin. Previous case reports have suggested that TXA may be associated with an increase in post-operative seizures in adult patients undergoing cardiac surgery (13