Anti-inflammatory effect of aprotinin: a meta-analysis

Abstract

It is important to define the extent, and any limitations, of potential anti-inflammatory regimens used in cardiac surgery to guide the rational combination of drugs to suppress the systemic inflammatory response. Aprotinin (Trasylol) is an anti-fibrinolytic agent with reported anti-inflammatory properties. In this study, we investigated the published data on aprotinin's effect on acute phase protein and cytokine levels in cardiac surgery patients. Randomized placebo-controlled trials of aprotinin published between 1985 and 2007, in adult cardiac surgery using cardiopulmonary bypass, reporting tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-8, and IL-10 levels were included for review. Two independent reviewers graded each paper and collected information on inflammatory markers. RevMan 4.3 statistical software was used to calculate and plot the weighted mean difference between placebo and aprotinin groups. Thirteen studies met the review criteria. None of the inflammatory markers were reduced by high-dose aprotinin treatment. Low-dose aprotinin significantly reduced IL-10 levels after protamine administration (-41.3 pg/ mL; 95% CI: -59.5, -23.1), but this result was gone by the first post-operative day. These meta-analyses showed no significant effect of aprotinin on acute phase proteins or systemic cytokine markers of inflammation during clinical adult cardiac surgery using cardiopulmonary bypass. While recognizing that other host defense systems, such as coagulation and complement, contribute to the overall systemic inflammatory response, the evidence presented here does not support the clinical use of aprotinin as an anti-inflammatory agent on its own.

Figure 1.

RCTs reporting inflammatory markers.

Figure 2.

Meta-analysis of TNF-α. Individual RCTs are listed in order by year of publication. The size of each square denotes the weight of each trial’s weighted mean difference in calculating the summary estimate for the overall effect on TNF-α. The diamond represents the summary estimate for the combined weighted mean difference at the center; opposing points of the diamond represent the 95% CIs. Three diamonds in each section represent high, low, and the overall effect. A, Meta-analysis for TNF-α directly after protamine administration. B, Meta-analysis plot for TNF-α on post-operative day 1.

Figure 3.

Meta-analysis of IL-6. Individual RCTs are listed in order by year of publication. The size of each square denotes the weight of each trial’s weighted mean difference in calculating the summary estimate for the overall effect on IL-6. The diamond represents the summary estimate for the combined weighted mean difference at the center; opposing points of the diamond represent the 95% CIs. Three diamonds in each section represent high, low, and overall effect. A, Meta-analysis for IL-6 directly after protamine administration. B, Meta-analysis plot for IL-6 on post-operative day 1.

Figure 4.

Meta-analysis of IL-8. Individual RCTs are listed in order by year of publication. The size of each square denotes the weight of each trial’s weighted mean difference in calculating the summary estimate for the overall effect on IL-8. The diamond represents the summary estimate for the combined weighted mean difference at the center; opposing points of the diamond represent the 95% CIs. Three diamonds in each section represent high, low, and overall effect. A, Meta-analysis for IL-8 directly after protamine administration. B, Meta-analysis plot for IL-8 on post-operative day 1.

Figure 5.

Meta-analysis of IL-10. Individual RCTs are listed in order by year of publication. The size of each square denotes the weight of each trial’s weighted mean difference in calculating the summary estimate for the overall effect on IL-10. The diamond represents the summary estimate for the combined weighted mean difference at the center; opposing points of the diamond represent the 95% CIs. Three diamonds in each section represent high, low, and overall effect. A, Meta-analysis for IL-10 directly after protamine administration. B, Meta-analysis plot for IL-10 on post-operative day 1.