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Since the 1980s, antifibrinolytic therapies have assisted surgical teams in reducing the amount of blood loss. To date, however, serious questions remain regarding the safety and effectiveness of these agents.We conducted a meta-analysis to compare aprotinin, ε-aminocaproic acid, and tranexamic acid with placebo and head to head on 8 clinical outcomes from 138 trials. Published randomized controlled trial data were collected from OVID/PubMed. Outcomes included total blood loss, transfusion of packed red blood cells, reexploration, mortality, stroke, myocardial infarction, dialysis-dependent renal failure, and renal dysfunction (0.5-mg/dL increase in creatinine from baseline). All agents were effective in significantly reducing blood loss by 226 to 348 mL and the proportion of patients transfused with packed red blood cells over placebo. Only high-dose aprotinin reduced the rate of reexploration (relative risk, 0.49; 95% CI, 0.33 to 0.73). There were no significant risks or benefits for any agent for mortality, stroke, myocardial infarction, or renal failure. However, high-dose aprotinin significantly increased the risk of renal dysfunction (relative risk, 1.47; 95% CI, 1.12 to 1.94), 12.9% versus 8.4%. Compared head to head, high-dose aprotinin demonstrated significant reduction in total blood loss over ε-aminocaproic acid (−184 mL; 95% CI, −256 to −112) and tranexamic acid (−195 mL; 95% CI, −286 to −105). There were no significant differences among any agent when compared head to head on other outcomes.All antifibrinolytic agents were effective in reducing blood loss and transfusion. There were no significant risks or benefits for mortality, stroke, myocardial infarction, or renal failure. However, high-dose aprotinin was associated with a statistically significant increased risk of renal dysfunction.