BACKGROUND: Until recently, aprotinin was the only antifibrinolytic drug with a licensed indication in cardiac surgery in the United States. The most popular alternative, ε-aminocaproic acid (EACA), has not been adequately compared with aprotinin. We undertook this study to test the hypothesis that EACA, when dosed appropriately, is not inferior to aprotinin at reducing fibrinolysis and blood loss. METHODS: Seventy-eight patients scheduled for primary, isolated coronary artery bypass graft surgery were randomly assigned to receive "full Hammersmith" dose aprotinin, high dose EACA (100 mg/kg initial loading dose, 5 g in the pump prime solution, 30 mg • kg • h maintenance infusion) or equal volumes of a saline-placebo in a double-blind trial. Reductions in peak d-dimer formation (a measure of fibrinolysis) and 24-h chest tube drainage (CTD) were the primary end points by which noninferiority of EACA was tested. The noninferiority limit was set at a 30% increase in peak d-dimer formation (a difference of 250 μg/mL) and 24-h CTD (a difference of 350 mL) relative to aprotinin. RESULTS: The between-group differences (EACA versus aprotinin) in peak d-dimer formation (-3.58 μg/L, 95% CI -203 to 195 μg/L) and 24-h CTD (67 mL, 95% CI -90 to 230 mL) were within the predetermined noninferiority margins (250 μg/mL and 350 mL, respectively) and satisfied the criteria for noninferiority. Compared with saline, significant between-group reductions in peak d-dimer formation were observed using EACA (589 μg/L, 95% CI 399-788 μg/L; P < 0.0001) and aprotinin (585 μg/L, 95% CI 393-778 μg/L; P < 0.0001). Similar reductions in 24 h CTD were also seen using EACA (239 mL, 95% CI 50-415 mL; P < 0.05) and aprotinin (323 mL, 95% CI 105-485 mL; P < 0.05) compared with saline. Plasma EACA levels were maintained well above a target of 260 μg/mL. CONCLUSIONS: When dosed in a pharmacologically guided manner, EACA is not inferior to aprotinin in reducing fibrinolysis and blood loss in patients undergoing primary, isolated coronary artery bypass surgery.