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CARDIOVASCULAR ANESTHESIOLOGY

The Effect of Epsilon-Aminocaproic Acid and Aprotinin on Fibrinolysis and Blood Loss in Patients Undergoing Primary, Isolated Coronary Artery Bypass Surgery: A Randomized, Double-Blind, Placebo-Controlled, Noninferiority Trial

Philip E. Greilich, MD, FAHA^*, Michael E. Jessen, MD, Neeraj Satyanarayana, BS^*, Charles W. Whitten, MD^*, Gregory A. Nuttall, MD, Joseph M. Beckham, MD^*, Michael H. Wall, MD, and John F. Butterworth, MD^||

From the Departments of *Anesthesiology and Pain Management, and Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota; Department of Anesthesiology, Washington University, St. Louis, Missouri; and ||Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana.

Address correspondence and reprint requests to Philip E. Greilich, MD, 5323 Harry Hines Blvd., Dallas, TX 75390-8894. Address e-mail to philip.greilich{at}utsouthwestern.edu.

Abstract

BACKGROUND: Until recently, aprotinin was the only antifibrinolytic drug with a licensed indication in cardiac surgery in the United States. The most popular alternative, -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^–1 · h^–1 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.