A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery

Michael George Moront, From the, Department of Cardiothoracic Sugery, Promedical Toledo Hospital, Toledo, Ohio.
Michael K. Woodward, Bioscience Research Group, Grifols, Barcelona, Spain.
Michael K. Essandoh, Department of Anesthesiology' Wexner Medical Center, The Ohio State University, Columbus, Ohio.
Edwin G. Avery, Department of Anesthesiology and Perioperative Medicine, University Hospital Case Medical Center, Cleveland, Ohio.
T Brett Reece, Department of Surgery' Division of Cardiothoracic Surgery, University of Colorado, Aurora, Colorado.
Marek Brzezinski, Department of Anesthesiology and Perioperative Care, University of California, San Francisco, California.
Bruce Spiess, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida.
Linda Shore-Lesserson, Department of Anesthesiology, North Shore University Hospital, New York, New York.
Junliang Chen, Bioscience Research Group, Grifols, Barcelona, Spain.
Waleska Henriquez, Bioscience Research Group, Grifols, Barcelona, Spain.
Miquel Barceló, Bioscience Research Group, Grifols, Barcelona, Spain.
George Despotis, Departments of Pathology, Immunology and Anesthesiology, Washington University School of Medicine, St. Louis, Missouri.
Keyvan Karkouti, Department of Anesthesia and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.
Jerrold H. Levy, Department of Anesthesiology and Critical Care, Duke University School of Medicine, Durham, North Carolina.
Marco Ranucci, Department of Cardiothoracic and Vascular Anesthesia and Intensive Care, IRCSS Policlinico San Donato, Milan, Italy.
Elsa Mondou, Bioscience Research Group, Grifols, Barcelona, Spain.


BACKGROUND: Antithrombin (AT) activity is reduced during cardiac operations with cardiopulmonary bypass (CPB), which is associated with adverse outcomes. Preoperative AT supplementation, to achieve >58% and <100% AT activity, may potentially reduce postoperative morbidity and mortality in cardiac operations with CPB. This prospective, multicenter, randomized, double-blind, placebo-controlled study was designed to evaluate the safety and efficacy of preoperative treatment with AT supplementation in patients at risk for low AT activity after undergoing cardiac surgery with CPB. METHODS: A total of 425 adult patients were randomized (1:1) to receive either a single dose of AT (n = 213) to achieve an absolute increase of 20% above pretreatment AT activity or placebo (n = 212) before surgery. The study duration was approximately 7 weeks. The primary efficacy end point was the percentage of patients with any component of a major morbidity composite (postoperative mortality, stroke, acute kidney injury [AKI], surgical reexploration, arterial or venous thromboembolic events, prolonged mechanical ventilation, and infection) in the 2 groups. Secondary end points included AT activity, blood loss, transfusion requirements, duration of intensive care unit (ICU), and hospital stays. Safety was also assessed. RESULTS: Overall, 399 patients (men, n = 300, 75.2%) with a mean (standard deviation [SD]) age of 66.1 (11.7) years, with the majority undergoing complex surgical procedures (n = 266, 67.9%), were analyzed. No differences in the percentage of patients experiencing morbidity composite outcomes between groups were observed (AT-treated 68/198 [34.3%] versus placebo 58/194 [29.9%]; P = .332; relative risk, 1.15). After AT infusion, AT activity was significantly higher in the AT group (108% [42-143]) versus placebo group (76% [40-110]), and lasted up to postoperative day 2. At ICU, the frequency of patients with AT activity ≥58% in the AT group (81.5%) was significantly higher (P < .001) versus placebo group (43.2%). Secondary end point analysis did not show any advantage of AT over placebo group. There were significantly more patients with AKI (P < .001) in the AT group (23/198; 11.6%) than in the placebo group (5/194, 2.6%). Safety results showed no differences in treatment-emergent adverse events nor bleeding events between groups. CONCLUSIONS: AT supplementation did not attenuate adverse postoperative outcomes in our cohort of patients undergoing cardiac surgery with CPB.