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Abstract

Introduction: During cardiac surgery requiring cardiopulmonary bypass (CPB), heparin resistance (HR) is associated with decreased antithrombin (AT) levels, which may increase operative times and potentially alter outcomes. Hypothesis: Recombinant human AT (rhAT), which may offer advantages over purified human plasma–derived AT for managing HR during CPB, will be well tolerated and safe in HR patients. Methods: An integrated safety summary of rhAT use to manage HR during CPB was obtained from a retrospective analysis of adult patients who received rhAT or placebo during CPB in either a dose-finding study of rhAT (10-200 IU/kg) or in any 1 of 3 phase 3 studies of rhAT (15 or 75 IU/kg). From study entry until hospital discharge, patients were followed for treatment-emergent adverse events (TEAEs), including severe and serious TEAEs. Results: A total of 175 patients received rhAT (n=118; mean age, 63.5 y) or placebo (n=57; mean age, 64.6 y). Overall, rhAT was well tolerated. The frequently reported TEAEs (?10% in either group) that occurred more often with rhAT than with placebo were hypotension (rhAT, 25/118 [21.2%]; placebo, 4/57 [7.0%]) and postprocedural bleeding (rhAT, 12/118 [10.2%]; placebo, 2/57 [3.5%]). Any TEAEs considered related to the study drug occurred in 22/118 (18.6%) and 6/57 (10.5%) of rhAT- and placebo-treated patients, respectively. In the rhAT group, 5 (4%) patients had 6 related serious TEAEs, most of which were associated with bleeding (postprocedural hemorrhage); all patients recovered. Although serious bleeding AEs did not occur with placebo, incidences of all bleeding TEAEs (serious and nonserious) were similar between the rhAT (28.8%) and placebo (29.8%) groups. Across the 4 studies, 3 (2.5%) deaths occurred in the rhAT group, and 1 (1.8%) in the placebo group. All were unrelated to treatment, and there were no immune reactions to any rhAT components. Conclusions: Results demonstrate that rhAT is well tolerated and has an acceptable safety profile, even at the high rhAT doses used in this integrated analysis. Our report represents the largest cohort of CPB patients with HR supplemented with AT to date.