Bivalirudin monitored with the ecarin clotting time for anticoagulation during cardiopulmonary bypass.
T he problem of heparin-induced thrombocytopenia (HIT) among patients undergoing cardiac surgery is increasingly being appreciated. However, no safe standard anticoagulation strategy has been established for the management of these patients during cardiopulmonary bypass (CPB). Recombinant hirudin (r-hirudin), a 65-amino acid polypeptide, is a direct thrombin inhibitor that has been used successfully in a larger series of patients with HIT during CPB (1). Because of its protein structure, r-hirudin is not associated with the risk of cross-reactivity to HIT antibodies, the plasma half-life is relatively short (approximately 40 min), and measurement of the ecarin clotting time (ECT) enables reliable on-line monitoring at the point of care (2). However, because of r-hirudin’s exclusive elimination via the kidneys and the lack of an antidote, impairment of renal function may lead to a dramatic increase of the drug’s half-life, a persistent anticoagulant effect, and hemorrhage (1). Bivalirudin is a new synthetic 20-amino acid polypeptide with a plasma half-life of 24 min. It is also a direct thrombin inhibitor with potent anticoagulant activity and has been successfully used in many patients during coronary angioplasty. A unique feature of bivalirudin is that the part of the molecule that binds to the active site of thrombin is cleaved by the thrombin molecule itself, providing an elimination mechanism independent of specific organ function (3). Therefore, the use of large doses of bivalirudin, as required during CPB, may be safer compared with r-hirudin. However, experience with the use of bivalirudin during CPB is limited, and use of this drug with an ECT-guided strategy has not been reported. We report the use of bivalirudin, monitored at the point of care via ECT, for anticoagulation during CPB in a patient with HIT, a history of severe anaphylactic reaction to unfractionated heparin, and impaired renal function. Currently there are no clinical data available about the concentrations or doses of bivalirudin needed to provide sufficient anticoagulation during CPB. An r-hirudin concentration of 4–5 g/mL has been successfully used for anticoagulation during CPB in a larger group of patients (1). We hypothesized that 1) a concentration of bivalirudin that provides a comparable antithrombin effect to r-hirudin concentrations of 4–5 g/mL should provide an analogous anticoagulant effect during CPB and 2) a bivalirudin concentration that achieves a prolongation of the ECT (the specific assay for direct thrombin inhibitors) (4) equivalent to 4–5 g/mL of r-hirudin defines the target concentration of bivalirudin for anticoagulation during CPB. Therefore, we performed an in vitro dosefinding study. After approval by the local ethics committee and informed consent were obtained, blood was collected from 10 healthy volunteers to establish calibration curves with r-hirudin and bivalirudin. Bivalirudin (0, 5, 10, 15, and 20 g/mL) or r-hirudin (0, 1, 3, and 5 g/mL) was added to samples of citrated whole blood. Measurement of the ECT (Pharmanetics, Raleigh, NC) was performed as previously described (2): 100 L of citrated whole blood was diluted with 100 L of standard human plasma (Behring, Marburg, Germany) to provide sufficient levels of prothrombin that are a prerequisite for reliable measurement of the ECT (2). Of this solution, 30 L was transferred to the ECT test card, and the test was initiated. The in vitro investigations were supported by the Medicines Company, Parsippany, NY. Drs. Spiess, Chew, and Koster are members of the advisory board of The Medicines Company. Accepted for publication October 21, 2002. Address correspondence and reprint requests to Andreas Koster, MD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. Address e-mail to koster@dhzb.de.