Bivalirudin (Angiomax, The Medicines Company, Parsippany, NJ) is a short-acting, bivalent, reversible DTI (see Chapter 16). Its pharmacokinetics are characterized by rapid onset of effect and a short half-life of approximately 25 min. The drug's elimination is predominaty achieved by proteolytic cleavage and to a minor extent by renal excretion. These pharmacologic features, particularly its rapid elimination essentially independent of specific organ involvement, renders bivali-rudin a potentially valuable alternative to UFH/protamine for high-dose anticoagulation during cardiac surgery with and without CPB (Warkentin and Koster, 2005).

Bivalirudin has been assessed in large trials (>40,000 patients) in patients undergoing percutaneous coronary intervention (PCI), including formal evaluation in patients with or at risk for HIT. Bivalirudin is approved by the U.S. Food and Drug Administration for angioplasty in patients with or without HIT (see Chapter 16).

Based on the favorable results in PCI, a large program was started for assessment of safety and efficacy of bivalirudin use in cardiac surgery. The first of these investigations was performed in OPCAB surgery in non-HIT patients, and involved a comparison between bivalirudin (given in the PCI dose) and UFH/ protamine. This investigation revealed comparable results with respect to safety parameters such as perioperative hemorrhage and transfusion requirements. Interestingly, bivalirudin demonstrated improved efficacy, as shown by enhanced graft patency (Merry et al., 2004).

A second pilot investigation assessing the use of bivalirudin in cardiac surgery with CPB also demonstrated an acceptable safety and efficacy profile (Koster et al., 2003a). Based on these data, dosing schemes, perfusion strategies and monitoring recommendations were formulated (Koster et al., 2004a, 2005; Veale et al., 2005; Zucker et al., 2005) (Table 3). Due to the fact that in areas of stagnant blood bivalirudin is cleaved by thrombin, surgical and perfusion practice must be adjusted to the unique pharmacology of the drug. In particular, any area of stasis within the CPB circuit must be avoided and cardiotomy suction from the operating field minimized whenever possible (Table 3).

After defining dosing protocols, and monitoring guidelines and surgical/ perfusion strategies, two multicenter investigations were begun with the goal of obtaining regulatory approval for cardiac surgery in HIT patients, either with CPB (CHOOSE-ON study) or OPCAB surgery (CHOOSE-OFF study). These investigations (The acronym CHOOSE, indicates CABG HIT/TS On- and Off-Pump Safety and Efficacy) were accompanied by "back up safety studies" in non-HIT patients that compared bivalirudin with UFH/protamine in OPCAB surgery (EVOLUTION-OFF study) and in CPB (EVOLUTION-ON study) surgery. (The acronym, EVOLUTION, indicates Evaluation of Patients during coronary artery bypass graft Operations: Linking UTilization of bivalirudin to Improved Outcomes and New anticoagulant strategies.) Results of the two EVOLUTION studies are published and reveal comparable safety and efficacy endpoints (Smedira et al., 2006; Dyke et al., 2006). Results of the CHOOSE-ON study also demonstrated an acceptable safety and efficacy profile even in patients with impaired renal function (Koster et al., 2007). The results of the CHOOSE-OFF study also showed good results in safety and efficacy data (Dyke et al., 2007).

In contrast to this relatively large pool of data in cardiac surgery, in vascular surgery no data are available. Theoretically, however, use of bivalirudin for this indication is problematic, since clamping of the vessel results in ischemia (stimulating generation of thrombin) and stagnation (preventing influx of fresh non-degraded bivalirudin molecules), with the potential for bivalirudin concentrations to decrease to critically low levels.

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