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Ann Thorac Surg 2004;77:931
© 2004 The Society of Thoracic Surgeons
Hamilton Regional Laboratory Medicine Program, McMaster University, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada
e-mail: twarken{at}mcmaster.ca
| Doctor Warkentin discloses that he has a financial relationship with The Medicines Company.
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Without question, heparin is not an ideal drug for anticoagulation during cardiac surgery, despite its near-monopoly status resulting from low cost, reversibility (using protamine), and easy monitoring (by activated clotting time). Among its disadvantages: progressive intraoperative activation of hemostasis due to inability of heparin to inhibit fibrin-bound thrombin (thus contributing to secondary hyperfibrinolysis and bleeding postsurgery), postprotamine heparin "rebound", and so forth. And, from my perspective as a hematologist, heparin use during cardiac surgery can produce the "time bomb" of immunization against platelet factor 4/heparin complexes, with the patient one week hence suddenly facing the life- and limb-threatening consequences of immune heparin-induced thrombocytopenia (HIT).
What replacement for heparin lies on the horizon? In this issue of The Annals, Merry and colleagues from New Zealand report their randomized trial of 100 patients undergoing off-pump coronary artery bypass grafting, wherein 50 patients received standard heparin (plus protamine reversal), and the other 50 patients received bivalirudin, a direct thrombin inhibitor with a relatively short half-life (25 minutes) but no antidote. The primary endpoint was bleeding at 12 hours after study drug initiation, and secondary endpoints included 3-month angiographic assessment of graft patency.
The results are noteworthy. Bleeding rates were similar between the two study arms (bivalirudin: median, 793 mL, versus heparin plus protamine, 805 mL; P = 0.165). Intriguingly, superior graft patency by several parameters was evident in the bivalirudin-treated patients, including a greater number of grafts with normal (grade 3) blood flow (82% vs 67%; P = 0.03). The (hematology) reader also wonders about intraoperative thrombin generation and postoperative formation of HIT antibodies, but these endpoints were not examined.
Could bivalirudin anticoagulation really improve graft patency? Yes, for at least four reasons. First, bivalirudin inhibits clot-bound thrombin, which could protect newly-sutured grafts. Second, thrombin has mitogenic properties, and its inhibition might reduce endothelial proliferation. Third, no antidote for bivalirudin means that its anticoagulant effects are not abruptly reversed, and so persistence of anticoagulation for a time during the early postoperative phase might protect nascent grafts. Fourth, reducing HIT antibody formation could reduce risk of graft occlusion by avoiding HIT.
As a "designer drug" modeled after—but with distinct advantages over—hirudin (such as predominant nonrenal clearance, shorter half-life, low immunogenicity), bivalirudin could be the "holy grail" eagerly sought by cardiac surgeons and anesthesiologists (and hematologists). Future studies with this novel anticoagulant, both off- and on-pump, are eagerly awaited.
This article has been cited by other articles:
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  N. G. Smedira, C. M. Dyke, A. Koster, M. Jurmann, D. S. Bhatia, T. Hu, H. L. McCarthy II, A. M. Lincoff, B. D. Spiess, and S. Aronson Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: The results of the EVOLUTION-OFF study J. Thorac. Cardiovasc. Surg., March 1, 2006; 131(3): 686 - 692. [Abstract] [Full Text] [PDF]
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