The First Alternative to Heparin for Anticoagulation during Cardiopulmonary Bypass
In the past 50 years anticoagulation during cardiopulmonary bypass (heart/lung machine) has been by unfractioned heparin. The effect of heparin has been counteracted by protamine at the end of operations.
Heparin is the only anticoagulant approved for this indication. However, some patients have heparin-induced thrombocytopenia (HIT). This is a condition in which the body forms antibodies to a combination of heparin and platelet factor 4, which can cause massive thromboembolic complications. Therefore heart operations in patients with HIT pose a problem. Numerous substances have been tested as an alternative to heparin, but most of them lead to bleeding complications, as they have no antidote.
Bivalirudin is a peptide with 20 amino acid sequences. It is a direct, bivalent, reversible thrombin antagonist and has a short elimination half-life of approximately 25 minutes. Bivalirudin inhibits thrombin formation by binding to the active center and the exosite 1 region. This inhibition is reversible, since thrombin cleaves bivalirudin and the two fragments have only slight affinity to thrombin (Fig. 1). This proteolysis is the main mechanism (80%) by which bivalrudin is rendered inactive. Approximately 20% is excreted by the kidneys.
Fig. 1. Mechanism of the effect and elimination of bivalirudin
This rapid, potent inhibition of thrombin and the fast elimination, which is mainly independent of kidney and liver function, make bivalirudin an interesting substance for high-dose anticoagulation. In the USA bivalirudin is now used in almost 30% of acute percutaneous coronary interventions. Studies have shown it to be effective and to bring about a clear reduction in bleeding complications.
Initially bivalirudin was used successfully in coronary bypass operations without use of the heart/lung machine. Following this success, the DHZB led the development of protocols for the application of bivalirudin with the heart/lung machine and tested them in pilot studies. These studies were the first worldwide in which alternative anticoagulation was employed in patients with no contraindication for the administration of heparin and protamine.
In 2006 the first four large multicentric studies aimed at obtaining approval of bivalirudin by the US Food and Drug Administration were conducted. The CHOOSE ON and CHOOSE OFF studies looked at bivalirudin in patients with HIT with and without use of the heart/lung machine, respectively. These two studies were accompanied by two large backup safety studies in patients without HIT (EVOLUTION ON and EVOLUTION OFF studies). These are the first studies since the introduction of the heart/lung machine that aimed at acquiring approval of an alternative anticoagulant to heparin in heart operations. The DHZB entered more patients than any other institution in these multicentric studies, making an important contribution to their success.
How bivalirudin works and how it is eliminated
Bivalirudin is bivalent, binding to the active center and the exosite 1 region of thrombin. This inhibits thrombin rapidly and effectively. In the further course, thrombin itself cleaves the bivalirudin molecule and thus ends its anticoagulatory effect. Bivalirudin is eliminated from the body without burdening a particular organ. These characteristics make this new substance safe and effective in anticoagulation in the heart catheterization laboratory and in cardiac surgery.
References
- Koster A, Spiess B, Chew DP, Krabatsch T, Tambeur L, DeAnda A, Hetzer R, Kuppe H, Smedira NG, Lincoff AM. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 2004; 93:356-359
- Koster A, Yeter R, Buz S, Kuppe H, Hetzer R, Lincoff AM, Dyke CM, Smedira NG, Spiess B. Assessment of hemostatic activation during cardiopulmonary bypass for coronary artery bypass grafting with bivalirudin: results of a pilot study. J Thorac Cardiovasc Surg 2005; 129:1391-1394
- Smedira NG, Dyke CM, Koster A, Jurmann M, Bhatia DS, Hu T, McCarthy HL II, Lincoff AM, Spiess BD, Aronson S. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 2006; 131:686-692
- Koster A, Spiess B, Jurmann M, Dyke CM, Smedira NG, Aronson S, Lincoff MA. Bivalirudin provides rapid, effective, and reliable anticoagulation during off-pump coronary revascularization: results of the “EVOLUTION OFF” trial. Anesth Analg 2006; 103:540-544
- Dyke CM, Smedira NG, Koster A, Aronson S, McCarthy HL II, Kirshner R, Lincoff AM, Spiess BD. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006; 131:533-539
- Koster A, Dyke CM, Aldea G, Smedira NG, McCarthy HL, Aronson S, Hetzer R, Avery E, Spiess B, Lincoff AM. Bivalirudin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and heparin antibodies: the CHOOSE-ON trial. Ann Thorac Surg 2007; 83: 572-577
- Dyke CM, Aldea G, Koster A, Smedira N, Avery E, Aronson S, Spiess BD, Lincoff AM. Off-pump coronary artery bypass with bivalirudin for patients with heparin-induced thrombocytopenia or anti-platelet factor 4/heparin antibodies. Ann Thorac Surg. 2007 ;84:836-9.
