Towards Balanced Anticoagulation
Alan Merry
University of Auckland
Auckland
Unfractionated heparin (UFH), usually reversed with protamine, has been the dominant drug for controlled anticoagulation for cadiopulmonary bypass (CPB) since the first use of this technique for surgery in 1953.[1, 2] Important complications of CPB include perioperative myocardial infarction, bleeding, stroke, defects in postoperative neurocognitive function and renal failure. There are many factors in the causation of these problems.[3, 4] However, the management of anticoagulation may be a central one, through its influence on the complex interplay between the endothelium, drugs, the coagulation cascade and the inflammatory response which characterises all cardiac surgery.[5]
UFH has limitations as an anticoagulant, and reversal with protamine may also cause undesirable effects. Alternative drugs for possible use in CPB include low molecular weight heparins (e.g. enoxaparin and dalteparin), Danaparoid (a mixture of the heparinoids heparan, dermatan, and chondroitin sulfate), Ancrod (a serine protease isolated from the Malayan pit viper), antiplatelet drugs (aspirin and dipyridomole), Iloprost (a stable prostacyclin analogue with a half-life of 15-30 minutes), platelet glycoprotein (GP) IIb/IIIa antagonists (e.g. tirofiban) and direct thrombin inhibitors (e.g. the univalent argatroban, efegatran and inogatran, and the bivalent hirudin and bivalirudin).
Direct thrombin inhibitors bind directly and specifically to thrombin. There is no commercially available reversal agent for these drugs. They do not require antithrombin, platelet factor II, or any other cofactor for their effect. Hirudin (lepirudin, Refludan) is a 65 amino-acid polypeptide originally isolated from leech saliva. Desuflatohirudin or desirudin (Revasc) is recombinant hirudin and lacks a sulphated tyrosine residue at position 63. It is eliminated by the kidney; it has a plasma half-life of about 60 minutes which is prolonged in renal insufficiency.[6] Bivalirudin (Angiomax, previously known as Hirulog) is a synthetic 20 amino-acid peptide in which the functional carboxy and amino terminals of hirudin have been retained. It is unlikely to be immunogenic. It binds bivalently with thrombin. The Arg-Pro bond at the amino-terminal of bivalirudin is cleaved by the thrombin, so the drug’s antithrombotic effect wears off rapidly. It is metabolised by proteolytic cleavage and residual drug is eliminated by the kidneys. A 20% reduction in bivalirudin clearance occurs with moderate renal impairment and a greater reduction with severe renal failure.[7] Its plasma elimination half-life is 25 minutes. It inhibits clot-bound and fluid-phase thrombin and thrombin-mediated platelet aggregation. It has a low propensity for the generation of immune or inflammatory responses.[6] As an enzymatic reaction, the hydrolysis of bivalirudin is temperature dependent, which may influence its kinetics during hypothermic CPB.
There is considerable experience with the use of bivalirudin in acute coronary syndromes.[8] Experience with its use in cardiac surgery is still quite limited, with only a small number of studies [2, 9, 10] and some case reports. There may well be advantages in a direct thrombin inhibitor as the sole agent for managing anticoagulation in CPB, and they offer a useful alternative when heparin or protamine is contraindicated, but these drugs are relatively expensive and there are technical challenges to their use, notably in relation to the lack of a reversal agent, but also in the potential for stagnant blood to clot with the use of bivalirudin alone. It may be that the way forward lies in combinations of drugs which act at different stages in the coagulation system to maximize the benefits and minimize the risks of each. A preliminary study in rats has examined the merits of combining low doses of bivalirudin with standard doses of heparin,[11] but exact dosage combinations will be important, and other combinations may also be worth considering. The concept of "balanced anticoagulation" is worthy of further study.
References
1. Gibbon, J H, Jr. The development of the heart-lung apparatus. American Journal of Surgery, 1978. 135: 608-619.
2. Merry, A F, Raudkivi, P J, et al. Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Annals of Thoracic Surgery, 2004. 77: 925-931.
3. Charlesworth, D C, Likosky, D S, et al. Development and validation of a prediction model for strokes after coronary artery bypass grafting. Annals of Thoracic Surgery, 2003. 76: 436-443.
4. Engoren, M C, Habib, R H, Zacharias, A, Schwann, T A, Riordan, C J, Durham, S J. Effect of blood transfusion on long-term survival after cardiac operation. Annals of Thoracic Surgery., 2002. 74: 1180-6.
5. Spiess, B D. Heparin: beyond an anticoagulant, in The relationship between coagulation, inflammation, and endothelium, B.D. Spiess, Editor. 2000: Baltimore. 169-190.
6. Weitz, J I and Crowther, M. Direct thrombin inhibitors. Thrombosis Research, 2002. 106: V275-V284.
7. Robson, R, White, H, Aylward, P, Frampton, C. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clinical Pharmacology and Therapeutics, 2002. 71: 433-439.
8. Antman, E M, Should bivalirudin replace heparin during percutaneous coronary interventions? JAMA, 2003. 289: 903-905.
9. Smedira, N G, Dyke, C M, et al. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. Journal of Thoracic & Cardiovascular Surgery, 2006. 131: 686-92.
10. Dyke, C M, Smedira, N G, et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. Journal of Thoracic & Cardiovascular Surgery, 2006. 131: 533-9.
11. Welsby, I J, Jones, W L, et al. Effect of combined anticoagulation using heparin and bivalirudin on the hemostatic and inflammatory responses to cardiopulmonary bypass in the rat. Anesthesiology, 2007. 106: 295-301.
Time of Presentation
1330
