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Ann Thorac Surg 2004;78:2208-2209
© 2004 The Society of Thoracic Surgeons

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Correspondence

Reply

Hamilton Regional Laboratory Medicine Program, Hamilton Health Science (General Site), 237 Barton St E, Hamilton, ON L8L 2X2, Canada

Andreas Greinacher, MD

Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Klinikum/Sauerbruchstrasse D-17487 Greifswald, Germany

twarken{at}mcmaster.ca

To the Editor:

Drs Furukawa and Ohteki challenge our statement that argatroban "cannot be recommended for use in CPB [cardiopulmonary bypass] operations." They cite anecdotal experiences with this direct thrombin inhibitor for cardiac surgery in humans [1–3]. However, these reports describe only two instances of argatroban use during conventional CPB for surgical procedures on the heart [2, 3] (other examples of its use included anticoagulation therapy after a cardiac operation, CPB for continuous hemofiltration, bypass during operation on the descending aorta, and off-pump surgery [1]). Only one of the two cases involved a patient with suspected heparin-induced thrombocytopenia, and that patient required 51 units of blood products during the early postoperative period [3]. In contrast, the published experiences [4, 5] with lepirudin and bivalirudin include case series of at least 20 patients using predefined protocols and systematic evaluation of clinical and laboratory outcomes.

Although we do not dispute the potential feasibility of argatroban anticoagulation during CPB, we disagree with the statement of the authors that "monitoring the anticoagulant effect of argatroban is superior to and simpler than monitoring the same effect of recombinant hirudin, bivalirudin, or danaparoid." In our opinion, this is not established and may not be true.

The basic mechanism of action of direct thrombin inhibitors is widely assumed to be fundamentally the same, namely, binding to thrombin at its active (catalytic) site. For two of these agents, bivalirudin and lepirudin, it has been shown that use of the activated clotting time is inappropriate to monitor the high concentrations of anticoagulation necessary for CPB [4, 5]. It therefore seems likely that argatroban would also require monitoring during CPB by means other than the activated clotting time. To our knowledge, this remains to be investigated.

However, there is an additional consideration. Argatroban prolongs the international normalized ratio (INR) to an extent greater than that observed with the bivalent direct thrombin inhibitors lepirudin and bivalirudin [6]. (Bivalent in this context indicates binding to both thrombin's fibrinogen-binding exosite and its active site [6].) The explanation for argatroban's greater relative effect on the INR is unclear. However, although our comments are not meant to imply that the INR plays any role in anticoagulant monitoring during CPB, the distinct prolongation of this laboratory assay by argatroban at least suggests its effects on anticoagulant monitoring assays are not fully understood.

Thus, until we understand better the similarities and differences of argatroban vis-à-vis other direct thrombin inhibitors during CPB and as long as its clinical experience is limited only to a few case reports, we cannot currently recommend this agent for this indication.

References

1. Ohteki H, Furukawa K, Ohnishi H, Narita Y, Sakai M, Doi K. Clinical experience of argatroban for anticoagulation in cardiovascular surgery. Jpn J Thorac Cardiovasc Surg. 2000;48:39–46[Medline]
2. Furukawa K, Ohteki H, Hirahara K, Narita Y, Koga S. The use of argatroban as an anticoagulant for cardiopulmonary bypass in cardiac operations. J Thorac Cardiovasc Surg. 2001;122:1255–1256[Free Full Text]
3. Edwards JT, Hamby JK, Worrall NK. Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg. 2003;75:1622–1624[Abstract/Free Full Text]
4. Koster A, Hansen R, Kuppe H, Hetzer R, Crystal GJ, Mertzlufft F. Recombinant hirudi as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients. J Cardiothorac Vasc Anesth. 2000;14:243–248[Medline]
5. Koster A, Spiess B, Chew DP, et al. 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[Medline]
6. Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Baillieres Best Pract Res Clin Haematol (in press)

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