Reply

Abstract

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 [1Ohteki 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: 39-46Crossref PubMed Scopus (39) Google Scholar, 2Furukawa 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: 1255-1256Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 3Edwards J.T. Hamby J.K. Worrall N.K. 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: 1622-1624Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. However, these reports describe only two instances of argatroban use during conventional CPB for surgical procedures on the heart [2Furukawa 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: 1255-1256Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 3Edwards J.T. Hamby J.K. Worrall N.K. 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: 1622-1624Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] (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 [1Ohteki 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: 39-46Crossref PubMed Scopus (39) Google Scholar]). 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 [3Edwards J.T. Hamby J.K. Worrall N.K. 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: 1622-1624Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. In contrast, the published experiences [4Koster A. Hansen R. Kuppe H. Hetzer R. Crystal G.J. Mertzlufft F. Recombinant hirudiń 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: 243-248Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 5Koster A. Spiess B. Chew D.P. 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: 356-359Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar] 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 [4Koster A. Hansen R. Kuppe H. Hetzer R. Crystal G.J. Mertzlufft F. Recombinant hirudiń 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: 243-248Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 5Koster A. Spiess B. Chew D.P. 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: 356-359Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar]. 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 [6Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Baillieres Best Pract Res Clin Haematol (in press)Google Scholar]. (Bivalent in this context indicates binding to both thrombin's fibrinogen-binding exosite and its active site [6Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Baillieres Best Pract Res Clin Haematol (in press)Google Scholar].) 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. 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 [1Ohteki 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: 39-46Crossref PubMed Scopus (39) Google Scholar, 2Furukawa 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: 1255-1256Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 3Edwards J.T. Hamby J.K. Worrall N.K. 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: 1622-1624Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. However, these reports describe only two instances of argatroban use during conventional CPB for surgical procedures on the heart [2Furukawa 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: 1255-1256Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 3Edwards J.T. Hamby J.K. Worrall N.K. 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: 1622-1624Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] (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 [1Ohteki 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: 39-46Crossref PubMed Scopus (39) Google Scholar]). 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 [3Edwards J.T. Hamby J.K. Worrall N.K. 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: 1622-1624Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. In contrast, the published experiences [4Koster A. Hansen R. Kuppe H. Hetzer R. Crystal G.J. Mertzlufft F. Recombinant hirudiń 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: 243-248Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 5Koster A. Spiess B. Chew D.P. 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: 356-359Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar] 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 [4Koster A. Hansen R. Kuppe H. Hetzer R. Crystal G.J. Mertzlufft F. Recombinant hirudiń 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: 243-248Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 5Koster A. Spiess B. Chew D.P. 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: 356-359Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar]. 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 [6Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Baillieres Best Pract Res Clin Haematol (in press)Google Scholar]. (Bivalent in this context indicates binding to both thrombin's fibrinogen-binding exosite and its active site [6Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Baillieres Best Pract Res Clin Haematol (in press)Google Scholar].) 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.