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J Thorac Cardiovasc Surg 2006;132:699-700
© 2006 The American Association for Thoracic Surgery

Brief Communication

Anticoagulation with argatroban in patients with heparin-induced thrombocytopenia antibodies after cardiovascular surgery with cardiopulmonary bypass: First results from the ARG-E03 trial

^a Department of Anesthesia, Deutsches Herzzentrum Berlin, Berlin, Germany
^b Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
^c International Institute of Thrombosis and Vascular Diseases, Frankfurt/Main, Germany
^d Department of Clinical Pharmacology, Klinikum, J.W. Goethe-Universität, Frankfurt/Main, Germany.

Received for publication March 16, 2006; revisions received April 5, 2006; accepted for publication April 25, 2006.

^_* Address for reprints: Andreas Koster, MD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin (Email: koster{at}dhzb.de).

Heparin-induced thrombocytopenia (HIT) is a severe thrombogenic disease requiring the use of alternative anticoagulants. Argatroban is a synthetic monovalent direct thrombin inhibitor hepatically metabolized with a 45-minute half-life.¹ Argatroban is the only anticoagulant indicated for prophylaxis and treatment of thrombosis in patients with HIT. However, there are scant data regarding use of argatroban in patients with HIT after cardiovascular surgery with cardiopulmonary bypass (CPB). We report on postoperative argatroban in 14 patients with HIT antibodies who underwent cardiovascular surgery with CPB.

Patients and Methods

The European ARG-E03 trial is a multicenter, open-label trial assessing argatroban as a replacement for heparin in patients with a history of HIT or suspected HIT. After ethics committee approval and having obtained informed consent, we enrolled 20 patients from our center. Four patients underwent procedures without CPB. Two of the patients undergoing CPB were treated according to the original protocol with an argatroban starting dose of 2 µg · kg^–1 · min^–1, and an activated partial thromboplastin time (aPTT) overshoot to values exceeding 80 seconds was observed. Therefore the starting dose was reduced to 0.8 to 1 µg · kg^–1 · min^–1 for further patients. We report on the 14 patients who underwent CPB procedures with this protocol.

Results

There were 9 female and 5 male patients with HIT antibodies present before surgical intervention, with a mean age of 61.2 ± 14.7 years and mean weight of 78.0 ± 16.6 kg. Surgical intervention was coronary artery bypass grafting in 6 patients, coronary artery bypass grafting plus valve repair-replacement in 3 patients, valve surgery only in 4 patients, and repair of a descending thoracic aortic aneurysm in 1 patient. Anticoagulation during CPB had been performed with heparin and tirofiban; postoperative argatroban anticoagulation was initiated immediately after surgical intervention, with a target aPTT of 50 to 70 seconds (STA aPTT, Roche; normal value, 20-22 seconds). Patients were maintained on argatroban anticoagulation for the routine duration of intravenous therapy. In patients without valve surgery (n = 7), anticoagulation was changed to single subcutaneous injection of 15 mg/d desirudin (Revasc, Canyon Pharma, Hunt Valley, Md) starting the day after the operation. In patients after valve repair (n = 4), anticoagulation was continued with argatroban for 3 days and thereafter changed to desirudin and then to warfarin sodium (Marcumar, Roche, Reinach, Switzerland). In 2 patients after valve replacement, argatroban was transited to warfarin sodium. In 2 patients who reacted rather sensitively to argatroban (<0.2 µg · kg^–1 · min^–1), the switch was made to lepirudin (Refludan, Hoechst Marion Roussel, Kansas City, Mo). However, in these patients the lepirudin requirement was also quite low (<0.001 mg · kg^–1 · h^–1). The mean duration of drug administration was 3.0 ± 1.2 days. In all patients the initial infusion rate achieved target aPTT within 30 minutes, and in all patients, this target aPTT could be maintained without a further increase of the dose. Instead, reduction of the dose to an average of 0.3 to 0.4 µg · kg^–1 · min^–1 was performed in most patients (Table 1 and Figure 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Mean dose of argatroban in the ARG 915 and ARG 911 study patients and the current investigation. HIT, Patients with heparin-induced thrombocytopenia without thromboembolism; HITT, patients with heparin-induced thrombocytopenia and concomitant thromboembolism. Current study data: S0.5, 30 minutes after start of argatroban; S2, 2 hours after start; S4, 4 hours after start; D1, end of first day; D2, day 2; D3, day 3; E0, before termination of argatroban infusion. Patient numbers were as follows: 14 at S0.5 to D1, 12 at D2, 10 at D3, and 14 at E0.

Discussion

In previous studies of patients with HIT in a non-CPB setting, argatroban therapy was initiated with 2 µg · kg^–1 · min^–1, and the mean doses necessary to achieve target aPTTs ranged between 1.7 and 2.0 µg · kg^–1 · min^–1.^2,3 In approximately 10% of these patients, a maximum dose of 10 µg · kg^–1 · min^–1 failed to achieve the target aPTTs.² In contrast, in a case series of 4 patients with HIT after cardiac surgery, excessive anticoagulation to aPTT values of greater than 100 seconds using the starting doses of 2 and 1 µg · kg^–1 · min^–1 has been reported.⁴

The starting dose of 0.8 to 1 µg · kg^–1 · min^–1 argatroban provided rapid anticoagulation to target aPTTs within 30 minutes in all patients, and in most patients, it was later reduced to rates of less than 0.5 µg · kg^–1 · min^–1 (Figure 1). After termination of argatroban, a marked decrease of aPTT was observed within 4 hours, indicating rapid fading of the anticoagulant effect (Table 1).

Different aPTT assays demonstrate significant variations regarding the response to argatroban.⁵ This might explain the large variation in patients' response to argatroban observed in the ARG 911 and ARG 915 investigations and has to be considered when evaluating our single-center data.

We conclude that in patients with HIT antibodies after cardiovascular surgery with CPB, argatroban given at a starting dose of 0.8 to 1 µg · kg^–1 · min^–1 provides rapid and effective anticoagulation without the need for bolus administration and almost exclusively without dramatic overshoot of the aPTT. However, the fact that this dose had to be reduced during the further course suggests that this patient population reacts sensitively to argatroban, and tight monitoring, particularly during the initiation of therapy, is recommended.

In conclusion, we have shown that argatroban provides rapid and effective anticoagulation in patients with HIT antibodies after cardiovascular surgery with CPB and that argatroban was safely used in the patients studied. However, further studies are needed to define in greater detail the safety profile of argatroban in critical indications.

Footnotes

Andreas Koster, Sebastian Harder, and HK Breddin report lecture fees from Mitsubishi Pharma. This study was supported by a grant from Mitsubishi Pharma Deutschland GmbH, the manufacturer of argatroban.

References

1. Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med 2005;353:1028-1040.[Free Full Text]
   
2. Lewis BE, Wallis DE, Berkowitz SD, Manthia WH, Fareed J, Walenga M, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001;1003:1838-1843.
   
3. Lewis BD, Wallis DE, Leya F, Hursting MJ, Kelton JG, Argatroban 915 investigators Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003;163:1849-1856.[Abstract/Free Full Text]
   
4. Reichert MG, MacGregor DA, Kincaid EH, Dolinski SY. Excessive argatroban anticoagulation for heparin-induced thrombocytopenia. Ann Pharmacother 2003;37:652-654.[Abstract/Free Full Text]
   
5. Francis JL, Hursting MJ. Effect of argatroban on the activated partial thromboplastin time. a comparison of 21 commercial reagents. Blood Coagul Fibrinolysis 2005;16:251-257.[Medline]
   

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