Argatroban anticoagulation for renal replacement therapy in patients with heparin-induced thrombocytopenia after cardiovascular surgery

Koster, Andreas; Hentschel, Thomas; Groman, Tom; Kuppe, Hermann; Hetzer, Roland; Harder, Sebastian; Fischer, Karl-Georg

doi:10.1016/j.jtcvs.2007.01.008

« Previous Next »The Journal of Thoracic and Cardiovascular Surgery
Volume 133, Issue 5 , Pages 1376-1377, May 2007

Argatroban anticoagulation for renal replacement therapy in patients with heparin-induced thrombocytopenia after cardiovascular surgery

Andreas Koster, MD, PhD
- Department of Anesthesia, Deutsches Herzzentrum Berlin, Germany
- Address for reprints: Andreas Koster, MD, PhD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
Thomas Hentschel, MD
- Department of Anesthesia, Deutsches Herzzentrum Berlin, Germany
Tom Groman, MD
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Germany
Hermann Kuppe, MD
- Department of Anesthesia, Deutsches Herzzentrum Berlin, Germany
Roland Hetzer, MD, PhD
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Germany
Sebastian Harder, MD, PhD
- Department of Clinical Pharmacology, Klinikum, J.W. Goethe-Universität Frankfurt/Main, Germany
Karl-Georg Fischer, MD, PhD
- Department of Medicine, Division of Nephrology and General Medicine, Universitätsklinikum Freiburg, Germany.

Received 16 November 2006; accepted 2 January 2007.

CTSNet classification: 25

Heparin-induced thrombocytopenia (HIT) is a severe thrombogenic disease requiring the use of alternative anticoagulants. Argatroban is a synthetic monovalent direct thrombin inhibitor indicated for prophylaxis and treatment of thrombosis in patients with HIT. Renal failure requiring renal replacement therapy (RRT) is a frequent complication in patients in whom HIT develops after cardiovascular surgery. The hepatic metabolism and relative short elimination half-life of 45 minutes render argatroban an interesting option for anticoagulation during RRT. However, there are scant data on dosing, pharmacokinetics, safety, and efficacy of argatroban in this indication. We report our initial experience with argatroban anticoagulation for continuous veno-venous hemofiltration (CVVH) and intermittent hemodialysis (IHD) in 10 patients diagnosed with HIT after cardiovascular surgery in whom acute renal failure developed necessitating RRT.

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Patients and Methods

After approval by the local ethics committee and having obtained informed consent, we analyzed the data of 10 patients. In accordance with the study protocol, data were collected for a maximum of 30 days during RRT. Clinical follow-up of patient outcome was performed for 3 months after initiation of RRT with argatroban. All patients had thrombocytopenia after surgery or presented persistent thrombocytopenia postoperatively. In all patients the diagnosis of HIT was confirmed in an antibody assay (Particle Gel Immune Assay; DiaMed, Cressier sur Morat, Switzerland) and in the heparin-induced platelet aggregation assay. The decision to perform CVVH (Ultraflux AV 600S; polysulfone high flux hemodialyzer, Fresenius Medical Care AG, Bad Homburg, Germany) or IHD (Polyflux 140 H; polyamix high flux hemodialyzer, Gambro, Hechingen, Germany) was based on stability of hemodynamics and mobility of the patient. In general, RRT was started with CVVH and changed to IHD after hemodynamics were stable and patient mobility increased. Only in 1 patient was RRT initiated with IHD. Target activated partial thromboplastin time (aPTT) (Roche Diagnostics, Mannheim, Germany, normal value 20-22 seconds) during RRT was 50 to 80 seconds and 40 to 60 seconds in periods without CVVD or IHD. Before the start of RRT, argatroban administration was started with a continuous infusion of 1 μg · kg⁻¹ · min⁻¹ for 1 hour. Thereafter, the aPTT was measured and RRT started. During the procedures, argatroban infusion rates were adjusted to target values in increments of 0.25 μg · kg⁻¹ · min⁻¹ depending on the results of coagulation tests.

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Results

There were 7 male and 3 female patients. The mean age was 58.8 ± 11.0 years. Surgery performed was implantation of a ventricular assist device in 2 patients, heart transplantations in 3, lung transplantation in 1, pulmonary artery thrombectomy in 1, replacement of a thoracoabdominal aortic aneurysm in 1, and coronary artery bypass grafting in 2. No bleeding events attributed to problems of anticoagulation were observed. Five patients died during the observation period. Data for argatroban dosing and aPTT values are presented in Table 1. The total duration of the 73 CVVH procedures was 2252 hours with a mean of 30.8 ± 27.1 hours. The total duration of the 29 IHD procedures was 160 hours with a mean of 3.9 ± 1.0 hours. No filter system had to be exchanged during IHD as a result of premature filter thrombosis.

TABLE 1. Argatroban dose and aPTT during and between CVVH and IHD

	During CVVH (n = 9)	Between CVVH procedures (n = 9)	Before IHD (n = 6)	During IHD (n = 6)	After IHD (n = 6)	Between IHD procedures (n = 6)
No. of procedures	73			29
Argatroban (μg · kg⁻¹ · min⁻¹)	0.13±0.21	0.29±0.31	0.07±0.11	0.06±0.11	0.07±0.12	0.20±0.20
aPTT	64.4±12.9	64.8±17.3	53.4±10.6	58.4±9.8	54.0±16.0	57.3±16.2

aPTT, Activated partial thromboplastin time; CVVH, continuous veno-venous hemodialysis; IHD, intermittent hemodialysis.

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Discussion

This is the first investigation providing a dosing regimen for the use of argatroban during RRT in patients with HIT after cardiovascular surgery. Our data provide convincing evidence that in these patients the current protocol provides safe and effective anticoagulation for CVVH and IHD. The data obtained suggest the following:

1.In view of the good patency of filters of approximately 30 hours and the low rate of bleeding complications, prolongation of the aPTT to the 3- to 4-fold appears to be safe and effective for argatroban anticoagulation for both CVVH and IHD in this patient population.

2.In a previous investigation, we¹ demonstrated that argatroban dosing in patients after cardiovascular surgery is considerably lower than in medical patients and that the anticoagulant effect of the drug is immediately achieved by continuous infusion so that no bolus administration is necessary. In line with these observations, in our patients the mean argatroban infusion rate during RRT of 0.06 to 0.12 μg · kg⁻¹ · min⁻¹ was considerably lower than the median infusion rate of 1.7 μg · kg⁻¹ · min⁻¹ in medical patients. Moreover, a starting infusion rate of 1 μg · kg⁻¹ · min⁻¹ for 1 hour provided reliable anticoagulation for the initiation of RRT, so that no bolus administration was necessary.²

3.In contrast to observations with the other direct thrombin inhibitors, bivalirudin and lepirudin, and in line with previous observations, the fact that argatroban dosing during and after CVVH and IHD was almost comparable with dosing during intervals without RRT suggests only minor elimination of the drug via the filter system.³, ⁴, ⁵ However, elimination of argatroban appears to be slightly more pronounced during CVVH.

On the basis of these observations, we conclude that dosing of argatroban according to the protocol outlined here provides reliable, safe, and effective anticoagulation during CVVH and IHD in patients with HIT after cardiovascular surgery. Inasmuch as the argatroban elimination half-life of 45 minutes is relatively short, elimination is independent of renal function and, as we observed, extracorporeal elimination during both CVVH and IHD is clinically insignificant, so that no dose adjustment is necessary during RRT, argatroban anticoagulation appears to be an excellent option in this indication. However, further detailed studies are needed to confirm this assumption.

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References

Koster A, Buz S, Hetzer R, Kuppe H, Breddin K, Harder S. Anticoagulation with argatroban in patients with heparin-induced thrombocytopenia antibodies after cardiac surgery with cardiopulmonary bypass: first results from the ARG-E03 trial. J Thorac Cardiovasc Surg. 2006;132:699–700

Reddy BV, Grossman EJ, Trevino SA, Hursting MJ, Murray PT. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia requiring renal replacement therapy. Ann Pharmacother. 2005;39:1601–1605

Koster A, Merkle F, Hansen R, Loebe M, Kuppe H, Hetzer R, et al. Elimination of recombinant hirudin by modified ultrafiltration during simulated cardiopulmonary bypass: assessment of different filter systems. Anesth Analg. 2000;91:265–269

Koster A, Chew D, Gruendel M, Hausmann H, Grauhahn O, Kuppe H, et al. An assessment of different filter systems for extracorporeal elimination of bivalirudin: an in vitro study. Anesth Analg. 2003;96:1316–1319
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Tang IY, Cox DS, Patel K, Reddy BV, Nahlik L, Trevino S, et al. Argatroban and renal replacement therapy in patients with heparin-induced thrombocytopenia. Ann Pharmacother. 2005;39:231–236