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Original Research: ANTICOAGULATION |

Argatroban Therapy in Heparin-Induced Thrombocytopenia With Hepatic Dysfunction*

Robert L. Levine, MD; Marcie J. Hursting, PhD; David McCollum, MS
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*From the University of Texas Health Science Center (Dr. Levine), Houston, TX; Clinical Science Consulting (Dr. Hursting), Austin, TX; and CTI Clinical Trial and Consulting Services (Mr. McCollum), Blue Ash, OH.

Correspondence to: Robert L. Levine, MD, University of Texas School of Medicine at Houston, 6431 Fannin, MSB 7.142, Houston, TX 77030; e-mail: rlevine@uth.tmc.edu



Chest. 2006;129(5):1167-1175. doi:10.1378/chest.129.5.1167
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Study objectives: We evaluated the dosing requirements in argatroban-treated patients with heparin-induced thrombocytopenia (HIT) and hepatic dysfunction, and compared efficacy and safety outcomes with historical control patients.

Design: Retrospective analysis.

Setting: Inpatient setting.

Patients: Patients with hepatic dysfunction, defined as total bilirubin > 25.5 μmol/L (1.5 mg/dL), aspartate aminotransferase >100 IU/L, and/or alanine aminotransferase >100 IU/L, were identified from previous multicenter, historical-controlled studies of argatroban therapy in HIT.

Interventions: Argatroban, adjusted to maintain activated partial thromboplastin times (aPTTs) 1.5 to 3 times baseline in the experimental group, vs no direct thrombin inhibition in the historical control patients.

Measurements and results: The analysis population included 82 argatroban patients and 34 historical control patients with hepatic impairment, of whom approximately 50% in each group had renal dysfunction (defined as a serum creatinine level > 1.3 mg/dL). The argatroban dosage was 1.6 ± 1.1 μg/kg/min (mean ± SD) over a mean 5-day course of therapy. Significantly lower doses were used in patients with elevated vs normal total bilirubin levels (0.8 ± 0.6 μg/kg/min vs 1.7 ± 0.8 μg/kg/min, p = 0.0063) and in patients with hepatic/renal dysfunction vs hepatic dysfunction alone (1.2 ± 1.1 μg/kg/min vs 2.0 ± 1.1 μg/kg/min, p < 0.001). The aPTT 24 h after argatroban initiation was 69 ± 22 s, with 80% of patients having a therapeutic level of anticoagulation. Thirty-four argatroban-treated patients (41.5%) and 17 control patients (50.0%) experienced the 37-day composite end point of death, amputation, or new thrombosis (p = 0.32). Argatroban significantly reduced new thrombosis (8.5% vs 26.5%, p = 0.012). Major bleeding was similar between treatment groups (4.9% vs 2.9%, p = 0.684).

Conclusions: Hepatic dysfunction affects argatroban dosing, with reduced doses required particularly in patients with serum total bilirubin levels > 25.5 μmol/L (1.5 mg/dL) or combined hepatic/renal dysfunction. Individual mean aPTT-adjusted doses typically remain ≥ 0.5 μg/kg/min, supporting the recommendation of 0.5 μg/kg/min as a conservative initial dose for most patients with hepatic impairment. Argatroban, with proper initial dosing and monitoring, can provide safe and effective antithrombotic therapy in patients with HIT and hepatic impairment.

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