Hemodialysis

Argatroban administration by bolus alone, infusion alone, or bolus plus infusion has been evaluated in a prospective three-way cross-over study of 13 patients with end-stage renal disease who underwent a total of 38 hemodialysis sessions of 3- or 4-h duration (Murray et al., 2004). Although dialysis dose was effectively delivered using each regimen, the most satisfactory intradialysis anticoagulation was achieved using a steady-state infusion of argatroban (2 mg/kg/min begun approximately 4h before dialysis), or a 250 mg/kg bolus dose at the start of dialysis followed by a continuous 2 mg/kg/min infusion. With those regimens, mean ACTs increased from 131 s at baseline to 200 and 197 s, respectively, after 60 min of dialysis. No dialysis membrane required changing, and one session was shortened by 15 min owing to circuit clotting. There were no thrombotic or bleeding events. Argatroban dialytic clearance was clinically insignificant. Although the study was conducted in patients without HIT, similar dosing regimens may be adequate for inpatients with HIT already at steady-state argatroban levels or outpatients with a history of HIT who require hemodialysis.

The pharmacokinetics, pharmacodynamics, and safety of argatroban during a single renal placement therapy session have been prospectively evaluated in five hospitalized patients with or at risk of HIT (Tang et al., 2005). The patients underwent hemodialysis (n = 4) or continuous venovenous hemofiltration (n = 1) while receiving continuous iv argatroban 0.5-2 mg/kg/min. ACTs, aPTTs, and plasma argatroban concentrations remained stable during the renal replacement therapy, and hemodialysis was effective as evidenced by the urea reduction ratio. No patient experienced bleeding or thrombosis. Argatroban clearance by the high-flux membranes was clinically insignificant, indicating that in patients with renal failure receiving argatroban therapy for HIT, no dosage adjustment is needed during renal replacement therapy.

A retrospective study evaluated the safety, outcomes, and argatroban dosing patterns in HIT patients requiring renal replacement therapy (Reddy et al., 2005). The patients (n = 47) were identified from the prospective ARG-911 and ARG-915 studies of argatroban in HIT. Patients with comorbid hepatic impairment required median lower doses (0.7mg/kg/min) than patients without hepatic impairment (1.7 mg/kg/min). Two (4%) patients experienced thrombosis while on argatroban.

Major bleeding occurred in three (6%) of 50 treatment courses within a 37-day follow-up period, generally similar to reported bleeding rates in argatroban-treated patients with HIT, irrespective of their renal function. Overall, argatroban provided effective anticoagulation and was well tolerated in this setting, upon initial and repeat administration.

Experience with argatroban in pediatric patients during hemodialysis is limited. A literature analysis identified five pediatric patients with HIT or a history of HIT who underwent hemodialysis using argatroban anticoagulation (Hursting et al., 2006). No patient experienced systemic thrombosis while on argatroban, one patient experienced clotting in the dialysis circuit, and one patient had bleeding that was multifactorial in origin. More recently, a pediatric patient with HIT and thrombosis has been described who underwent continuous renal replacement therapy and extracorporeal membrane oxygenation (ECMO) successfully while on argatroban therapy (Scott et al., 2006).

Argatroban is approved in Japan as an anticoagulant for hemodialysis in patients with congenital or acquired antithrombin deficiency. The recommended dose is generally similar to that used in HIT patients undergoing hemodialysis (Matsuo et al., 1988, 1990; Koide et al., 1995; Tang et al., 2005; Reddy et al., 2005).

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