350 mg/kg (given over 3-5 min)

25 mg/kg/min

Infusion dose adjusted (15-40 mg/kg/min) to achieve an ACT 300-450 s; additional bolus doses of 150 mg/kg may be given as neededj,k

aBased on patient's body weight.

bIncludes patients with active HIT who have isolated thrombocytopenia or associated thrombosis, as well as patients with a documented history of HIT who are no longer thrombocytopenic but require anticoagulation. cArgatroban is approved in the United States as an anticoagulant for prophylaxis or treatment of thrombosis in patients with HIT, and is also available for use in Austria, Canada, Denmark, Iceland, Germany, The Netherlands, Norway, and Sweden as an anticoagulant in HIT.

dFor patients with moderate hepatic impairment, an initial dose of 0.5mg/kg/min is recommended. eThe aPTT should be checked at least 2 h after the initiation of argatroban or any dosage change. fFor patients in studies ARG-911 and ARG-915, the mean ±SEM dose of argatroban was 1.9 ±0.1 mg/kg/min. gFor transferring a patient to warfarin anticoagulant therapy: After substantial resolution of thrombocytopenia, initiate warfarin therapy using the expected daily dose of warfarin (do not use a loading dose) while maintaining argatroban infusion. At least 5 days of warfarin therapy are required to lower functional prothrombin concentrations to a therapeutic, steady state level. For monitoring the conversion to warfarin during coadministration of argatroban at doses up to 2mg/kg/min, see text and Figure 6.

hArgatroban is approved in the United States as an anticoagulant in patients with or at risk for HIT undergoing PCI. Argatroban has not been evaluated in hepatically impaired patients undergoing PCI. These recommendations do not consider the combination use of argatroban with glycoprotein IIb/IIIa antagonists, wherein lower doses of argatroban (e.g., 250-300mg/kg bolus followed by infusion of 15mg/kg/min) have been shown to provide effective anticoagulation with an acceptable bleeding risk (Jang et al., 2004).

Includes percutaneous transluminal coronary angioplasty (balloon angioplasty), stent implantation, and atherectomy; oral aspirin 325 mg should be given 2-24h prior to PCI.

jThe ACT should be checked 5-10 min following the initial bolus dose and after any additional bolus dose or change in the infusion rate. In studies ARG-216, ARG-310, and ARG-311, the majority of patients required only one bolus dose during the interventional procedure, and the mean ± SEM dose of argatroban was 23.1 ± 0.7 mg/kg/min.

kAfter the procedure, the sheaths should be removed no sooner than 2 h after discontinuing argatroban and when the ACT is <160 s.

Abbreviations: ACT, activated clotting time; aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; IV, intravenous; PCI, percutaneous coronary intervention.

total serum bilirubin (>1.5mg/dL) (Levine et al., 2006) and for patients with combined hepatic and renal impairment (Williamson et al., 2004; Levine et al., 2006). A conservative, reduced initial dose may also be prudent for patients with heart failure, multiple organ system failure, severe anasarca, or postcardiac surgery, that is, conditions associated with increased hepatic congestion or fluid overload, and possibly decreased argatroban clearance (de Denus and Spinler, 2003; Reichert et al., 2003; Baghdasarian et al., 2004; Levine et al., 2006; Czyz et al., 2006; Koster et al., 2006). The effect of decreased cardiac output or hepatic congestion, particularly in the absence of abnormal liver function tests, on argatroban pharmacokinetics remains to be prospectively studied.

No initial dosage adjustment is required in patients with renal impairment. Clinical data indicate that argatroban pharmacodynamics and pharmacokinetics are not affected by renal impairment, including severe insufficiency (Swan and Hursting, 2000; Murray et al., 2004; Tang et al., 2005). Creatinine clearance predicts the aPTT-adjusted argatroban dose across a range of renal functioning (Arpino and Hallisey, 2004; Guzzi et al., 2006), with multicenter data indicating that this effect is clinically insignificant, a 0.1 mg/kg/min decrease in dose for each 30 mL/ min decrease in creatinine clearance (Guzzi et al., 2006).

The initial dose should be adjusted, as needed, to achieve a target aPTT 1.5-3 times the baseline value. The aPTT should be checked 2 h after initiating therapy or at dose adjustment. Because achievement of steady-state anticoagulation will be delayed in many patients with hepatic impairment, it would be prudent to check their aPTT after at least 4-5 h (Levine et al., 2007). The choice of aPTT reagent does not materially affect assessment of argatroban therapy (Francis and Hursting, 2005). Body mass index does not significantly affect the argatroban dose required to achieve therapeutic aPTTs, and no modification of dosing or monitoring is required for obese patients (Rice et al., 2007). Approximately one in six patients in study ARG-911 maintained their initial argatroban dose for the duration of therapy, indicating that dosage adjustment is often unnecessary (Verme-Gibboney and Hursting, 2003). When dosage adjustment is necessary, the patient's current dose, aPTT, and clinical status (e.g., hepatic function) should be considered. A reasonable increment for most patients is 0.5 mg/kg/min. Smaller increments (e.g., 0.25 mg/kg/min) are appropriate when dosing is already reduced for reasons such as hepatic impairment (Verme-Gibboney and Hursting, 2003). At substantially higher argatroban doses, such as used during PCI, increments of 5 mg/kg/min are recommended (see Sec. V.A). In HIT patients with elevated baseline aPTT due to antiphospholipid antibody syndrome, the successful use of weight-based, fixed-dose argatroban without laboratory monitoring has been reported (Pendleton et al., 2006).

In recent reports of argatroban-treated patients with or at risk of HIT in single centers (Arpino and Hallisey, 2004; Smythe et al., 2005; Kiser et al., 2005; Kodityal et al., 2006) or in a multicenter registry (Bartholomew et al., 2007; Rice et al., 2007), mean or median doses of 0.5-1.2 mg/kg/min yielded target aPTTs. The reasons for the lower dose requirement in these patients, as compared with the ARG-911 and ARG-915 patients, remain unclear. Possibilities include the enrichment of particular patient types, e.g., cardiac surgery patients or patients with hepatic insufficiency, in certain centers; increasing physician preference to target the lower range of therapeutic aPTTs; and/or simply the reflection of more "real world" (outside the bounds of clinical trials) or contemporary experiences. Regardless of the use of a more conservative or less conservative initial dose, the infusion should be adjusted as needed according to the patient's aPTT response. Importantly, argatroban should be initiated upon strong suspicion of HIT, and not delayed pending laboratory diagnostic tests, to reduce thrombotic consequences (Warkentin and Greinacher, 2004) and associated healthcare costs (Arnold et al., 2006).

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