DTI Dosing

An emerging issue is the growing recognition that the approved dosing regimens of the DTIs—as presented within the product monographs—is often too high, especially with lepirudin (Lubenow et al., 2005; Tardy et al., 2006; see also Chapter 14). Accordingly, it is recommended that for most situations, the initial iv bolus be omitted and the initial iv infusion rate be reduced by about 50% (from 0.15 mg/ kg/h to 0.05-0.10 mg/kg/h), even in patients with normal renal function (the dose is reduced substantially more in the presence of renal dysfunction) (Warkentin et al., 2007). Moreover, aPTT monitoring should be performed at 4-h intervals until stable anticoagulation within the therapeutic range is observed (whereupon once-daily monitoring is appropriate). For argatroban, post-marketing studies indicate that it is increasingly common to reduce the initial infusion rate from the approved dose (2 mg/kg/min) to 0.5-1.2 mg/kg/min, especially in

TABLE 5 Main Characteristics of the Direct Thrombin Inhibitor, Argatroban

Monitoring Undesirable effects Comments

Mechanism of action, pharmacokinetics

Direct, noncovalent, reversible inhibitor of free and clot-bound thrombin ~50% of the drug is plasma protein bound Steady state is reached 1-3 h after starting iv infusion Mean plasma ty2 is 40-50 min; ty2 is prolonged 4- to 5-fold in moderate liver impairment aPTT during treatment; no data exist as to whether more precise monitoring at higher doses would be achieved using other methods, such as ECT Target INR is >4.0 when warfarin is overlapped with argatroban (however, following discontinuation of argatroban, the usual target INR of 2.0-3.0 applies during further warfarin treatment) Note: in case of prothrombin deficiency, aPTT gives falsely high values

No major side effects besides bleeding complications Argatroban makes all functional clotting assays unreliable

Only iv use of argatroban has been tested in HIT Reduce dosage by 75% in case of liver impairment No dose reduction in renal failure No antidote: in case of overdosage or severe bleeding, stop the drug and treat bleeding with blood products as indicated Argatroban prolongs the INR and requires a strategy adopted to the INR reagent used for overlapping treatment with warfarin

(see Chapter 15)

Abbreviations: aPTT, activated partial thromboplastin time; ECT, ecarin-clotting time; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; iv, intravenous; t1/2, drug half-life.

critically ill patients or in patients with cardiac dysfunction, even when hepatic dysfunction is not clinically apparent (see Chapter 15).

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