Conversion to Warfarin Anticoagulation

Because argatroban is a DTI, its concomitant use with warfarin prolongs the PT/ INR beyond that produced by warfarin alone (Hursting et al., 1999; Sheth et al.,

2001). In the clinical studies of argatroban therapy in HIT, the majority of patients transferred to warfarin therapy for continued anticoagulation, although the method of transition was not specified in the protocols. Even in the absence of guidelines, there was no evidence of systematic underdosing or overdosing of warfarin (Hursting et al., 2005). INRs > 5 commonly occurred during argatroban monotherapy and argatroban/warfarin cotherapy, without major bleeding (Hursting et al., 2005), and among patients with INRs > 4 while on combined argatroban <2 mg/kg/min and warfarin therapy, the thrombotic risk remained greater than the bleeding risk (Bartholomew and Hursting, 2005).

Guidelines for monitoring the transition from argatroban to warfarin using the INR are published (Sheth et al., 2001). The relationship between the INR on cotherapy and the INR on warfarin monotherapy can be used to interpret the INR during the transition period. Specifically, INR on cotherapy increases linearly with the INR on warfarin monotherapy, with the relationship sensitive to the argatro-ban dose and thromboplastin reagent used, particularly, its International Sensitivity Index (ISI). For argatroban 1-2 mg/kg/min, prediction errors for monotherapy INRs from cotherapy INRs are sufficiently low (±0.4 units) to allow for clinically reliable estimations of a monotherapy INR from a cotherapy INR. For most combinations of argatroban dose 1-2 mg/kg/min and commercial thromboplas-tins, a cotherapy INR > 4 predicts a monotherapy INR between approximately 2.0 and 3.0, i.e., in the therapeutic range for warfarin monotherapy. In general, after at least 4-5 days of coadministration of warfarin and argatroban at doses up to 2 mg/kg/min, argatroban can be discontinued when the cotherapy INR is >4 (and ideally has been for 2 days). Upon cessation of argatroban, the INR should be checked 4-6 h later, when the effect of argatroban is negligible, to ensure an actual therapeutic value reflective of warfarin monotherapy. For coadministration of warfarin and argatroban at doses >2 mg/kg/min, the argatroban dose should be temporarily (4-6 h) reduced to 2 mg/kg/min. Then the procedure for predicting the warfarin monotherapy INR from the cotherapy INR at doses up to 2 mg/kg/ min can be followed. These guidelines are summarized in Figure 6.

Factor assays that are insensitive to argatroban interference, such as the two-stage chromogenic factor X assay, may also be useful for monitoring the transition (Hoppensteadt et al., 1997; Sheth et al., 2001). A chromogenic factor X level of 45% or less is a reliable predictor that the INR will be therapeutic when argatroban therapy is discontinued (Arpino et al., 2005).

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