Prospective Evaluation of An Argatroban Dosing Nomogram Using the Ecarin Chromogenic Assay at a Tertiary Institution

Abstract There is a lack of consensus on how to best monitor therapy with the direct thrombin inhibitor argatroban. Currently, the most commonly used test is the activated partial thromboplastin time (aPTT). However, it has limited reliability, as it is easily affected by other factors, and the target is unclear in patients whose baseline values are abnormal. The ecarin chromogenic assay (ECA) reaction time is strongly correlated with plasma argatroban concentrations (r2 = 0.9994), and thus, can be used for direct quantification of argatroban concentrations. Moreover, the ECA is unaffected by low levels of prothrombin and fibrinogen, making it a more reliable and accurate test. Our institution developed a unique dosing and monitoring protocol for argatroban therapy incorporating the use of nomograms to dose argatroban and the ECA to monitor argatroban concentrations. The purpose of this study was to evaluate the ability of our current argatroban protocol to achieve and maintain ECA levels within the desired target range of 0.2 to 0.5 mcg/mL, validate the safety and efficacy of an ECA-based nomogram, and determine the relationship between argatroban concentrations and aPTT values. We conducted a prospective observational study of all patients receiving argatroban at the University Health Network (UHN) from September 1, 2007 to May 15, 2008. The UHN consists of three tertiary care hospitals in Toronto, Canada. The argatroban protocol consists of an initial infusion rate and two dose titration nomograms, one based on the ECA and the other based on the aPTT (for dose adjustment when the ECA result was unavailable during evenings and weekends). The recommended initial infusion rate was 1 mcg/kg/min, with a lower rate of 0.5 mcg/kg/min reserved for patients with liver dysfunction and/or an increased risk of bleeding. Both ECA levels and aPTT values were measured 6 hours after the initiation of argatroban and any change in rate. The primary outcome measures were the proportion of patients who achieved argatroban concentrations within the target range after the first level, the number of rate changes required to achieve target levels, and the proportion of time spent in the target range in the first 24, 48 and 72 hours. Secondary outcome measures included the proportion of patients who developed a thrombotic event or major bleed, as well as the correlation between argatroban concentrations and aPTT values. A total of 33 patients were enrolled. Protocol violations in the initial dosing and titration of argatroban led to the exclusion of 6 patients from all primary outcome analyses. Of the patients with ECA levels available at the initial rate, 35% of all patients had levels in the target range with the first ECA level. This proportion increased to 54% for patients started at 1 mcg/kg/min. The mean number of rate changes required to achieve levels in the target range was 1.15 and the mean time was 21.7 hours. The proportion of time spent in the target range in the first 72 hours was 78%. Two patients (6%) had thrombotic events during argatroban therapy with levels in the target range, and 1 patient (3%) who had previously bled prior to argatroban therapy had a confirmed major bleed. The correlation co-efficient between ECA levels and aPTT using 125 data points was 0.2475. In conclusion, our institution’s argatroban protocol enabled the majority of patients to achieve target argatroban concentrations in a timely manner, and resulted in safe and effective anticoagulation. Most patients could be started at a dose of 1 mcg/kg/min. The aPTT is poorly correlated with argatroban concentrations, we recommend using the ECA to more directly quantify argatroban concentrations and to dose and monitor argatroban therapy.

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