Argatroban Therapy Using Enzymatic Anti-Factor IIa Monitoring

Abstract

TO THE EDITOR: Current treatment of heparin-induced thrombocytopenia (HIT) is replacement of heparin with a direct thrombin-inhibitor (DTI) such as argatroban. 1 The argatroban package insert recommends that initial dosage be based on patient weight. However, this may be suboptimal, since argatroban is distributed predominantly in blood and extracellular fluid and not in lean tissue and/or adipose. 2 Additionally, monitoring argatroban therapy is challenging because the gold standard assays are not routinely available. Therefore, the activated partial thromboplastin time (aPTT) is used as a surrogate; a target of 1.5-3 times the baseline aPTT value, not to exceed 100 seconds, is recommended in the package insert. At our institution, this target would be approximately 40-100 seconds. However, studies have shown that the aPTT is not linearly related to DTI concentration, there are interlaboratory differences in aPTT assays, and there is significant interpatient variability. 3, 4 We developed a pharmacist-managed, computerized argatroban dosage protocol based on estimated patient blood volume 5 and monitored with a routine enzymatic anti-factor IIa argatroban concentration assay (developed in-house). Based on information provided in Figure 1 (Relationship at Steady State Between Argatroban Dose, Plasma Argatroban Concentration and Anticoagulant Effect) of the package insert, 2 we chose a conservative target therapeutic concentration of 0.5 µg/mL which, in the figure, corresponds to an approximate aPTT of 55 seconds, or about 1.7 times baseline.Initial argatroban dosage, based on estimated patient blood volume and creatinine clearance, was calculated with a network-deployed Microsoft Excel dosing tool. Although not recommended in the package insert, we administered a loading dose to achieve a therapeutic argatroban concentration as quickly as possible. Subsequent infusion rate adjustments were based on the enzymatic drug concentration and pharmacokinetic principles for continuous drug infusion.Initially, consistent with current package insert recommendation, the protocol did not account for renal function, although the drug is known to be partially renally eliminated. 2 However, experience with our first 17 patients demonstrated that reductions in starting infusion rates were necessary in patients with renal dysfunction to avoid elevated argatroban concentrations. Patients with significant hepatic dysfunction were treated with empirically reduced doses but were excluded from the data analysis.The final version of the protocol was implemented in March 2007. Data were collected from 44 subsequent patients. The median initial argatroban infusion rate was 35% (range 12-59%) of that recommended by the package insert. The first argatroban concentration was drawn per protocol approximately 8 hours after administration of the loading dose and initiation of infusion. The median initial argatroban concentration was 0.47 µg/mL (target 0.5 µg/mL), with the middle 80% of values between 0.27 and 0.85 µg/mL. The first infusion r...

Managing argatroban in heparin‐induced thrombocytopenia: A retrospective analysis of 729 treatment days in 32 patients with confirmed heparin‐induced thrombocytopenia

“…21 Our group and others have shown that TT is more reliable and robust for the monitoring of argatroban. 6,22 Figure 6A confirms a linear relationship between PAC and corresponding TT intervals. In contrast, the relationship between increasing PAC and correspondent simultaneous aPTT intervals is not linear, reaching a plateau for aPTT values above 70 s (Figure 6B), underscoring that this coagulation assay is less accurate for monitoring argatroban anticoagulation.…”

Recommendations on the use of anticoagulants for the treatment of patients with heparin-induced thrombocytopenia in Switzerland

“…In the absence of organ failure, the dose recommended in the manufacturer's prescribing information is 2 μg/kg/min. However, several publications indicate that this dose is too high and that an initial dose of 1 μg/kg/min is adequate for patients without organ function impairment [22,29,30].…”

“…Antifactor IIa and/or aPTT monitoring is scheduled before and 2 hours after the start of the argatroban infusion (steadystate levels of drug and anticoagulant effect are expected after five half-lives), 2 hours after each dose adjustment and then daily. The proposed target argatroban concentration is 0.4-1.5 μg/ml [22,25]. The aPTT is aimed at 1.5−3.0 times the patient's baseline (provided baseline aPTT was within the reference range) without exceeding 100 sec with most reagents; the precise target range depends very much on the local reagent/coagulometer combination and has to be established in-house.…”

Measurement of non‐Coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology

“…Specific chromogenic anti‐IIa assays are available for the measurement of drugs that inhibit thrombin, including DTIs (Shepherd et al , ; Harenberg et al , ). These assays should be calibrated with product‐specific calibrators which are available commercially for dabigatran and argatroban.…”