Monitoring of argatroban in critically ill patients: a prospective study comparing aPTT, point-of-care viscoelastic testing with ecarin clotting time and dTT to mass spectrometry

The direct thrombin inhibitor argatroban is indicated for the treatment of heparin-induced thrombocytopenia II, but it is also used off-label to treat critically ill patients presenting with heparin resistance, severe antithrombin deficiency or hypercoagulability. Direct drug monitoring is not routinely available and argatroban dosing is mainly based on global coagulation assays such as activated partial thromboplastin time (aPTT) or diluted thrombin time (dTT), both of which have limitations in patients with hypercoagulability.Blood samples were obtained from critically ill patients treated with argatroban, aPTT and dTT were measured with a STA R Max3-Analyzer using an argatroban-calibrated kit. Ecarin clotting time (ECA-CT) was measured using a POC viscoelastic test device. Liquid chromatography with tandem mass spectrometry (LC/MS/MS) was performed using a reversed phase column, a solvent gradient and a API4000 mass spectrometer with electrospray. Correlation was described using Pearson correlation coefficient r and Bayesian multilevel regression to estimate relationships between outcomes and covariates.From 06/2021 to 03/2022, 205 blood samples from 22 patients were analyzed, allowing for 195 aPTT - LC/MS/MS comparisons, 153 ECA-CT - and 105 dTT - LC/MS/MS comparisons. Compared to LC/MS/MS, performance of argatroban quantification was best for dTT (r =0.91), followed by ECA-CT (r=0.58) and aPTT (r=0.48). Regression analysis revealed that patients with sepsis were more prone to argatroban overdosing (coefficient: 4.194; 95% Crl 2.220, 6.792).Althought aPTT monitoring of argatroban is the most commonly used test, in critically ill patients dTT provides more precise measurements. Alternately, point-of-care viscoelastic ECA-CT also provides guidance for argatroban dosing to identify overdosing if available. Our data also suggests patients with sepsis are at a greater risk for argatroban overdosing.