Abstract
BackgroundArgatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population.Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients.MethodsThis study was part of the double-blind randomized trial “Argatroban versus Lepirudin in critically ill patients (ALicia)”, which compared critically ill patients treated with argatroban or lepirudin. Following institutional review board approval and written informed consent, for this sub-study blood of 35 critically ill patients was analysed. Before as well as 12, 24, 48 and 72 h after initiation of argatroban or lepirudin infusion, blood was analysed for aPTT, aPTT ratios, thrombin time (TT), INTEM CT,INTEM CT ratios, EXTEM CT, EXTEM CT ratios and maximum clot firmness (MCF) and correlated with the corresponding plasma concentrations of the direct thrombin inhibitor.ResultsTo reach a target aPTT of 1.5 to 2 times baseline, median [IQR] plasma concentrations of 0.35 [0.01–1.2] μg/ml argatroban and 0.17 [0.1–0.32] μg/ml lepirudin were required. For both drugs, there was no significant correlation between aPTT and aPTT ratios and plasma concentrations. INTEM CT, INTEM CT ratios, EXTEM CT, EXTEM CT ratios, TT and TT ratios correlated significantly with plasma concentrations of both drugs. Additionally, agreement between argatroban plasma levels and EXTEM CT and EXTEM CT ratios were superior to agreement between argatroban plasma levels and aPTT in the Bland Altman analysis. MCF remained unchanged during therapy with both drugs.Conclusion In critically ill patients, TT and ROTEM parameters may provide better correlation to argatroban and lepirudin plasma concentrations than aPTT.Trial registrationClinicalTrials.gov, NCT00798525, registered on 25 Nov 2008
Highlights
Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time
As a preplanned sub-study of the recently published larger doubleblinded clinical trial (“Argatroban versus Lepirudin in critically ill patients (ALicia”) [15], we evaluated the results of rotational thromboelastometry (ROTEM) measurements and conventional laboratory parameters for monitoring anticoagulation and tested their correlation to drug plasma levels in critically ill patients undergoing argatroban and lepirudin therapy
Correlations Correlations between monitoring parameters and argatroban and lepirudin plasma levels were graphically displayed and correlation coefficients calculated for activated partial thromboplastin time (aPTT), aPTT ratios, which are the quotient of every aPTT and the corresponding baseline value, Prothrombin time (PT) (Quick), thrombin time (TT) and TT ratios, Rotational thromboelastometry assay measuring intrinsic coagulation pathway (INTEM) Clotting time (CT), INTEM CT ratios, Rotational thromboelastometry assay measuring extrinsic coagulation pathway (EXTEM) CT and EXTEM CT
Summary
Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). APTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. We studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients. Argatroban and lepirudin are direct thrombin inhibitors, approved for alternative anticoagulation of patients with proven or suspected heparin induced thrombocytopenia. Argatroban, a parenteral recombinant L-arginine derivate, is primarily metabolized in the liver. Lepirudin, a parenteral recombinant hirudin, is eliminated primarily through the kidneys. Argatroban has to be carefully titrated in patients with reduced liver function. Lepirudin needs to be carefully adapted to those with reduced kidney function. In critically ill patients, the appropriate dosage of both drugs has been shown to be very challenging [1, 2]
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