Monitoring of argatroban and lepirudin anticoagulation in critically ill patients by conventional laboratory parameters and rotational thromboelastometry - a prospectively controlled randomized double-blind clinical trial

Abstract

Background: 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). 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.

Methods: This 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.

Results: To 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 registration: ClinicalTrials.gov , NCT00798525 , registered on 25 Nov 2008.

Keywords: Argatroban; Heparin-induced thrombocytopenia; Lepirudin; Maximum clot firmness; Monitoring; Rotational thromboelastometry.

Conflict of interest statement

Ethics approval and consent to participate

The Ethics committee of the Medical Faculty, Heinrich-Heine-University Düsseldorf, Germany and the Bundesinstitut für Arzneimittel, EudraCT number 2006–003122-28 approved this study (Consent for publication

Not applicable.

Competing interests

Martin Beiderlinden: received honorary for lectures and financial support for research. All other authors declared no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Plasma concentrations of argatroban and lepirudin over time. Data are depicted as boxes showing median and interquartile range, whiskers indicate 1.5 times interquartile range. Outliers are depicted as circles and stars

Fig. 2

Conventional laboratory coagulation parameters over time. In all panels data are depicted as boxes showing median and interquartile range, whiskers indicate 1.5 times interquartile range. Outliers are depicted as circles and stars. # significant difference to baseline measurements (p < 0.0125), § significant differences between groups (p < 0.01): (a) aPTT, (b) PT, “Quick”, (c)TT

Fig. 3

Flow chart of ROTEM measurement. Data are numbers of patients or ROTEM samples. ROTEM measurements were assessed as invalid and results not used for analysis in 25 out of 478 cases (5%) due to automatically generated failure codes such as early drying of the sample or lack of measureable coagulation

Fig. 4

Clotting time measured by INTEM and EXTEM over time. In all panels data are depicted as boxes showing median and interquartile range, whiskers indicate 1.5 times interquartile range. Outliers are depicted as circles and stars. # significant difference to baseline measurements (p < 0.0125), § significant differences between groups (p < 0.01): (a) INTEM CT, (b) EXTEM CT

Fig. 5

Correlation between conventional coagulation parameters, ROTEM parameters and argatroban plasma levels. X-axis depicts argatroban plasma concentration in μg/ml, Y-axis displays unit of specific coagulation parameter: a) aPTT, b) aPTT ratio, c) INTEM CT, d) INTEM CT ratio, e) EXTEM CT, f) EXTEM CT ratio, g) TT and h) TT ratio. s = seconds. Each dot represents one pair of measurements. Spearman correlation coefficient (r) and level of significance are presented in each panel, p < 0.01 was considered statistically significant

Fig. 6

Bland Altman plots for agreement between argatroban plasma levels and aPTT (a), EXTEM CT (b) and EXTEM CT (c) ratios. X-axis depicts the mean between two parameters, Y-axis displays the difference between two parameters. The lowest difference between means is displayed for EXTEM CT ratios

Fig. 7

Correlation between conventional coagulation parameters, ROTEM parameters and lepirudin plasma levels. X-axis depicts lepirudin plasma concentration in μg/ml, Y-axis displays unit of specific coagulation parameter. a) aPTT, b) aPTT Ratio, c) INTEM CT, d) INTEM CT Ratio, e) EXTEM CT, f) EXTEM CT Ratio, g) TT, h) TT Ratio; s = seconds. Each dot represents one pair of measurements. Spearman correlation coefficient (r) and level of significance are presented in each panel, p < 0.01 was considered statistically significant

Fig. 8

Maximum clot firmness measured by INTEM, EXTEM and FIBTEM over time. In all panels data are depicted as boxes showing median and interquartile range, whiskers indicate 1.5 times interquartile range. Outliers are depicted as circles and stars. There were no statistically significant differences within the argatroban or lepirudin group as compared to baseline or between the argatroban and lepirudin group: a) INTEM MCF, b) EXTEM MCF, c) FIBTEM MCF