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

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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

Electronic supplementary material

The online version of this article (10.1186/s12871-018-0475-y) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 25

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Point-of-care thromboelastography/thromboelastometry-based coagulation management in cardiac surgery: a meta-analysis of 8332 patients.

Elmar W Kuhn, Antje-Christin Deppe, Carolyn Weber … (2016)

Severe bleeding related to cardiac surgery is associated with increased morbidity and mortality. Thromboelastography (TEG) and thromboelastometry (ROTEM) are point-of-care tests (POCT). Bedside ROTEM/TEG can rapidly detect changes in blood coagulation and therefore provide a goal-directed, individualized coagulation therapy. In this meta-analysis, we aimed to determine the current evidence for or against POCT-guided algorithm in patients with severe bleeding after cardiac surgery.

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Is Open Access

Routine use of viscoelastic blood tests for diagnosis and treatment of coagulopathic bleeding in cardiac surgery: updated systematic review and meta-analysis.

G F Serraino, G J Murphy (2017)

Viscoelastic point-of-care tests are commonly used to provide prompt diagnosis of coagulopathy and allow targeted treatments in bleeding patients. We updated existing meta-analyses that have evaluated the clinical effectiveness of viscoelastic point-of-care tests vs the current standard of care for the management of cardiac surgery patients at risk of coagulopathic bleeding. Randomized controlled trials comparing viscoelastic point-of-care diagnostic testing with standard care in cardiac surgery patients were sought. All-cause mortality, blood loss, reoperation, blood transfusion, major morbidity, and intensive care unit and hospital length of stay were analysed using random-effects modelling. Fifteen trials that randomized a total of 8737 participants were included for the analysis. None of the trials was classified as low risk of bias. The use of thromboelastography- (TEG®) or thromboelastometry (ROTEM®)-guided algorithms did not reduce mortality [risk ratio (RR) 0.55, 95% confidence interval (CI) 0.28-1.10] without heterogeneity (I2=1%), reoperation for bleeding, stroke, ventilation time, or hospital length of stay compared with standard care. Use of TEG® or ROTEM® resulted in reductions in the frequency of red blood cell (Risk Ratio 0.88, 95% Confidence Interval 0.79-0.97; I2=43%) and platelet transfusion (Risk Ratio 0.78, 95% Confidence Interval 0.66-0.93; I2=0%). Group Reading Assessment and Diagnostic Evaluation (GRADE) assessment demonstrated that the quality of the evidence was low or very low for all estimated outcomes. Routine use of viscoelastic point-of-care tests did not improve important clinical outcomes beyond transfusion in adults undergoing cardiac surgery.

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Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.

Bruce E Lewis, Diane Wallis, Fred Leya … (2016)

Heparin-induced thrombocytopenia (HIT) is an intensely prothrombotic syndrome managed by discontinuation of heparin therapy and substitution of an alternative inhibitor of thrombin. We describe our experience with argatroban, a direct thrombin inhibitor, in patients with HIT or HIT with thrombosis (HITTS). In this multicenter, nonrandomized prospective study, 418 patients with HIT were administered intravenous argatroban, 2 micro g/kg per minute, adjusted to maintain the activated partial thromboplastin time at 1.5 to 3 times the baseline value for a mean of 5 to 7 days. Comparisons were made with a historical control cohort (n = 185). The prospectively defined, primary efficacy end point was a composite of all-cause death, all-cause amputation, or new thrombosis in 37 days. Other end points included the components of the composite, death due to thrombosis, increased platelet count, and bleeding. In the HIT arm, the composite end point was significantly reduced in argatroban-treated patients vs controls (28.0% vs 38.8%; P =.04). In the HITTS arm, the composite end point occurred in 41.5% of argatroban-treated patients vs 56.5% of controls (P =.07). By time-to-event analysis of the composite end point, argatroban therapy was significantly better than historical control therapy in HIT (P =.02) and HITTS (P =.008). Argatroban therapy also significantly reduced new thrombosis in HIT and HITTS and death due to thrombosis in HITTS. There were no significant between-group differences in all-cause death or amputation. Platelet counts recovered more rapidly in argatroban-treated patients than in controls. Bleeding rates were similar between groups. Argatroban therapy, compared with historical control, improves outcomes, particularly new thrombosis and death due to thrombosis, in patients with heparin-induced thrombocytopenia.

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Author and article information

Contributors

Martin Beiderlinden: martin.beiderlinden@mho.de

Patrick Werner: patrick.werner.koeln@gmail.com

Astrid Bahlmann: Astrid.Bahlmann@med.uni-duesseldorf.de

Johann Kemper: Johann.Kemper@med.uni-duesseldorf.de

Tobias Brezina: tobias.brezina@netcologne.de

Maximilian Schäfer: Maximilian.Schaefer@med.uni-duesseldorf.de

Klaus Görlinger: klaus.goerlinger@tem-international.de

Holger Seidel: h.seidel@cbtmed.de

Peter Kienbaum: Peter.Kienbaum@med.uni-duesseldorf.de

Tanja A. Treschan:

ORCID: http://orcid.org/0000-0001-9363-1028

+49 211 81 17491 , tanja.treschan@med.uni-duesseldorf.de

Journal

Journal ID (nlm-ta): BMC Anesthesiol

Journal ID (iso-abbrev): BMC Anesthesiol

Title: BMC Anesthesiology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2253

Publication date (Electronic): 9 February 2018

Publication date PMC-release: 9 February 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 18

Affiliations

[1 ]Klinik für Anästhesiologie, Marienhospital Osnabrück, Bischofsstr. 1, 49076 Osnabrück, Germany

[2 ]Klinik für Anästhesiologie, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany

[3 ]TEM International GmbH, Martin-Kollar-Str. 13-15, 81829 Munich, Germany

[4 ]Institut für Hämostaseologie, Hämotherapie und Transufsionsmedizin, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany

Author information

Tanja A. Treschan http://orcid.org/0000-0001-9363-1028

Article

Publisher ID: 475

DOI: 10.1186/s12871-018-0475-y

PMC ID: 5810183

PubMed ID: 29426286

SO-VID: 055fd74f-7aac-4190-be9a-d3400b90727b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 13 July 2017

Date accepted : 18 January 2018

Funding

Funded by: Mitsubishi Pharma

Custom metadata

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: heparin-induced thrombocytopenia,rotational thromboelastometry,argatroban,lepirudin,monitoring,maximum clot firmness

Data availability: